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stringclasses 2
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38.2M
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0
|
Is the long-term rate of overall lymphocyst formation higher, lower, or the same when comparing retroperitoneal drainage to no drainage?
|
no difference
|
high
|
no
|
['17466514']
| 28,660,687
| 2,017
|
{'17466514': {'article_id': '17466514', 'content': "Drainage, following radical hysterectomy and pelvic lymph node dissection to prevent postoperative lymphocyst formation and surgical morbidity, is controversial. To study the clinical significance of drainage, 253 patients were registered and 234 patients were randomised into two arms. In one arm (n=117) postoperative drainage was performed, in the other arm (n=117) no drains were inserted. In both arms closure of the peritoneum of the operating field was omitted. The main exclusion criteria were blood loss of more than 3000 ml during surgery or persistent oozing at the end of the operation. Clinical and ultrasound or CT-scan evaluation was done at one and 12 months postoperatively. The median follow-up amounted to 13.3 months. No difference in the incidence of postoperative lymphocyst formation or postoperative complications was found between the two study arms. The late (12 months) incidence of symptomatic lymphocysts was 3.4% (drains: 5.9%; no drains: 0.9%). The difference showed a p-value of 0.06 in Fisher's Exact test. The operating time was related to the occurrence of postoperative lymphocyst formation. It was concluded that drains can be safely omitted following radical hysterectomy and pelvic node dissection without pelvic reperitonisation in patients without excessive bleeding during or oozing at the end of surgery.", 'title': 'Randomised trial of drains versus no drains following radical hysterectomy and pelvic lymph node dissection: a European Organisation for Research and Treatment of Cancer-Gynaecological Cancer Group (EORTC-GCG) study in 234 patients.', 'date': '2007-05-01'}}
| 1
|
Surgery
|
1
|
Is the short-term rate of overall lymphocyst formation higher, lower, or the same when comparing retroperitoneal drainage to no drainage?
|
no difference
|
moderate
|
no
|
['9190979', '12214830']
| 28,660,687
| 2,017
|
{'9190979': {'article_id': '9190979', 'content': 'To evaluate the clinical effectiveness of retroperitoneal drainage following lymphadenectomy in gynecologic surgery.\nOne hundred thirty-seven consecutive patients undergoing systematic lymphadenectomy for gynecologic malignancies were randomized to receive (Group A, 68) or not (Group B, 69) retroperitoneal drainage. The pelvic peritoneum and the paracolic gutters were not sutured after node dissection. Perioperative data and complications were recorded.\nClinical and surgical parameters were comparable in the two groups. Postoperative hospital stay was significantly shorter in Group B (P < 0.001), whereas the complication rate was significantly higher in Group A (P = 0.01). This was mainly due to a significant increase in lymphocyst and lymphocyst-related morbidity. Sonographic monitoring for lymphocyst showed free abdominal fluid in 18% of drained and 36% of not-drained patients (P = 0.03). Symptomatic ascites developed in 2 drained (3%) and 3 not-drained (4%) patients (NS), respectively.\nProphylactic drainage of the retroperitoneum seems to increase lymphadenectomy-related morbidity and postoperative stay. Therefore, routine drainage following lymphadenectomy seems to be no longer indicated when the retroperitoneum is left open.', 'title': 'A randomized study comparing retroperitoneal drainage with no drainage after lymphadenectomy in gynecologic malignancies.', 'date': '1997-06-01'}, '12214830': {'article_id': '12214830', 'content': 'To evaluate the postoperative morbidity and lymphocyst formation in invasive cervical cancer patients undergoing radical hysterectomy and pelvic lymphadenectomy (RHPL) with no drainage and no peritonization compared with retroperitoneal drainage and peritonization.\nBetween July 1999 and May 2000, 100 patients with stage IA-IIA cervical cancer undergoing RHPL in Chiang Mai University Hospital were prospectively randomized to receive either no peritonization and no drainage (Group A = 48 cases) or retroperitoneal drainage and peritonization (Group B = 52 cases). Perioperative data and morbidity were recorded. Transabdominal and transvaginal sonography were performed at 4, 8 and 12 weeks postoperatively to detect lymphocyst formation.\nBoth groups were similar regarding age, size and gross appearance of tumor, tumor histology and stage. There was no difference between groups in respect of operative time, need for blood transfusion, intraoperative complications, hospital stay, number of nodes removed, nodal metastases, and need for adjuvant radiation and chemotherapy. Asymptomatic lymphocysts were sonographically detected at 4, 8 and 12 weeks postoperatively in 3 (6.8%), 2 (4.6%), and 3 (7.7%) of 44, 43, and 39 patients, respectively in Group A, whereas none was found in Group B (P = 0.2). No significant difference was found in term of postoperative morbidity in the two groups.\nRoutine retroperitoneal drainage and peritonization after RHPL for invasive cervical cancer can be safely omitted.', 'title': 'A prospective randomized study comparing retroperitoneal drainage with no drainage and no peritonization following radical hysterectomy and pelvic lymphadenectomy for invasive cervical cancer.', 'date': '2002-09-07'}}
| 0.5
|
Surgery
|
2
|
Is the rate of clinician impression of cognitive change higher, lower, or the same when comparing cholinase inhibitors to placebo in patients with MS?
|
higher
|
high
|
no
|
['15534239', '21519001']
| 25,734,590
| 2,015
|
{'15534239': {'article_id': '15534239', 'content': 'To determine the effect of donepezil in treating memory and cognitive dysfunction in multiple sclerosis (MS).\nThis single-center double-blind placebo-controlled clinical trial evaluated 69 MS patients with cognitive impairment who were randomly assigned to receive a 24-week treatment course of either donepezil (10 mg daily) or placebo. Patients underwent neuropsychological assessment at baseline and after 24 weeks of treatment. The primary outcome was change in verbal learning and memory on the Selective Reminding Test (SRT). Secondary outcomes included other tests of cognitive function, patient-reported change in memory, and clinician-reported impression of cognitive change.\nDonepezil-treated patients showed significant improvement in memory performance on the SRT compared to placebo (p = 0.043). The benefit of donepezil remained significant after controlling for various covariates including age, Expanded Disability Status Scale, baseline SRT score, reading ability, MS subtype, and sex. Donepezil-treated patients did not show significant improvements on other cognitive tests, but were more than twice as likely to report memory improvement than those in the placebo group (p = 0.006). The clinician also reported cognitive improvement in almost twice as many donepezil vs placebo patients (p = 0.036). No serious adverse events related to study medication occurred, although more donepezil (34.3%) than placebo (8.8%) subjects reported unusual/abnormal dreams (p = 0.010).\nDonepezil improved memory in MS patients with initial cognitive impairment in a single center clinical trial. A larger multicenter investigation of donepezil in MS is warranted in order to more definitively assess the efficacy of this intervention.', 'title': 'Donepezil improved memory in multiple sclerosis in a randomized clinical trial.', 'date': '2004-11-10'}, '21519001': {'article_id': '21519001', 'content': "The goal of this study was to determine if memory would be improved by donepezil as compared to placebo in a multicenter, double-blind, randomized clinical trial (RCT).\nDonepezil 10 mg daily was compared to placebo to treat memory impairment. Eligibility criteria included the following: age 18-59 years, clinically definite multiple sclerosis (MS), and performance ≤ ½ SD below published norms on the Rey Auditory Verbal Learning Test (RAVLT). Neuropsychological assessments were performed at baseline and 24 weeks. Primary outcomes were change on the Selective Reminding Test (SRT) of verbal memory and the participant's impression of memory change. Secondary outcomes included changes on other neuropsychological tests and the evaluating clinician's impression of memory change.\nA total of 120 participants were enrolled and randomized to either donepezil or placebo. No significant treatment effects were found between groups on either primary outcome of memory or any secondary cognitive outcomes. A trend was noted for the clinician's impression of memory change in favor of donepezil (37.7%) vs placebo (23.7%) (p = 0.097). No serious or unanticipated adverse events attributed to study medication developed.\nDonepezil did not improve memory as compared to placebo on either of the primary outcomes in this study.\nThis study provides Class I evidence which does not support the hypothesis that 10 mg of donepezil daily for 24 weeks is superior to placebo in improving cognition as measured by the SRT in people with MS whose baseline RAVLT score was 0.5 SD or more below average.", 'title': 'Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis.', 'date': '2011-04-27'}}
| 0.5
|
Psychiatry & Neurology
|
3
|
Is the rate of patient self-reported impression of memory change higher, lower, or the same when comparing cholinase inhibitors to placebo in patients with MS?
|
uncertain effect
|
high
|
no
|
['15534239', '21519001']
| 25,734,590
| 2,015
|
{'15534239': {'article_id': '15534239', 'content': 'To determine the effect of donepezil in treating memory and cognitive dysfunction in multiple sclerosis (MS).\nThis single-center double-blind placebo-controlled clinical trial evaluated 69 MS patients with cognitive impairment who were randomly assigned to receive a 24-week treatment course of either donepezil (10 mg daily) or placebo. Patients underwent neuropsychological assessment at baseline and after 24 weeks of treatment. The primary outcome was change in verbal learning and memory on the Selective Reminding Test (SRT). Secondary outcomes included other tests of cognitive function, patient-reported change in memory, and clinician-reported impression of cognitive change.\nDonepezil-treated patients showed significant improvement in memory performance on the SRT compared to placebo (p = 0.043). The benefit of donepezil remained significant after controlling for various covariates including age, Expanded Disability Status Scale, baseline SRT score, reading ability, MS subtype, and sex. Donepezil-treated patients did not show significant improvements on other cognitive tests, but were more than twice as likely to report memory improvement than those in the placebo group (p = 0.006). The clinician also reported cognitive improvement in almost twice as many donepezil vs placebo patients (p = 0.036). No serious adverse events related to study medication occurred, although more donepezil (34.3%) than placebo (8.8%) subjects reported unusual/abnormal dreams (p = 0.010).\nDonepezil improved memory in MS patients with initial cognitive impairment in a single center clinical trial. A larger multicenter investigation of donepezil in MS is warranted in order to more definitively assess the efficacy of this intervention.', 'title': 'Donepezil improved memory in multiple sclerosis in a randomized clinical trial.', 'date': '2004-11-10'}, '21519001': {'article_id': '21519001', 'content': "The goal of this study was to determine if memory would be improved by donepezil as compared to placebo in a multicenter, double-blind, randomized clinical trial (RCT).\nDonepezil 10 mg daily was compared to placebo to treat memory impairment. Eligibility criteria included the following: age 18-59 years, clinically definite multiple sclerosis (MS), and performance ≤ ½ SD below published norms on the Rey Auditory Verbal Learning Test (RAVLT). Neuropsychological assessments were performed at baseline and 24 weeks. Primary outcomes were change on the Selective Reminding Test (SRT) of verbal memory and the participant's impression of memory change. Secondary outcomes included changes on other neuropsychological tests and the evaluating clinician's impression of memory change.\nA total of 120 participants were enrolled and randomized to either donepezil or placebo. No significant treatment effects were found between groups on either primary outcome of memory or any secondary cognitive outcomes. A trend was noted for the clinician's impression of memory change in favor of donepezil (37.7%) vs placebo (23.7%) (p = 0.097). No serious or unanticipated adverse events attributed to study medication developed.\nDonepezil did not improve memory as compared to placebo on either of the primary outcomes in this study.\nThis study provides Class I evidence which does not support the hypothesis that 10 mg of donepezil daily for 24 weeks is superior to placebo in improving cognition as measured by the SRT in people with MS whose baseline RAVLT score was 0.5 SD or more below average.", 'title': 'Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis.', 'date': '2011-04-27'}}
| 0
|
Psychiatry & Neurology
|
4
|
Is the number of people with at least one neoplastic lesion detected higher, lower, or the same when comparing chromoscopy to conventional endoscopy?
|
higher
| null |
no
|
['12196768', '16527699', '21159889', '16767577']
| 27,056,645
| 2,016
|
{'12196768': {'article_id': '12196768', 'content': 'Small adenomas may be missed during colonoscopy, but chromoscopy has been reported to enhance detection. The aim of this randomized-controlled trial was to determine the effect of total colonic dye spray on adenoma detection during routine colonoscopy.\nConsecutive outpatients undergoing routine colonoscopy were randomized to a dye-spray group (0.1% indigo carmine used to coat the entire colon during withdrawal from the cecum) or control group (no dye).\nTwo hundred fifty-nine patients were randomized, 124 to the dye-spray and 135 to the control group; demographics, indication for colonoscopy, and quality of the preparation were similar between the groups. Extubation from the cecum took a median of 9:05 minutes (range: 2:48-24:44 min) in the dye-spray group versus 4:52 minutes (range: 1:42-15:21 min) in the control group (p < 0.0001). The proportion of patients with at least 1 adenoma and the total number of adenomas were not different between groups. However, in the dye-spray group significantly more diminutive adenomas (<5 mm) were detected proximal to the sigmoid colon (p = 0.026) and more patients were identified with 3 or more adenomas (p = 0.002). More non-neoplastic polyps were detected throughout the colon in the dye-spray group (p = 0.003). There were no complications.\nDye-spray increases the detection of small adenomas in the proximal colon and patients with multiple adenomas, but long-term outcomes should be studied to determine the clinical value of these findings.', 'title': 'Total colonic dye-spray increases the detection of diminutive adenomas during routine colonoscopy: a randomized controlled trial.', 'date': '2002-08-28'}, '16527699': {'article_id': '16527699', 'content': 'High-resolution colonoscopy with chromoscopy (HRC) is a technique designed to improve the detection of colonic neoplasias. We prospectively compared standard colonoscopy (SC) and HRC in a randomized multicenter trial.\nPatients (n = 203; age, 58 +/- 10 years; sex ratio, 1) were recruited according to the following criteria: (1) a history of either familial or personal colonic neoplasia or (2) alarm symptoms after the age of 60 years. After randomization, an SC was performed in 100 patients (resolution, < or = 410,000 pixels) and a HRC in 103 patients (Fujinon EC485ZW, 850,000 pixels). In the HRC group, each colonic segment was examined before and after spraying with indigo carmine 0.4%.\nTwo hundred seventy-six polyps were detected in 198 patients. One hundred sixty of them were hyperplastic polyps, 116 were adenomas, and 2 were carcinomas. The numbers of hyperplastic polyps and purely flat adenomas were significantly higher in the HRC group than in the SC group (1.1 +/- 1.6 vs 0.5 +/- 1.4 and 0.22 +/- 0.68 vs 0.07 +/- 0.29, respectively; P = .01 and P = .04), but there was no significant difference in the total number of adenomas per patient (primary end point) detected between the HRC and the SC groups (0.6 +/- 1.0 vs 0.5 +/- 0.9, respectively).\nAlthough HRC improves detection of purely flat adenomas and hyperplastic polyps, the overall detection of colonic adenomas in a population at increased risk of neoplasia is not significantly improved. These findings do not support the routine use of HRC in clinical practice.', 'title': 'High resolution colonoscopy with chromoscopy versus standard colonoscopy for the detection of colonic neoplasia: a randomized study.', 'date': '2006-03-11'}, '21159889': {'article_id': '21159889', 'content': "Colonoscopy is the accepted gold standard for detecting colorectal adenomas, but the miss rate, especially for small and flat lesions, remains unacceptably high. The aim of this study was to determine whether enhanced mucosal contrast using pancolonic chromoendoscopy (PCC) allows higher rates of adenoma detection.\nIn a prospective, randomised two-centre trial, PCC (with 0.4% indigo carmine spraying during continuous extubation) was compared with standard colonoscopy (control group) in consecutive patients attending for routine colonoscopy. The histopathology of the lesions detected was confirmed by evaluating the endoscopic resection or biopsy specimens.\nA total of 1008 patients were included (496 in the PCC group, 512 in the control group). The patients' demographic characteristics and indications for colonoscopy were similar in the two groups. The proportion of patients with at least one adenoma was significantly higher in the PCC group (46.2%) than in the control group (36.3%; p = 0.002). Chromoendoscopy increased the overall detection rate for adenomas (0.95 vs 0.66 per patient), flat adenomas (0.56 vs 0.28 per patient) and serrated lesions (1.19 vs 0.49 per patient) (p < 0.001). There was a non-significant trend towards increased detection of advanced adenomas (103 vs 81; p = 0.067). Mean extubation times were slightly but significantly longer in the PCC group in comparison with the control group (11.6 ± 3.36 min vs 10.1 ± 2.03 min; p < 0.001).\nPancolonic chromoendoscopy markedly enhances adenoma detection rates in an average-risk population and is practicable enough for routine application.", 'title': 'Pancolonic chromoendoscopy with indigo carmine versus standard colonoscopy for detection of neoplastic lesions: a randomised two-centre trial.', 'date': '2010-12-17'}, '16767577': {'article_id': '16767577', 'content': 'Colonoscopy is still considered the standard investigation for the detection of colorectal adenomas, but the miss rate, especially for small and flat lesions, remains unacceptably high. Chromoscopy has been shown to increase the yield for lesion detection in inflammatory bowel disease. The aim of this randomized prospective study was to determine whether a combination of chromoscopy and structure enhancement could increase the adenoma detection rate in high-risk patients.\nAll patients included in the trial had a personal history of colorectal adenomas and/or a family history of colorectal cancer (but excluding genetic syndromes). They were randomized to one of two tandem colonoscopy groups, with the first pass consisting of conventional colonoscopy for both groups, followed by either chromoscopy and structure enhancement (the "study" group) or a second conventional colonoscopy (the control group) for the second-pass colonoscopy. All detected lesions was examined histopathologically after endoscopic resection or biopsy. The principal outcome parameter was the adenoma detection rate; the number, histopathology, and location of lesions was also recorded.\nA total of 292 patients were included in the study (146 patients in each group). The patients\' demographic characteristics, the indications for colonoscopy, and the quality of bowel preparation were similar in the two groups. There was a significant difference between the two groups with respect to the median duration of the examination (18.9 minutes in the control group vs. 27.1 minutes for the study group, P < 0.001). Although more hyperplastic lesions were detected throughout the colon in the study group ( P = 0.033), there was no difference between the two groups in either the proportion of patients with at least one adenoma or in the total number of adenomas detected. Chromoscopy and structure enhancement diagnosed significantly more diminutive adenomas (< 5mm) in the right colon, compared with controls ( P = 0.039).\nOn the basis of our results we cannot generally recommend the systematic use of chromoscopy and structure enhancement in a high-risk patient population, although the detection of small adenomas in the proximal colon was improved.', 'title': 'Does chromoendoscopy with structure enhancement improve the colonoscopic adenoma detection rate?', 'date': '2006-06-13'}}
| 0.25
|
Internal Medicine & Subspecialties
|
5
|
Is total polyp detection higher, lower, or the same when comparing chromoscopy to conventional endoscopy?
|
higher
| null |
no
|
['12196768', '14960519', '20179689', '16527699', '21159889', '16767577', '19139000']
| 27,056,645
| 2,016
|
{'12196768': {'article_id': '12196768', 'content': 'Small adenomas may be missed during colonoscopy, but chromoscopy has been reported to enhance detection. The aim of this randomized-controlled trial was to determine the effect of total colonic dye spray on adenoma detection during routine colonoscopy.\nConsecutive outpatients undergoing routine colonoscopy were randomized to a dye-spray group (0.1% indigo carmine used to coat the entire colon during withdrawal from the cecum) or control group (no dye).\nTwo hundred fifty-nine patients were randomized, 124 to the dye-spray and 135 to the control group; demographics, indication for colonoscopy, and quality of the preparation were similar between the groups. Extubation from the cecum took a median of 9:05 minutes (range: 2:48-24:44 min) in the dye-spray group versus 4:52 minutes (range: 1:42-15:21 min) in the control group (p < 0.0001). The proportion of patients with at least 1 adenoma and the total number of adenomas were not different between groups. However, in the dye-spray group significantly more diminutive adenomas (<5 mm) were detected proximal to the sigmoid colon (p = 0.026) and more patients were identified with 3 or more adenomas (p = 0.002). More non-neoplastic polyps were detected throughout the colon in the dye-spray group (p = 0.003). There were no complications.\nDye-spray increases the detection of small adenomas in the proximal colon and patients with multiple adenomas, but long-term outcomes should be studied to determine the clinical value of these findings.', 'title': 'Total colonic dye-spray increases the detection of diminutive adenomas during routine colonoscopy: a randomized controlled trial.', 'date': '2002-08-28'}, '14960519': {'article_id': '14960519', 'content': 'Diminutive and flat colorectal lesions can be difficult to detect using conventional colonoscopic techniques. Previous data have suggested that pan-chromoscopy may improve detection rates. No randomised control trial has been performed examining detection rates of such lesions while controlling for extubation time and lavage effect.\nWe conducted a randomised controlled trial of pan-colonic chromoscopic colonoscopy for the detection of diminutive and flat colorectal lesions while controlling for extubation time and lavage effect.\nConsecutive patients attending for routine colonoscopy were randomised to either pan-chromoscopy using 0.5% indigo carmine (IC) or targeted chromoscopy (control group). A minimum diagnostic extubation time was set at eight minutes with controls undergoing a matched volume of saline wash.\nA total of 260 patients were randomised; 132 controls and 128 to pan-colonic chromoscopy. Extubation times did not differ significantly between the control (median 15 minutes (range 8-41)) and chromoscopy (median 17 minutes (range 8-39)) groups. The volume of IC used in the pan-chromoscopy group (median 68 ml (range 65-90)) and normal saline used in the control group (69 ml (range 60-93)) did not differ significantly. There was a statistically significant difference between the groups regarding the total number of adenomas detected (p<0.05) with significantly more diminutive (<4 mm) adenomas detected in the pan-chromoscopy group (p = 0.03). Pan-chromoscopy diagnosed more diminutive and flat lesions in the right colon compared with controls (p<0.05), with more patients with multiple adenomas (>3) detected using pan-chromoscopy (p<0.01). Hyperplastic lesions were more commonly detected in the pan-chromoscopy group compared with controls (p<0.001). More hyperplastic polyps were detected in the left colon (86% rectosigmoid) using chromoscopy compared with controls.\nChromoscopy improves the total number of adenomas detected and enhances the detection of diminutive and flat lesions. Importantly, eight diminutive lesions had foci of high grade dysplasia. Chromoscopy may benefit patients, assuming a high risk of colorectal cancer, and help in risk stratification and planning follow up colonoscopy intervals.', 'title': 'Detecting diminutive colorectal lesions at colonoscopy: a randomised controlled trial of pan-colonic versus targeted chromoscopy.', 'date': '2004-02-13'}, '20179689': {'article_id': '20179689', 'content': 'Flat and depressed colon neoplasms are an increasingly recognized precursor for colorectal cancer (CRC) in Western populations. High-definition chromoscopy is used to increase the yield of colonoscopy for flat and depressed neoplasms; however, its role in average-risk patients undergoing routine screening remains uncertain.\nAverage-risk patients referred for screening colonoscopy at four U.S. medical centers were randomized to high-definition chromocolonoscopy or high-definition white light colonoscopy. The primary outcomes, patients with at least one adenoma and the number of adenomas per patient, were compared between the two groups. The secondary outcome was patients with flat or depressed neoplasms, as defined by the Paris classification.\nA total of 660 patients were randomized (chromocolonoscopy: 321, white light: 339). Overall, the mean number of adenomas per patient was 1.2+/-2.1, the mean number of flat polyps per patient was 1.4+/-1.9, and the mean number of flat adenomas per patient was 0.5+/-1.0. The number of patients with at least one adenoma (55.5% vs. 48.4%, absolute difference 7.1%, 95% confidence interval (-0.5% to 14.7%), P=0.07), and the number of adenomas per patient (1.3+/-2.4 vs. 1.1+/-1.8, P=0.07) were marginally higher in the chromocolonoscopy group. There were no significant differences in the number of advanced adenomas per patient (0.06+/-0.37 vs. 0.04+/-0.25, P=0.3) and the number of advanced adenomas<10 mm per patient (0.02+/-0.26 vs. 0.01+/-0.14, P=0.4). Two invasive cancers were found, one in each group; neither was a flat neoplasm. Chromocolonoscopy detected significantly more flat adenomas per patient (0.6+/-1.2 vs. 0.4+/-0.9, P=0.01), adenomas<5 mm in diameter per patient (0.8+/-1.3 vs. 0.7+/-1.1, P=0.03), and non-neoplastic lesions per patient (1.8+/-2.3 vs. 1.0+/-1.3, P<0.0001).\nHigh-definition chromocolonoscopy marginally increased overall adenoma detection, and yielded a modest increase in flat adenoma and small adenoma detection, compared with high-definition white light colonoscopy. The yield for advanced neoplasms was similar for the two methods. Our findings do not support the routine use of high-definition chromocolonoscopy for CRC screening in average-risk patients. The high adenoma detection rates observed in this study may be due to the high-definition technology used in both groups.', 'title': 'High-definition chromocolonoscopy vs. high-definition white light colonoscopy for average-risk colorectal cancer screening.', 'date': '2010-02-25'}, '16527699': {'article_id': '16527699', 'content': 'High-resolution colonoscopy with chromoscopy (HRC) is a technique designed to improve the detection of colonic neoplasias. We prospectively compared standard colonoscopy (SC) and HRC in a randomized multicenter trial.\nPatients (n = 203; age, 58 +/- 10 years; sex ratio, 1) were recruited according to the following criteria: (1) a history of either familial or personal colonic neoplasia or (2) alarm symptoms after the age of 60 years. After randomization, an SC was performed in 100 patients (resolution, < or = 410,000 pixels) and a HRC in 103 patients (Fujinon EC485ZW, 850,000 pixels). In the HRC group, each colonic segment was examined before and after spraying with indigo carmine 0.4%.\nTwo hundred seventy-six polyps were detected in 198 patients. One hundred sixty of them were hyperplastic polyps, 116 were adenomas, and 2 were carcinomas. The numbers of hyperplastic polyps and purely flat adenomas were significantly higher in the HRC group than in the SC group (1.1 +/- 1.6 vs 0.5 +/- 1.4 and 0.22 +/- 0.68 vs 0.07 +/- 0.29, respectively; P = .01 and P = .04), but there was no significant difference in the total number of adenomas per patient (primary end point) detected between the HRC and the SC groups (0.6 +/- 1.0 vs 0.5 +/- 0.9, respectively).\nAlthough HRC improves detection of purely flat adenomas and hyperplastic polyps, the overall detection of colonic adenomas in a population at increased risk of neoplasia is not significantly improved. These findings do not support the routine use of HRC in clinical practice.', 'title': 'High resolution colonoscopy with chromoscopy versus standard colonoscopy for the detection of colonic neoplasia: a randomized study.', 'date': '2006-03-11'}, '21159889': {'article_id': '21159889', 'content': "Colonoscopy is the accepted gold standard for detecting colorectal adenomas, but the miss rate, especially for small and flat lesions, remains unacceptably high. The aim of this study was to determine whether enhanced mucosal contrast using pancolonic chromoendoscopy (PCC) allows higher rates of adenoma detection.\nIn a prospective, randomised two-centre trial, PCC (with 0.4% indigo carmine spraying during continuous extubation) was compared with standard colonoscopy (control group) in consecutive patients attending for routine colonoscopy. The histopathology of the lesions detected was confirmed by evaluating the endoscopic resection or biopsy specimens.\nA total of 1008 patients were included (496 in the PCC group, 512 in the control group). The patients' demographic characteristics and indications for colonoscopy were similar in the two groups. The proportion of patients with at least one adenoma was significantly higher in the PCC group (46.2%) than in the control group (36.3%; p = 0.002). Chromoendoscopy increased the overall detection rate for adenomas (0.95 vs 0.66 per patient), flat adenomas (0.56 vs 0.28 per patient) and serrated lesions (1.19 vs 0.49 per patient) (p < 0.001). There was a non-significant trend towards increased detection of advanced adenomas (103 vs 81; p = 0.067). Mean extubation times were slightly but significantly longer in the PCC group in comparison with the control group (11.6 ± 3.36 min vs 10.1 ± 2.03 min; p < 0.001).\nPancolonic chromoendoscopy markedly enhances adenoma detection rates in an average-risk population and is practicable enough for routine application.", 'title': 'Pancolonic chromoendoscopy with indigo carmine versus standard colonoscopy for detection of neoplastic lesions: a randomised two-centre trial.', 'date': '2010-12-17'}, '16767577': {'article_id': '16767577', 'content': 'Colonoscopy is still considered the standard investigation for the detection of colorectal adenomas, but the miss rate, especially for small and flat lesions, remains unacceptably high. Chromoscopy has been shown to increase the yield for lesion detection in inflammatory bowel disease. The aim of this randomized prospective study was to determine whether a combination of chromoscopy and structure enhancement could increase the adenoma detection rate in high-risk patients.\nAll patients included in the trial had a personal history of colorectal adenomas and/or a family history of colorectal cancer (but excluding genetic syndromes). They were randomized to one of two tandem colonoscopy groups, with the first pass consisting of conventional colonoscopy for both groups, followed by either chromoscopy and structure enhancement (the "study" group) or a second conventional colonoscopy (the control group) for the second-pass colonoscopy. All detected lesions was examined histopathologically after endoscopic resection or biopsy. The principal outcome parameter was the adenoma detection rate; the number, histopathology, and location of lesions was also recorded.\nA total of 292 patients were included in the study (146 patients in each group). The patients\' demographic characteristics, the indications for colonoscopy, and the quality of bowel preparation were similar in the two groups. There was a significant difference between the two groups with respect to the median duration of the examination (18.9 minutes in the control group vs. 27.1 minutes for the study group, P < 0.001). Although more hyperplastic lesions were detected throughout the colon in the study group ( P = 0.033), there was no difference between the two groups in either the proportion of patients with at least one adenoma or in the total number of adenomas detected. Chromoscopy and structure enhancement diagnosed significantly more diminutive adenomas (< 5mm) in the right colon, compared with controls ( P = 0.039).\nOn the basis of our results we cannot generally recommend the systematic use of chromoscopy and structure enhancement in a high-risk patient population, although the detection of small adenomas in the proximal colon was improved.', 'title': 'Does chromoendoscopy with structure enhancement improve the colonoscopic adenoma detection rate?', 'date': '2006-06-13'}, '19139000': {'article_id': '19139000', 'content': 'Conventional colonoscopy misses some neoplastic lesions. We compared the sensitivity of chromoendoscopy and colonoscopy with intensive inspection for detecting adenomatous polyps missed by conventional colonoscopy. Fifty subjects with a history of colorectal cancer or adenomas underwent tandem colonoscopies at one of five centers of the Great Lakes New England Clinical Epidemiology and Validation Center of the Early Detection Research Network. The first exam was a conventional colonoscopy with removal of all visualized polyps. The second exam was randomly assigned as either pan-colonic indigocarmine chromoendoscopy or standard colonoscopy with intensive inspection lasting >20 minutes. Size, histology, and numbers of polyps detected on each exam were recorded. Twenty-seven subjects were randomized to a second exam with chromoendoscopy and 23 underwent intensive inspection. Forty adenomas were identified on the first standard colonoscopies. The second colonoscopies detected 24 additional adenomas: 19 were found using chromoendoscopy and 5 were found using intensive inspection. Chromoendoscopy found additional adenomas in more subjects than did intensive inspection (44% versus 17%) and identified significantly more missed adenomas per subject (0.7 versus 0.2, P < 0.01). Adenomas detected with chromoendoscopy were significantly smaller (mean size 2.66 +/- 0.97 mm) and were more often right-sided. Chromoendoscopy was associated with more normal tissue biopsies and longer procedure times than intensive inspection. After controlling for procedure time, chromoendoscopy detected more adenomas and hyperplastic polyps compared with colonoscopy using intensive inspection alone. Chromoendoscopy detected more polyps missed by standard colonoscopy than did intensive inspection. The clinical significance of these small missed lesions warrants further study.', 'title': 'Chromoendoscopy detects more adenomas than colonoscopy using intensive inspection without dye spraying.', 'date': '2009-01-14'}}
| 0.285714
|
Internal Medicine & Subspecialties
|
219
|
Is the risk of adverse events higher, lower, or the same when comparing chromoscopy to conventional endoscopy?
|
insufficient data
| null |
no
|
['12196768', '14960519', '20179689', '16527699', '21159889', '16767577', '19139000']
| 27,056,645
| 2,016
|
{'12196768': {'article_id': '12196768', 'content': 'Small adenomas may be missed during colonoscopy, but chromoscopy has been reported to enhance detection. The aim of this randomized-controlled trial was to determine the effect of total colonic dye spray on adenoma detection during routine colonoscopy.\nConsecutive outpatients undergoing routine colonoscopy were randomized to a dye-spray group (0.1% indigo carmine used to coat the entire colon during withdrawal from the cecum) or control group (no dye).\nTwo hundred fifty-nine patients were randomized, 124 to the dye-spray and 135 to the control group; demographics, indication for colonoscopy, and quality of the preparation were similar between the groups. Extubation from the cecum took a median of 9:05 minutes (range: 2:48-24:44 min) in the dye-spray group versus 4:52 minutes (range: 1:42-15:21 min) in the control group (p < 0.0001). The proportion of patients with at least 1 adenoma and the total number of adenomas were not different between groups. However, in the dye-spray group significantly more diminutive adenomas (<5 mm) were detected proximal to the sigmoid colon (p = 0.026) and more patients were identified with 3 or more adenomas (p = 0.002). More non-neoplastic polyps were detected throughout the colon in the dye-spray group (p = 0.003). There were no complications.\nDye-spray increases the detection of small adenomas in the proximal colon and patients with multiple adenomas, but long-term outcomes should be studied to determine the clinical value of these findings.', 'title': 'Total colonic dye-spray increases the detection of diminutive adenomas during routine colonoscopy: a randomized controlled trial.', 'date': '2002-08-28'}, '14960519': {'article_id': '14960519', 'content': 'Diminutive and flat colorectal lesions can be difficult to detect using conventional colonoscopic techniques. Previous data have suggested that pan-chromoscopy may improve detection rates. No randomised control trial has been performed examining detection rates of such lesions while controlling for extubation time and lavage effect.\nWe conducted a randomised controlled trial of pan-colonic chromoscopic colonoscopy for the detection of diminutive and flat colorectal lesions while controlling for extubation time and lavage effect.\nConsecutive patients attending for routine colonoscopy were randomised to either pan-chromoscopy using 0.5% indigo carmine (IC) or targeted chromoscopy (control group). A minimum diagnostic extubation time was set at eight minutes with controls undergoing a matched volume of saline wash.\nA total of 260 patients were randomised; 132 controls and 128 to pan-colonic chromoscopy. Extubation times did not differ significantly between the control (median 15 minutes (range 8-41)) and chromoscopy (median 17 minutes (range 8-39)) groups. The volume of IC used in the pan-chromoscopy group (median 68 ml (range 65-90)) and normal saline used in the control group (69 ml (range 60-93)) did not differ significantly. There was a statistically significant difference between the groups regarding the total number of adenomas detected (p<0.05) with significantly more diminutive (<4 mm) adenomas detected in the pan-chromoscopy group (p = 0.03). Pan-chromoscopy diagnosed more diminutive and flat lesions in the right colon compared with controls (p<0.05), with more patients with multiple adenomas (>3) detected using pan-chromoscopy (p<0.01). Hyperplastic lesions were more commonly detected in the pan-chromoscopy group compared with controls (p<0.001). More hyperplastic polyps were detected in the left colon (86% rectosigmoid) using chromoscopy compared with controls.\nChromoscopy improves the total number of adenomas detected and enhances the detection of diminutive and flat lesions. Importantly, eight diminutive lesions had foci of high grade dysplasia. Chromoscopy may benefit patients, assuming a high risk of colorectal cancer, and help in risk stratification and planning follow up colonoscopy intervals.', 'title': 'Detecting diminutive colorectal lesions at colonoscopy: a randomised controlled trial of pan-colonic versus targeted chromoscopy.', 'date': '2004-02-13'}, '20179689': {'article_id': '20179689', 'content': 'Flat and depressed colon neoplasms are an increasingly recognized precursor for colorectal cancer (CRC) in Western populations. High-definition chromoscopy is used to increase the yield of colonoscopy for flat and depressed neoplasms; however, its role in average-risk patients undergoing routine screening remains uncertain.\nAverage-risk patients referred for screening colonoscopy at four U.S. medical centers were randomized to high-definition chromocolonoscopy or high-definition white light colonoscopy. The primary outcomes, patients with at least one adenoma and the number of adenomas per patient, were compared between the two groups. The secondary outcome was patients with flat or depressed neoplasms, as defined by the Paris classification.\nA total of 660 patients were randomized (chromocolonoscopy: 321, white light: 339). Overall, the mean number of adenomas per patient was 1.2+/-2.1, the mean number of flat polyps per patient was 1.4+/-1.9, and the mean number of flat adenomas per patient was 0.5+/-1.0. The number of patients with at least one adenoma (55.5% vs. 48.4%, absolute difference 7.1%, 95% confidence interval (-0.5% to 14.7%), P=0.07), and the number of adenomas per patient (1.3+/-2.4 vs. 1.1+/-1.8, P=0.07) were marginally higher in the chromocolonoscopy group. There were no significant differences in the number of advanced adenomas per patient (0.06+/-0.37 vs. 0.04+/-0.25, P=0.3) and the number of advanced adenomas<10 mm per patient (0.02+/-0.26 vs. 0.01+/-0.14, P=0.4). Two invasive cancers were found, one in each group; neither was a flat neoplasm. Chromocolonoscopy detected significantly more flat adenomas per patient (0.6+/-1.2 vs. 0.4+/-0.9, P=0.01), adenomas<5 mm in diameter per patient (0.8+/-1.3 vs. 0.7+/-1.1, P=0.03), and non-neoplastic lesions per patient (1.8+/-2.3 vs. 1.0+/-1.3, P<0.0001).\nHigh-definition chromocolonoscopy marginally increased overall adenoma detection, and yielded a modest increase in flat adenoma and small adenoma detection, compared with high-definition white light colonoscopy. The yield for advanced neoplasms was similar for the two methods. Our findings do not support the routine use of high-definition chromocolonoscopy for CRC screening in average-risk patients. The high adenoma detection rates observed in this study may be due to the high-definition technology used in both groups.', 'title': 'High-definition chromocolonoscopy vs. high-definition white light colonoscopy for average-risk colorectal cancer screening.', 'date': '2010-02-25'}, '16527699': {'article_id': '16527699', 'content': 'High-resolution colonoscopy with chromoscopy (HRC) is a technique designed to improve the detection of colonic neoplasias. We prospectively compared standard colonoscopy (SC) and HRC in a randomized multicenter trial.\nPatients (n = 203; age, 58 +/- 10 years; sex ratio, 1) were recruited according to the following criteria: (1) a history of either familial or personal colonic neoplasia or (2) alarm symptoms after the age of 60 years. After randomization, an SC was performed in 100 patients (resolution, < or = 410,000 pixels) and a HRC in 103 patients (Fujinon EC485ZW, 850,000 pixels). In the HRC group, each colonic segment was examined before and after spraying with indigo carmine 0.4%.\nTwo hundred seventy-six polyps were detected in 198 patients. One hundred sixty of them were hyperplastic polyps, 116 were adenomas, and 2 were carcinomas. The numbers of hyperplastic polyps and purely flat adenomas were significantly higher in the HRC group than in the SC group (1.1 +/- 1.6 vs 0.5 +/- 1.4 and 0.22 +/- 0.68 vs 0.07 +/- 0.29, respectively; P = .01 and P = .04), but there was no significant difference in the total number of adenomas per patient (primary end point) detected between the HRC and the SC groups (0.6 +/- 1.0 vs 0.5 +/- 0.9, respectively).\nAlthough HRC improves detection of purely flat adenomas and hyperplastic polyps, the overall detection of colonic adenomas in a population at increased risk of neoplasia is not significantly improved. These findings do not support the routine use of HRC in clinical practice.', 'title': 'High resolution colonoscopy with chromoscopy versus standard colonoscopy for the detection of colonic neoplasia: a randomized study.', 'date': '2006-03-11'}, '21159889': {'article_id': '21159889', 'content': "Colonoscopy is the accepted gold standard for detecting colorectal adenomas, but the miss rate, especially for small and flat lesions, remains unacceptably high. The aim of this study was to determine whether enhanced mucosal contrast using pancolonic chromoendoscopy (PCC) allows higher rates of adenoma detection.\nIn a prospective, randomised two-centre trial, PCC (with 0.4% indigo carmine spraying during continuous extubation) was compared with standard colonoscopy (control group) in consecutive patients attending for routine colonoscopy. The histopathology of the lesions detected was confirmed by evaluating the endoscopic resection or biopsy specimens.\nA total of 1008 patients were included (496 in the PCC group, 512 in the control group). The patients' demographic characteristics and indications for colonoscopy were similar in the two groups. The proportion of patients with at least one adenoma was significantly higher in the PCC group (46.2%) than in the control group (36.3%; p = 0.002). Chromoendoscopy increased the overall detection rate for adenomas (0.95 vs 0.66 per patient), flat adenomas (0.56 vs 0.28 per patient) and serrated lesions (1.19 vs 0.49 per patient) (p < 0.001). There was a non-significant trend towards increased detection of advanced adenomas (103 vs 81; p = 0.067). Mean extubation times were slightly but significantly longer in the PCC group in comparison with the control group (11.6 ± 3.36 min vs 10.1 ± 2.03 min; p < 0.001).\nPancolonic chromoendoscopy markedly enhances adenoma detection rates in an average-risk population and is practicable enough for routine application.", 'title': 'Pancolonic chromoendoscopy with indigo carmine versus standard colonoscopy for detection of neoplastic lesions: a randomised two-centre trial.', 'date': '2010-12-17'}, '16767577': {'article_id': '16767577', 'content': 'Colonoscopy is still considered the standard investigation for the detection of colorectal adenomas, but the miss rate, especially for small and flat lesions, remains unacceptably high. Chromoscopy has been shown to increase the yield for lesion detection in inflammatory bowel disease. The aim of this randomized prospective study was to determine whether a combination of chromoscopy and structure enhancement could increase the adenoma detection rate in high-risk patients.\nAll patients included in the trial had a personal history of colorectal adenomas and/or a family history of colorectal cancer (but excluding genetic syndromes). They were randomized to one of two tandem colonoscopy groups, with the first pass consisting of conventional colonoscopy for both groups, followed by either chromoscopy and structure enhancement (the "study" group) or a second conventional colonoscopy (the control group) for the second-pass colonoscopy. All detected lesions was examined histopathologically after endoscopic resection or biopsy. The principal outcome parameter was the adenoma detection rate; the number, histopathology, and location of lesions was also recorded.\nA total of 292 patients were included in the study (146 patients in each group). The patients\' demographic characteristics, the indications for colonoscopy, and the quality of bowel preparation were similar in the two groups. There was a significant difference between the two groups with respect to the median duration of the examination (18.9 minutes in the control group vs. 27.1 minutes for the study group, P < 0.001). Although more hyperplastic lesions were detected throughout the colon in the study group ( P = 0.033), there was no difference between the two groups in either the proportion of patients with at least one adenoma or in the total number of adenomas detected. Chromoscopy and structure enhancement diagnosed significantly more diminutive adenomas (< 5mm) in the right colon, compared with controls ( P = 0.039).\nOn the basis of our results we cannot generally recommend the systematic use of chromoscopy and structure enhancement in a high-risk patient population, although the detection of small adenomas in the proximal colon was improved.', 'title': 'Does chromoendoscopy with structure enhancement improve the colonoscopic adenoma detection rate?', 'date': '2006-06-13'}, '19139000': {'article_id': '19139000', 'content': 'Conventional colonoscopy misses some neoplastic lesions. We compared the sensitivity of chromoendoscopy and colonoscopy with intensive inspection for detecting adenomatous polyps missed by conventional colonoscopy. Fifty subjects with a history of colorectal cancer or adenomas underwent tandem colonoscopies at one of five centers of the Great Lakes New England Clinical Epidemiology and Validation Center of the Early Detection Research Network. The first exam was a conventional colonoscopy with removal of all visualized polyps. The second exam was randomly assigned as either pan-colonic indigocarmine chromoendoscopy or standard colonoscopy with intensive inspection lasting >20 minutes. Size, histology, and numbers of polyps detected on each exam were recorded. Twenty-seven subjects were randomized to a second exam with chromoendoscopy and 23 underwent intensive inspection. Forty adenomas were identified on the first standard colonoscopies. The second colonoscopies detected 24 additional adenomas: 19 were found using chromoendoscopy and 5 were found using intensive inspection. Chromoendoscopy found additional adenomas in more subjects than did intensive inspection (44% versus 17%) and identified significantly more missed adenomas per subject (0.7 versus 0.2, P < 0.01). Adenomas detected with chromoendoscopy were significantly smaller (mean size 2.66 +/- 0.97 mm) and were more often right-sided. Chromoendoscopy was associated with more normal tissue biopsies and longer procedure times than intensive inspection. After controlling for procedure time, chromoendoscopy detected more adenomas and hyperplastic polyps compared with colonoscopy using intensive inspection alone. Chromoendoscopy detected more polyps missed by standard colonoscopy than did intensive inspection. The clinical significance of these small missed lesions warrants further study.', 'title': 'Chromoendoscopy detects more adenomas than colonoscopy using intensive inspection without dye spraying.', 'date': '2009-01-14'}}
| 1
|
Internal Medicine & Subspecialties
|
6
|
Is stroke prevention higher, lower, or the same when comparing Transcatheter Device Closure (TDC) to medical therapy?
|
no difference
| null |
no
|
['22417252', '23514285', '23514286']
| 26,346,232
| 2,015
|
{'22417252': {'article_id': '22417252', 'content': 'The prevalence of patent foramen ovale among patients with cryptogenic stroke is higher than that in the general population. Closure with a percutaneous device is often recommended in such patients, but it is not known whether this intervention reduces the risk of recurrent stroke.\nWe conducted a multicenter, randomized, open-label trial of closure with a percutaneous device, as compared with medical therapy alone, in patients between 18 and 60 years of age who presented with a cryptogenic stroke or transient ischemic attack (TIA) and had a patent foramen ovale. The primary end point was a composite of stroke or transient ischemic attack during 2 years of follow-up, death from any cause during the first 30 days, or death from neurologic causes between 31 days and 2 years.\nA total of 909 patients were enrolled in the trial. The cumulative incidence (Kaplan-Meier estimate) of the primary end point was 5.5% in the closure group (447 patients) as compared with 6.8% in the medical-therapy group (462 patients) (adjusted hazard ratio, 0.78; 95% confidence interval, 0.45 to 1.35; P=0.37). The respective rates were 2.9% and 3.1% for stroke (P=0.79) and 3.1% and 4.1% for TIA (P=0.44). No deaths occurred by 30 days in either group, and there were no deaths from neurologic causes during the 2-year follow-up period. A cause other than paradoxical embolism was usually apparent in patients with recurrent neurologic events.\nIn patients with cryptogenic stroke or TIA who had a patent foramen ovale, closure with a device did not offer a greater benefit than medical therapy alone for the prevention of recurrent stroke or TIA. (Funded by NMT Medical; ClinicalTrials.gov number, NCT00201461.).', 'title': 'Closure or medical therapy for cryptogenic stroke with patent foramen ovale.', 'date': '2012-03-16'}, '23514285': {'article_id': '23514285', 'content': 'The options for secondary prevention of cryptogenic embolism in patients with patent foramen ovale are administration of antithrombotic medications or percutaneous closure of the patent foramen ovale. We investigated whether closure is superior to medical therapy.\nWe performed a multicenter, superiority trial in 29 centers in Europe, Canada, Brazil, and Australia in which the assessors of end points were unaware of the study-group assignments. Patients with a patent foramen ovale and ischemic stroke, transient ischemic attack (TIA), or a peripheral thromboembolic event were randomly assigned to undergo closure of the patent foramen ovale with the Amplatzer PFO Occluder or to receive medical therapy. The primary end point was a composite of death, nonfatal stroke, TIA, or peripheral embolism. Analysis was performed on data for the intention-to-treat population.\nThe mean duration of follow-up was 4.1 years in the closure group and 4.0 years in the medical-therapy group. The primary end point occurred in 7 of the 204 patients (3.4%) in the closure group and in 11 of the 210 patients (5.2%) in the medical-therapy group (hazard ratio for closure vs. medical therapy, 0.63; 95% confidence interval [CI], 0.24 to 1.62; P=0.34). Nonfatal stroke occurred in 1 patient (0.5%) in the closure group and 5 patients (2.4%) in the medical-therapy group (hazard ratio, 0.20; 95% CI, 0.02 to 1.72; P=0.14), and TIA occurred in 5 patients (2.5%) and 7 patients (3.3%), respectively (hazard ratio, 0.71; 95% CI, 0.23 to 2.24; P=0.56).\nClosure of a patent foramen ovale for secondary prevention of cryptogenic embolism did not result in a significant reduction in the risk of recurrent embolic events or death as compared with medical therapy. (Funded by St. Jude Medical; ClinicalTrials.gov number, NCT00166257.).', 'title': 'Percutaneous closure of patent foramen ovale in cryptogenic embolism.', 'date': '2013-03-22'}, '23514286': {'article_id': '23514286', 'content': 'Whether closure of a patent foramen ovale is effective in the prevention of recurrent ischemic stroke in patients who have had a cryptogenic stroke is unknown. We conducted a trial to evaluate whether closure is superior to medical therapy alone in preventing recurrent ischemic stroke or early death in patients 18 to 60 years of age.\nIn this prospective, multicenter, randomized, event-driven trial, we randomly assigned patients, in a 1:1 ratio, to medical therapy alone or closure of the patent foramen ovale. The primary results of the trial were analyzed when the target of 25 primary end-point events had been observed and adjudicated.\nWe enrolled 980 patients (mean age, 45.9 years) at 69 sites. The medical-therapy group received one or more antiplatelet medications (74.8%) or warfarin (25.2%). Treatment exposure between the two groups was unequal (1375 patient-years in the closure group vs. 1184 patient-years in the medical-therapy group, P=0.009) owing to a higher dropout rate in the medical-therapy group. In the intention-to-treat cohort, 9 patients in the closure group and 16 in the medical-therapy group had a recurrence of stroke (hazard ratio with closure, 0.49; 95% confidence interval [CI], 0.22 to 1.11; P=0.08). The between-group difference in the rate of recurrent stroke was significant in the prespecified per-protocol cohort (6 events in the closure group vs. 14 events in the medical-therapy group; hazard ratio, 0.37; 95% CI, 0.14 to 0.96; P=0.03) and in the as-treated cohort (5 events vs. 16 events; hazard ratio, 0.27; 95% CI, 0.10 to 0.75; P=0.007). Serious adverse events occurred in 23.0% of the patients in the closure group and in 21.6% in the medical-therapy group (P=0.65). Procedure-related or device-related serious adverse events occurred in 21 of 499 patients in the closure group (4.2%), but the rate of atrial fibrillation or device thrombus was not increased.\nIn the primary intention-to-treat analysis, there was no significant benefit associated with closure of a patent foramen ovale in adults who had had a cryptogenic ischemic stroke. However, closure was superior to medical therapy alone in the prespecified per-protocol and as-treated analyses, with a low rate of associated risks. (Funded by St. Jude Medical; RESPECT ClinicalTrials.gov number, NCT00465270.).', 'title': 'Closure of patent foramen ovale versus medical therapy after cryptogenic stroke.', 'date': '2013-03-22'}}
| 1
|
Surgery
|
7
|
Is the composite endpoint of recurrent stroke or TIA higher, lower, or the same when comparing Transcatheter Device Closure (TDC) to medical therapy?
|
no difference
| null |
no
|
['22417252', '23514285']
| 26,346,232
| 2,015
|
{'22417252': {'article_id': '22417252', 'content': 'The prevalence of patent foramen ovale among patients with cryptogenic stroke is higher than that in the general population. Closure with a percutaneous device is often recommended in such patients, but it is not known whether this intervention reduces the risk of recurrent stroke.\nWe conducted a multicenter, randomized, open-label trial of closure with a percutaneous device, as compared with medical therapy alone, in patients between 18 and 60 years of age who presented with a cryptogenic stroke or transient ischemic attack (TIA) and had a patent foramen ovale. The primary end point was a composite of stroke or transient ischemic attack during 2 years of follow-up, death from any cause during the first 30 days, or death from neurologic causes between 31 days and 2 years.\nA total of 909 patients were enrolled in the trial. The cumulative incidence (Kaplan-Meier estimate) of the primary end point was 5.5% in the closure group (447 patients) as compared with 6.8% in the medical-therapy group (462 patients) (adjusted hazard ratio, 0.78; 95% confidence interval, 0.45 to 1.35; P=0.37). The respective rates were 2.9% and 3.1% for stroke (P=0.79) and 3.1% and 4.1% for TIA (P=0.44). No deaths occurred by 30 days in either group, and there were no deaths from neurologic causes during the 2-year follow-up period. A cause other than paradoxical embolism was usually apparent in patients with recurrent neurologic events.\nIn patients with cryptogenic stroke or TIA who had a patent foramen ovale, closure with a device did not offer a greater benefit than medical therapy alone for the prevention of recurrent stroke or TIA. (Funded by NMT Medical; ClinicalTrials.gov number, NCT00201461.).', 'title': 'Closure or medical therapy for cryptogenic stroke with patent foramen ovale.', 'date': '2012-03-16'}, '23514285': {'article_id': '23514285', 'content': 'The options for secondary prevention of cryptogenic embolism in patients with patent foramen ovale are administration of antithrombotic medications or percutaneous closure of the patent foramen ovale. We investigated whether closure is superior to medical therapy.\nWe performed a multicenter, superiority trial in 29 centers in Europe, Canada, Brazil, and Australia in which the assessors of end points were unaware of the study-group assignments. Patients with a patent foramen ovale and ischemic stroke, transient ischemic attack (TIA), or a peripheral thromboembolic event were randomly assigned to undergo closure of the patent foramen ovale with the Amplatzer PFO Occluder or to receive medical therapy. The primary end point was a composite of death, nonfatal stroke, TIA, or peripheral embolism. Analysis was performed on data for the intention-to-treat population.\nThe mean duration of follow-up was 4.1 years in the closure group and 4.0 years in the medical-therapy group. The primary end point occurred in 7 of the 204 patients (3.4%) in the closure group and in 11 of the 210 patients (5.2%) in the medical-therapy group (hazard ratio for closure vs. medical therapy, 0.63; 95% confidence interval [CI], 0.24 to 1.62; P=0.34). Nonfatal stroke occurred in 1 patient (0.5%) in the closure group and 5 patients (2.4%) in the medical-therapy group (hazard ratio, 0.20; 95% CI, 0.02 to 1.72; P=0.14), and TIA occurred in 5 patients (2.5%) and 7 patients (3.3%), respectively (hazard ratio, 0.71; 95% CI, 0.23 to 2.24; P=0.56).\nClosure of a patent foramen ovale for secondary prevention of cryptogenic embolism did not result in a significant reduction in the risk of recurrent embolic events or death as compared with medical therapy. (Funded by St. Jude Medical; ClinicalTrials.gov number, NCT00166257.).', 'title': 'Percutaneous closure of patent foramen ovale in cryptogenic embolism.', 'date': '2013-03-22'}}
| 1
|
Surgery
|
8
|
Is the length of hospital stay higher, lower, or the same when comparing Pancreatojejunostomy (PJ) to Pancreatogastrostomy (PG)?
|
no difference
|
low
|
no
|
['16327486', '19092337', '7574936']
| 28,898,386
| 2,017
|
{'16327486': {'article_id': '16327486', 'content': 'To compare the results of pancreaticogastrostomy versus pancreaticojejunostomy following pancreaticoduodenectomy in a prospective and randomized setting.\nWhile several techniques have been proposed for reconstructing pancreatico-digestive continuity, only a limited number of randomized studies have been carried out.\nA total of 151 patients undergoing pancreaticoduodenectomy with soft residual tissue were randomized to receive either pancreaticogastrostomy (group PG) or end-to-side pancreaticojejunostomy (group PJ).\nThe 2 treatment groups showed no differences in vital statistics or underlying disease, mean duration of surgery, and need for intraoperative blood transfusion. Overall, the incidence of surgical complications was 34% (29% in PG, 39% in PJ, P = not significant). Patients receiving PG showed a significantly lower rate of multiple surgical complications (P = 0.002). Pancreatic fistula was the most frequent complication, occurring in 14.5% of patients (13% in PG and 16% in PJ, P = not significant). Five patients in each treatment arm required a second surgical intervention; the postoperative mortality rate was 0.6%. PG was favored over PJ due to significant differences in postoperative collections (P = 0.01), delayed gastric emptying (P = 0.03), and biliary fistula (P = 0.01). The mean postoperative hospitalization period stay was comparable in both groups.\nWhen compared with PJ, PG did not show any significant differences in the overall postoperative complication rate or incidence of pancreatic fistula. However, biliary fistula, postoperative collections and delayed gastric emptying are significantly reduced in patients treated by PG. In addition, pancreaticogastrostomy is associated with a significantly lower frequency of multiple surgical complications.', 'title': 'Reconstruction by pancreaticojejunostomy versus pancreaticogastrostomy following pancreatectomy: results of a comparative study.', 'date': '2005-12-06'}, '19092337': {'article_id': '19092337', 'content': 'To compare the results of postoperative morbidity rate of a new pancreatogastrostomy technique, pylorus-preserving pancreaticoduodenectomy (PPPD) with gastric partition (PPPD-GP) with the conventional technique of pancreaticojejunostomy (PJ).\nPancreatojejunostomy and pancreatogastrostomy (PG) are the commonly preferred methods of anastomosis after pancreatoduodenectomy (PD). All randomized controlled trials failed to show advantage of a particular technique, suggesting that both PJ and PG provide equally results. However, postoperative morbidity remains high. The best technique in pancreatic anastomosis is still debated.\nDescribed here is a new technique, PPPD-GP; in this technique the gastroepiploic arcade is preserved. Gastric partition was performed using 2 endo-Gia staplers along the greater curvature of the stomach, 3 cm from the border. This gastric segment, 10 to 12 cm in length is placed in close proximity to the cut edge of the pancreatic stump. An end-to-side, duct-to-mucosa anastomosis (with pancreatic duct stent) is constructed. One hundred eight patients undergoing PPPD for benign and malignant diseases of the pancreatic head and the periampullary region were randomized to receive PG (PPPD-GP) or end-to-side PJ (PPPD-PJ).\nThe two treatment groups showed no differences in preoperative parameters and intraoperative factors. The overall postoperative complications were 23% after PPPD-GP and 44% after PPPD-PJ (P < 0.01). The incidence of pancreatic fistula was 4% after PPPD-GP and 18% after PPPD-PJ (P < 0.01). The mean + SD hospital stay was 12 +/- 2 days after PPPD-GP and 16 +/- 3 days after PPPD-PJ.\nThis study shows that PPPD-GP can be performed safely and is associated with less complication than PPPD-PJ. The advantage of this technique over other PG techniques is that the anastomosis is outside the area of the stomach where the contents empty into the jejunum, but pancreatic juice drains directly into the stomach.', 'title': 'Pancreatogastrostomy with gastric partition after pylorus-preserving pancreatoduodenectomy versus conventional pancreatojejunostomy: a prospective randomized study.', 'date': '2008-12-19'}, '7574936': {'article_id': '7574936', 'content': 'The authors hypothesized that pancreaticogastrostomy is safer than pancreaticojejunostomy after pancreaticoduodenectomy and less likely to be associated with a postoperative pancreatic fistula.\nPancreatic fistula is a leading cause of morbidity and mortality after pancreaticoduodenectomy, occurring in 10% to 20% of patients. Nonrandomized reports have suggested that pancreaticogastrostomy is less likely than pancreaticojejunostomy to be associated with postoperative complications.\nBetween May 1993 and January 1995, the findings for 145 patients were analyzed in this prospective trial at The Johns Hopkins Hospital. After giving their appropriate preoperative informed consent, patients were randomly assigned to pancreaticogastrostomy or pancreaticojejunostomy after completion of the pancreaticoduodenal resection. All pancreatic anastomoses were performed in two layers without pancreatic duct stents and with closed suction drainage. Pancreatic fistula was defined as drainage of greater than 50 mL of amylase-rich fluid on or after postoperative day 10.\nThe pancreaticogastrostomy (n = 73) and pancreaticojejunostomy (n = 72) groups were comparable with regard to multiple parameters, including demographics, medical history, preoperative laboratory values, and intraoperative factors, such as operative time, blood transfusions, pancreatic texture, length of pancreatic remnant mobilized, and pancreatic duct diameter. The overall incidence of pancreatic fistula after pancreaticoduodenectomy was 11.7% (17/145). The incidence of pancreatic fistula was similar for the pancreaticogastrostomy (12.3%) and pancreaticojejunostomy (11.1%) groups. Pancreatic fistula was associated with a significant prolongation of postoperative hospital stay (36 +/- 5 vs. 15 +/- 1 days) (p < 0.001). Factors significantly increasing the risk of pancreatic fistula by univariate logistic regression analysis included ampullary or duodenal disease, soft pancreatic texture, longer operative time, greater intraoperative red blood cell transfusions, and lower surgical volume (p < 0.05). A multivariate logistic regression analysis revealed the factors most highly associated with pancreatic fistula to be lower surgical volume and ampullary or duodenal disease in the resected specimen.\nPancreatic fistula is a common complication after pancreaticoduodenectomy, with an incidence most strongly associated with surgical volume and underlying disease. These data do not support the hypothesis that pancreaticogastrostomy is safer than pancreaticojejunostomy or is associated with a lower incidence of pancreatic fistula.', 'title': 'A prospective randomized trial of pancreaticogastrostomy versus pancreaticojejunostomy after pancreaticoduodenectomy.', 'date': '1995-10-01'}}
| 0.333333
|
Surgery
|
9
|
Is the overall risk of postoperative pancreatic fistula higher, lower, or the same when comparing Pancreatojejunostomy (PJ) to Pancreatogastrostomy (PG)?
|
no difference
|
low
|
no
|
['24467711', '16327486', '15910726', '19092337', '24264781', '25799130', '26135690', '23643139', '7574936']
| 28,898,386
| 2,017
|
{'24467711': {'article_id': '24467711', 'content': 'The optimal strategy for the reconstruction of the pancreas following pancreaticoduodenectomy (PD) is still debated. The aim of this study was to compare the outcomes of isolated Roux loop pancreaticojejunostomy (IRPJ) with those of pancreaticogastrostomy (PG) after PD.\nConsecutive patients submitted to PD were randomized to either method of reconstruction. The primary outcome measure was the rate of postoperative pancreatic fistula (POPF). Secondary outcomes included operative time, day to resumption of oral feeding, postoperative morbidity and mortality, and exocrine and endocrine pancreatic functions.\nNinety patients treated by PD were included in the study. The median total operative time was significantly longer in the IRPJ group (320\u2009min versus 300\u2009min; P = 0.047). Postoperative pancreatic fistula developed in nine of 45 patients in the IRPJ group and 10 of 45 patients in the PG group (P = 0.796). Seven IRPJ patients and four PG patients had POPF of type B or C (P = 0.710). Time to resumption of oral feeding was shorter in the IRPJ group (P = 0.03). Steatorrhea at 1 year was reported in nine of 42 IRPJ patients and 18 of 41 PG patients (P = 0.029). Albumin levels at 1 year were 3.6\u2009g/dl in the IRPJ group and 3.3\u2009g/dl in the PG group (P = 0.001).\nIsolated Roux loop PJ was not associated with a lower rate of POPF, but was associated with a decrease in the incidence of postoperative steatorrhea. The technique allowed for early oral feeding and the maintenance of oral feeding even if POPF developed.', 'title': 'Isolated Roux loop pancreaticojejunostomy versus pancreaticogastrostomy after pancreaticoduodenectomy: a prospective randomized study.', 'date': '2014-01-29'}, '16327486': {'article_id': '16327486', 'content': 'To compare the results of pancreaticogastrostomy versus pancreaticojejunostomy following pancreaticoduodenectomy in a prospective and randomized setting.\nWhile several techniques have been proposed for reconstructing pancreatico-digestive continuity, only a limited number of randomized studies have been carried out.\nA total of 151 patients undergoing pancreaticoduodenectomy with soft residual tissue were randomized to receive either pancreaticogastrostomy (group PG) or end-to-side pancreaticojejunostomy (group PJ).\nThe 2 treatment groups showed no differences in vital statistics or underlying disease, mean duration of surgery, and need for intraoperative blood transfusion. Overall, the incidence of surgical complications was 34% (29% in PG, 39% in PJ, P = not significant). Patients receiving PG showed a significantly lower rate of multiple surgical complications (P = 0.002). Pancreatic fistula was the most frequent complication, occurring in 14.5% of patients (13% in PG and 16% in PJ, P = not significant). Five patients in each treatment arm required a second surgical intervention; the postoperative mortality rate was 0.6%. PG was favored over PJ due to significant differences in postoperative collections (P = 0.01), delayed gastric emptying (P = 0.03), and biliary fistula (P = 0.01). The mean postoperative hospitalization period stay was comparable in both groups.\nWhen compared with PJ, PG did not show any significant differences in the overall postoperative complication rate or incidence of pancreatic fistula. However, biliary fistula, postoperative collections and delayed gastric emptying are significantly reduced in patients treated by PG. In addition, pancreaticogastrostomy is associated with a significantly lower frequency of multiple surgical complications.', 'title': 'Reconstruction by pancreaticojejunostomy versus pancreaticogastrostomy following pancreatectomy: results of a comparative study.', 'date': '2005-12-06'}, '15910726': {'article_id': '15910726', 'content': 'Only 2 large (more than 100 patients) prospective trials comparing pancreatogastrostomy (PG) with pancreatojejunostomy (PJ) after pancreatoduodenectomy (PD) have been reported until now. One nonrandomized study showed that there were less pancreatic and digestive tract fistula with PG, whereas the other, a randomized trial from a single high-volume center, found no significant differences between the two techniques.\nSingle blind, controlled randomized, multicenter trial. The main endpoint was intra-abdominal complications (IACs).\nOf 149 randomized patients, 81 underwent PG and 68 PJ. No significant difference was found between the two groups concerning pre- or intraoperative patient characteristics. The rate of patients with one or more IACs was 34% in each group. Twenty-seven patients sustained a pancreatoenteric fistula (18%), 13 in PG (16%; 95% confidence interval [CI] 8-24%) and 14 in PJ (20%; 95% CI 10.5-29.5%). No statistically significant difference was found between the 2 groups concerning the mortality rate (11% overall), the rate of reoperations and/or postoperative interventional radiology drainages (23%), or the length of hospital stay (median 20.5 days). Univariate analysis found the following risk factors: (1) age > or =70 years old, (2) extrapancreatic disease, (3) normal consistency of pancreas, (4) diameter of main pancreatic duct <3 mm, (5) duration of operation >6 hours, and (6) a center effect. Significantly more IAC, pancreatoenteric fistula, and deaths occurred in one center (that included the most patients) (P = .05), but there were significantly more high-risk patients in this center (normal pancreas consistency, extrapancreatic pathology, small pancreatic duct, higher transfusion requirements, and duration of operation >6 hours) compared with the other centers. In multivariate analysis, the center effect disappeared. Independent risk factors included duration of operation >6 hours for IAC and for pancreatoenteric fistula (P = .01), extrapancreatic disease for pancreatoenteric fistulas (P < .04), and age > or =70 years for mortality (P < .02).\nThe type of pancreatoenteric anastomosis (PJ or PG) after PD does not significantly influence the rate of patients with one or more IAC and/or pancreatic fistula or the severity of complications.', 'title': 'A controlled randomized multicenter trial of pancreatogastrostomy or pancreatojejunostomy after pancreatoduodenectomy.', 'date': '2005-05-25'}, '19092337': {'article_id': '19092337', 'content': 'To compare the results of postoperative morbidity rate of a new pancreatogastrostomy technique, pylorus-preserving pancreaticoduodenectomy (PPPD) with gastric partition (PPPD-GP) with the conventional technique of pancreaticojejunostomy (PJ).\nPancreatojejunostomy and pancreatogastrostomy (PG) are the commonly preferred methods of anastomosis after pancreatoduodenectomy (PD). All randomized controlled trials failed to show advantage of a particular technique, suggesting that both PJ and PG provide equally results. However, postoperative morbidity remains high. The best technique in pancreatic anastomosis is still debated.\nDescribed here is a new technique, PPPD-GP; in this technique the gastroepiploic arcade is preserved. Gastric partition was performed using 2 endo-Gia staplers along the greater curvature of the stomach, 3 cm from the border. This gastric segment, 10 to 12 cm in length is placed in close proximity to the cut edge of the pancreatic stump. An end-to-side, duct-to-mucosa anastomosis (with pancreatic duct stent) is constructed. One hundred eight patients undergoing PPPD for benign and malignant diseases of the pancreatic head and the periampullary region were randomized to receive PG (PPPD-GP) or end-to-side PJ (PPPD-PJ).\nThe two treatment groups showed no differences in preoperative parameters and intraoperative factors. The overall postoperative complications were 23% after PPPD-GP and 44% after PPPD-PJ (P < 0.01). The incidence of pancreatic fistula was 4% after PPPD-GP and 18% after PPPD-PJ (P < 0.01). The mean + SD hospital stay was 12 +/- 2 days after PPPD-GP and 16 +/- 3 days after PPPD-PJ.\nThis study shows that PPPD-GP can be performed safely and is associated with less complication than PPPD-PJ. The advantage of this technique over other PG techniques is that the anastomosis is outside the area of the stomach where the contents empty into the jejunum, but pancreatic juice drains directly into the stomach.', 'title': 'Pancreatogastrostomy with gastric partition after pylorus-preserving pancreatoduodenectomy versus conventional pancreatojejunostomy: a prospective randomized study.', 'date': '2008-12-19'}, '24264781': {'article_id': '24264781', 'content': 'Anastomotic leakage of pancreaticojejunostomy (PJ) remains the single most important source of morbidity after pancreaticoduodenectomy (PD). The primary aim of this randomized clinical trial comparing PG with PJ after PD was to test the hypothesis that invaginated PG would result in a lower rate and severity of pancreatic fistula.\nPatients undergoing PD were randomized to receive either a duct-to-duct PJ or a double-layer invaginated PG. The primary endpoint was the rate of pancreatic fistula, using the definition of the International Study Group on Pancreatic Fistula. Secondary endpoints were the evaluation of severe abdominal complications (Clavien-Dindo grade IIIa or above), endocrine and exocrine function.\nOf 123 patients randomized, 58 underwent PJ and 65 had PG. The incidence of pancreatic fistula was significantly higher following PJ than for PG (20 of 58 versus 10 of 65 respectively; P\u2009=\u20090.014), as was the severity of pancreatic fistula (grade A: 2 versus 5 per cent; grade B-C: 33 versus 11 per cent; P\u2009=\u20090.006). The hospital readmission rate for complications was significantly lower after PG (6 versus 24 per cent; P\u2009=\u20090.005), weight loss was lower (P\u2009=\u20090.025) and exocrine function better (P\u2009=\u20090.022).\nThe rate and severity of pancreatic fistula was significantly lower with this PG technique compared with that following PJ.\nISRCTN58328599 (http://www.controlled-trials.com).', 'title': 'Randomized clinical trial of pancreaticogastrostomy versus pancreaticojejunostomy on the rate and severity of pancreatic fistula after pancreaticoduodenectomy.', 'date': '2013-11-23'}, '25799130': {'article_id': '25799130', 'content': 'It has been suggested that pancreaticogastrostomy (PG) is a safer reconstruction than pancreaticojejunostomy (PJ), resulting in lower morbidity, including lower pancreatic leak rates and decreased postoperative mortality. We compared PJ and PG after pancreaticoduodenectomy (PD).\nA randomized clinical trial was designed. It was stopped with 50% accrual. Patients underwent either PG or PJ reconstruction. The primary outcome was the pancreatic fistula rate, and the secondary outcomes were overall morbidity and mortality. We used the Student t, Mann-Whitney U and χ(2) tests for intention to treat analysis. The effect of randomization, American Society of Anesthesiologists score, soft pancreatic texture and use of pancreatic stent on overall complications and fistula rates was calculated using logistic regression.\nOur trial included 98 patients. The rate of pancreatic fistula formation was 18% in the PJ and 25% in the PG groups (p = 0.40). Postoperative complications occurred in 48% of patients in the PJ and 58% in the PG groups (p = 0.31). There were no significant predictors of overall complications in the multivariate analysis. Only soft pancreatic gland predicted the occurrence of pancreatic fistula (odds ratio 5.89, p = 0.003).\nThere was no difference in the rates of pancreatic leak/fistula, overall complications or mortality between patients undergoing PG and and those undergoing PJ after PD.\nSelon certains, la pancréatogastrostomie (PG) est une technique de reconstruction plus sécuritaire que la pancréatojéjunostomie (PJ) et entraîne une morbidité moindre, y compris un taux moins élevé de fuites pancréatiques et une mortalité postopératoire diminuée. Nous avons comparé la PJ et la PG post-pancréatoduodénectomie.\nUn essai clinique randomisé a été conçu et cessé à l’atteinte d’un taux de participation de 50 %. Les patients ont subi une reconstruction par PG ou par PJ. Le paramètre principal était le taux de fistules pancréatiques et les paramètres secondaires étaient la morbidité et la mortalité globales. Nous avons utilisé les tests \nNotre essai a regroupé 98 patients. Le taux de fistules pancréatiques a été de 18 % dans le groupe soumis à la PJ et de 25 % dans le groupe soumis à la PG (\nNous n’avons noté aucune différence quant aux taux de fuites ou de fistules pancréatiques, de complications globales ou de mortalité entre les patients soumis à la PG et à la PJ post-pancréatoduodénectomie.', 'title': 'In search of the best reconstructive technique after pancreaticoduodenectomy: pancreaticojejunostomy versus pancreaticogastrostomy.', 'date': '2015-03-24'}, '26135690': {'article_id': '26135690', 'content': "Ann SurgAnn. SurgANSUAnnals of Surgery0003-49321528-1140Lippincott, Williams, and Wilkins26135690474141710.1097/SLA.000000000000124000006Randomized Controlled TrialsPancreatogastrostomy Versus Pancreatojejunostomy for RECOnstruction After PANCreatoduodenectomy (RECOPANC, DRKS 00000767)Perioperative and Long-term Results of a Multicenter Randomized Controlled TrialKeckTobiasMD, MBA, FACS∗†WellnerU. F.MD∗†BahraM.MD‡KleinF.MD‡SickO.MSc†NiedergethmannM.MD§WilhelmT. J.MD§FarkasS. A.MD¶BörnerT.MD¶BrunsC.MD||KleespiesA.MD||KleeffJ.MD∗∗MihaljevicA. L.MD∗∗UhlW.MD††ChromikA.MD††FendrichV.MD‡‡HeegerK.MD‡‡PadbergW.MD§§HeckerA.MD§§NeumannU. P.MD¶¶JungeK.MD¶¶KalffJ. C.MD||||GlowkaT. R.MD||||WernerJ.MD∗∗∗KnebelP.MD∗∗∗PisoP.MD†††MayrM.MD†††IzbickiJ.MD‡‡‡VashistY.MD‡‡‡BronsertP.MD§§§¶¶¶BrucknerT.PhD||||||LimprechtR.MSc||||||DienerM. K.MD∗∗∗∗∗∗∗RossionI.MD∗∗∗∗WegenerI.MD∗∗∗∗HoptU. T.MD†∗Klinik für Chirurgie, UKSH Campus Lübeck, Lübeck, Germany†Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Freiburg, Freiburg, Germany‡Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Charité - Universitätsmedizin Berlin - Campus Virchow-Klinikum, Berlin, Germany§Chirurgische Klinik, Universitätsmedizin Mannheim, Mannheim, Germany¶Klinik für Chirurgie, Universitätsklinikum Regensburg, Regensburg, Germany||Klinik für Allgemeine, Viszeral-, Transplantations-, Gefäß- und Thoraxchirurgie, Klinikum der Universität München, Munich, Germany∗∗Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München und CHIR-Net München, Munich, Germany††Chirurgische Klinik, St. Josef-Hospital, Klinikum der Ruhr-Universität Bochum, Bochum, Germany‡‡Klinik für Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Marburg, Marburg, Germany§§Klinik für Allgemein-, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie des Universitätsklinikums Gießen, Gießen, Germany¶¶Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Aachen, Aachen, Germany||||Klinik und Poliklinik für Allgemein-, Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Bonn, Bonn, Germany∗∗∗Abteilung für Allgemeine, Viszerale und Transplantationschirurgie, Universität Heidelberg, Heidelberg, Germany†††Klinik für Allgemein- und Viszeralchirurgie, Krankenhaus Barmherzige Brüder, Regensburg, Germany‡‡‡Klinik und Poliklinik für Allgemein-, Viszeral- und Thoraxchirurgie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany§§§Institut für Pathologie, Universitätsklinikum Freiburg, Freiburg, Germany¶¶¶Comprehensive Cancer Center Freiburg, Freiburg Germany||||||Institut für Medizinische Biometrie und Informatik (IMBI), Universität Heidelberg, Heidelberg, Germany∗∗∗∗Studienzentrum der Deutschen Gesellschaft für Chirurgie (SDGC), Heidelberg, Germany.Reprints: Tobias Keck, MD, MBA, FACS, Klinik für Chirurgie, University Hospital Schleswig Holstein, Campus Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, Germany. E-mail: tobias.keck@uksh.de.3201608220162633440449Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.2015This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0Objectives:To assess pancreatic fistula rate and secondary endpoints after pancreatogastrostomy (PG) versus pancreatojejunostomy (PJ) for reconstruction in pancreatoduodenectomy in the setting of a multicenter randomized controlled trial.Background:PJ and PG are established methods for reconstruction in pancreatoduodenectomy. Recent prospective trials suggest superiority of the PG regarding perioperative complications.Methods:A multicenter prospective randomized controlled trial comparing PG with PJ was conducted involving 14 German high-volume academic centers for pancreatic surgery. The primary endpoint was clinically relevant postoperative pancreatic fistula. Secondary endpoints comprised perioperative outcome and pancreatic function and quality of life measured at 6 and 12 months of follow-up.Results:From May 2011 to December 2012, 440 patients were randomized, and 320 were included in the intention-to-treat analysis. There was no significant difference in the rate of grade B/C fistula after PG versus PJ (20% vs 22%, P = 0.617). The overall incidence of grade B/C fistula was 21%, and the in-hospital mortality was 6%. Multivariate analysis of the primary endpoint disclosed soft pancreatic texture (odds ratio: 2.1, P = 0.016) as the only independent risk factor. Compared with PJ, PG was associated with an increased rate of grade A/B bleeding events, perioperative stroke, less enzyme supplementation at 6 months, and improved results in some quality of life parameters.Conclusions:The rate of grade B/C fistula after PG versus PJ was not different. There were more postoperative bleeding events with PG. Perioperative morbidity and mortality of pancreatoduodenectomy seem to be underestimated, even in the high-volume center setting.Keywordspancreatoduodenectomypancreatogastrostomypancreatojejunostomypostoperative pancreatic fistulapostoperative pancreatic functionOPEN-ACCESSTRUEThe first successful pancreatoduodenectomy was performed as a 2-stage procedure by Walter Kausch in 1909.1 Later, Allen O. Whipple popularized the procedure by a series of 37 pancreatoduodenectomies during his career.2 Because of high mortality, the operation was nearly abandoned in the 1970s.2 In the 1990s, large retrospective series from specialized centers around the world set a benchmark for operative mortality of below 5%.2 Nevertheless, morbidity remains substantial after pancreatoduodenectomy.3–10 The main contributing factor is postoperative pancreatic fistula (POPF), involving leakage of pancreatic juice from the pancreatic anastomosis, which can lead to severe secondary complications such as intra-abdominal abscesses and erosion bleeding.9,11,12 Data regarding the prevention of POPF by application of somatostatin analogues have been controversial thus far,13,14 but a recent randomized trial strongly suggests that pasireotide successfully reduces POPF rates.15 Numerous attempts at improving pancreatic anastomosis techniques to lower POPF rates have been proposed.2,16,17 The hypothesis of this trial dates back to Walter Kausch, who discussed the possibility of anastomosis of the pancreatic remnant to the jejunum (pancreatojejunostomy, PJ) or the stomach (pancreatogastrostomy, PG) in his 1912 original publication of the first successful pancreatoduodenectomy.1Almost all retrospective studies suggest superiority of PG over PJ in terms of reduced POPF and other complications.18 To date, however, conflicting results have been reported from 8 prospective randomized controlled trials (RCTs) published from 1995 to 201419–26 (see Supplemental Digital Content Table S1, available at): Only 3 RCTs22,24,25 have demonstrated a reduced rate of POPF after PG, and 4 RCTs20,22,24,25 found advantages of PG over PJ in terms of postoperative complications. Soft pancreatic texture was identified as a risk factor for POPF and other complications in 4 RCTs.19,21,23,25 However, the available RCTs have some limitations. With the exception of the recent Belgian multicenter RCT24 including 329 patients, total case numbers of the RCTs are relatively low (n = 90–151) and only 2 RCTs are multicenter trials. Definitions of perioperative outcomes vary as early trials did not use the current consensus definitions of specific complications in pancreatic surgery established by the International Study Group for Pancreatic Surgery (ISGPS). Although many technical variations of PG and PJ have been reported,16,17 all 8 RCTs were restricted to specific subtypes of PG and PJ. Only 2 RCTs with contradictory results report on postoperative pancreatic function measured during follow-up of 3 to 12 months: the Egyptian trial26 reports worse and the Spanish trial25 reports better pancreatic function. None of the RCTs report on quality of life during follow-up.Here we present data collected at 14 high-volume centers for pancreatic surgery in Germany from the currently largest multicenter randomized trial comparing PG with PJ with respect to perioperative complications and long-term pancreatic function and quality of life.PATIENTS AND METHODSStudy Design, Hypothesis, and Inclusion CriteriaThe RECOnstruction after PANCreatoduodenectomy Study (RECOPANC) was designed as a randomized, controlled, observer- and patient-blinded multicenter trial with 2 parallel treatment arms (PG and PJ) (see Supplemental Digital Content, available at). The hypothesis was that the rate of clinically relevant POPF is lower after PG. Inclusion criteria were planned pancreatoduodenectomy at one of the participating academic centers and age more than 18 years. Exclusion criteria were participation in interfering clinical trials and expected lack of compliance. With the rationale to increase willingness of participating surgeons to recruit patients and to achieve greater generalizability of the results, we did not restrict PG or PJ to a special technique. Fourteen German academic centers (RECOPANC Trial Group27) with a median case load of 78 major pancreatic resections per year (range: 29–499, figures for year 2012 from the Association of German University Clinics, http://www.uniklinika.de) participated in the trial.Primary Endpoint and Sample SizePOPF is defined by ISGPS as the occurrence of amylase activity in abdominal drain fluid of 3 times the upper serum limit on postoperative day 3 or later.28,29 In brief, grade A fistula is self-limited and does not need specific treatment, grade B requires medical or invasive interventional treatment, and grade C leads to reoperation and/or severe secondary complications. The primary endpoint chosen for this trial was clinically relevant POPF, that is, ISGPS grade B or C, with the modification that application of somatostatin analogues was not considered a criterion for grading. The primary endpoint was assessed on postoperative day 3 at hospital discharge and on postoperative day 30 to detect all POPFs.Based on the prior assumption of a POPF B/C rate of 6% and 16% with PG and PJ, respectively, α = 5% and β = 20%, a sample size of 153 per treatment arm (PG vs PJ) was calculated with the 2-sided χ2 test. An adaptive interim analysis of the primary endpoint according to Bauer and Koehne30 was planned after recruitment of 152 patients to allow for premature trial termination (with 1-sided stopping boundaries of P < 0.0038) and sample size recalculation.Secondary Endpoints and Follow-upSecondary surgical endpoints were death, relaparotomy, completion pancreatectomy, anastomotic leak other than pancreatic fistula, wound infection, delayed gastric emptying, postpancreatectomy hemorrhage according to the ISGPS definitions,31,32 intra-abdominal abscess requiring invasive treatment, operation time (skin incision to skin closure), and postoperative hospital stay. Further secondary endpoints included septic shock, respiratory failure, deep venous thrombosis, lung embolism, myocardial infarction, and stroke. Pancreatic endocrine and exocrine functions and quality of life were evaluated in long-term follow-up at baseline, 6 and 12 months after the operation by the validated European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ) C30 and the pancreatic cancer module PAN26.33,34Randomization and BlindingCenter-based block randomization was performed by the participating centers using a centralized Web-based tool (Randomizer Software, Institute for Medical Informatics, Statistics and Documentation of the Medical University of Graz, www.randomizer.at) with allocation concealment. To avoid a possible intraoperative selection of low-risk patients,23 randomization was performed preoperatively. Obviously, the surgeons were not blinded concerning the intervention. Therefore, blinded observers at the participating centers assessed the primary endpoint. Patients were kept blinded regarding the intervention and unblinded only in the case of emergencies where necessary.Ethical Approval, Safety, and RegistrationThe study protocol was approved by the local ethics committees of the participating centers and carried out according to the rules of Good Clinical Practice and the Declaration of Helsinki.35 Written informed consent was obtained from each patient. An independent institution served as the Data Safety Monitoring Board and was responsible for on-site clinical monitoring, source data verification, and management of severe adverse event reports (Center for Clinical Studies, Freiburg, Germany). The trial was assigned a Universal Trial Number (UTN U1111-1117-9588) and registered in the German Trials Register (DRKS 00000767) on March 23, 2011. The study protocol was published in Trials.27Statistical AnalysisThe primary endpoint was analyzed according to the intention-to-treat principle (see Supplemental Digital Content, available at). A multivariate logistic regression model adjusting a priori for age, center, surgeon volume/experience, and pancreatic texture was applied to compare POPF rates in both treatment groups. Missing values for the primary endpoint were replaced by imputed case analysis according to Higgins et al.36 Exploratory analysis was planned for secondary endpoints. SAS software 9.1 (SAS 9.1 software, SAS, Cary NC) and 2-sided tests were used for all calculations.RESULTSTrial FlowA total of 618 patients were screened and 440 patients were randomized from May 31, 2011, through December 5, 2012. The number of patients randomized per center is shown in Supplemental Digital Content Fig. S1, available at, and ranged from 6 to 84, with 5 centers recruiting less than 20 patients and 2 centers recruiting more than 50 patients. After the interim analysis of the first 152 included patients, the Data Safety and Monitoring Board advised continuation of the trial. A total of 120 randomized patients were excluded from the final analysis: 3 patients were randomized by mistake (randomized but not eligible), 5 did not undergo laparotomy, and 112 did not receive pancreatoduodenectomy and were, therefore, excluded from further analysis. Fifteen patients randomized to PG received PJ and 12 patients randomized to PG received PJ because of the surgeon's technical preference. Reasons given for PJ instead of PG included technical problems with PG: short pancreatic remnant (n = 9), difficult pancreatic remnant mobilization (n = 2), and gastric ulcer (n = 1); reasons for PG instead of PJ were soft pancreas with small duct (n = 11) and pancreas divisum (n = 1). In total, 320 patients were included in the intention-to-treat analysis of the primary endpoint: 149 patients randomized for PJ and 171 randomized for PG. Ninety-six patients did not finish the whole 12-month follow-up because of prior death (n = 75), loss to follow-up (n = 10), withdrawal of consent (n = 5), and other reasons (n = 6) (Fig. 1).FIGURE 1Trial flow chart. ITT indicates intention to treat; PP, per protocol.Patient Baseline Characteristics and OperationsPatient baseline parameters are shown in Table 1. The treatment groups were balanced in terms of age, sex, body mass index, indications, symptoms, preoperative biliary drainage, comorbidities, American Society of Anesthesiologists (ASA) Classification, medication, and standard laboratory parameters. The treatment groups were also comparable in terms of operation technique, surgeon experience/volume, and blood loss/intraoperative transfusion requirement. In particular, the rates of soft pancreata (PG vs PJ, 59% vs 57%) and nondilated pancreatic ducts (PG vs PJ, 58% vs 55%), which are indicators for increased risk of fistula formation,5,37–40 were not significantly different between the 2 groups (Table 1).Supplemental Digital Content Table S2, available at, shows the technical varieties used for PG and PJ at the trial centers. According to the ISGPS classification for pancreatic anastomoses,16 the most commonly performed techniques were nonstented duct-mucosa anastomosis (ISGPS type I-A-S0) with 2 interrupted monofilament resorbable suture rows for PJ and nonstented dunking PG (ISGPS type II-B-S0) anastomosis with purse-string plus interrupted monofilament resorbable suture.Primary Endpoint AnalysisThe rate of clinically relevant POPF was 20% after PG and 22% after PJ in the control group (P = 0.62, 2-sided χ2 test, Table 2). In a multivariate logistic regression model (Table 2), including anastomotic technique (PG vs PJ), age, center (north vs south), pancreatic texture (soft vs hard) and surgeon volume (pancreatic resections per year), and soft pancreatic texture was the only significant factor affecting POPF B/C, with an odds ratio estimate of 2.1 (P = 0.016) (Table 2).As there were 12 patients allocated to PG receiving PJ instead and 15 patients with PG instead of PJ, we also performed an as-treated analysis of the primary endpoint (see Supplemental Digital Content Table S3, available at). The results did not differ from those of the intention-to-treat analysis.Assessment of Learning EffectsThe odds ratio estimate for fistula rate in surgeons with less than 10 pancreatoduodenectomies was 1.2 to 6.8 (95% confidence interval) but did not reach the significance level (P = 0.064 in multivariate analysis, see Table 2). Surgeons with less than 10 pancreatoduodenectomies per year had a higher fistula rate with PJ (46%) than with PG (27%), and this effect was gradually lost with increasing individual case load (see Supplemental Digital Content Table S4, available at); however, these differences did not reach statistical significance. There was also no significant center effect as to the preferred type of anastomosis in the participating centers (see Supplemental Digital Content Table S4, available at).Perioperative Secondary Endpoint AnalysisOperation time did not differ between PG and PJ. There were no significant differences between PG and PJ with regard to the frequency of surgical complications such as delayed gastric emptying, intra-abdominal abscesses, relaparotomy, completion pancreatectomy, anastomotic leaks, and surgical site infection. There was also no difference in the incidence of systemic complications such as septic shock, respiratory failure, deep vein thrombosis, lung embolism, and myocardial infarction. There were more (n = 5) stroke events in the PG group but none in the PJ group (P = 0.035) and significantly more postpancreatectomy hemorrhage events in the PG group (P = 0.023), the latter due to more grade A (5% vs 1%) and B (9% vs 4%) hemorrhages. Stroke and grade A/B bleeding were not associated, however (P = 0.998). Perioperative in-house mortality in the treatment groups (PG vs PJ, 6% vs 5%, P = 0.963) and 90-day mortality (PG vs PJ, 10% vs 5%, P = 0.167) were not statistically different. Postoperative hospital stay was equal with a median of 16 days (Table 3).Survival During Follow-upOverall survival curves are given in Supplemental Digital Content Fig. S2, available at. One-year (365 days) Kaplan-Meier survival estimates (±standard error) were 77%\u200a±\u200a3% in PG and 76%\u200a±\u200a4% in PJ and thus comparable (P = 0.675 in 2-sided log-rank test) (see Supplemental Digital Content Fig. S2, available at).Pancreatic Function and Long-term Follow-upThe percentage of patients receiving oral enzyme replacement rose from 8% preoperatively to around 80% during 6- and 12-month follow-up. Exploratory analysis also suggested a significantly reduced rate of oral enzyme replacement therapy in patients with PG at 6 months after the operation (PG vs PJ, 72% vs 89%, P < 0.001). This difference did not persist at 12-month follow-up because of a slightly decreasing percentage of PJ patients using oral enzyme supplementation (PG vs PJ, 72% vs 81%, P = 0.11). However, simultaneously the rate of patients reporting steatorrhea in the PJ group increased (from 17% at 6 months to 22% at 12 months), suggesting now insufficient enzyme supplementation in some patients. This was not the case with PG, where reported steatorrhea decreased from 20% to 13%. The amount of enzyme units taken per day was comparable in both treatment groups.The prevalence of diabetes mellitus rose only slightly after pancreatoduodenectomy (from 25% at operation to 31% at 12-month follow-up) and was comparable after PG and PJ. Among diabetic patients, there was an increase of insulin dependence from around 50% to around 70% after pancreatoduodenectomy, whereas the percentage of patients with dietary therapy dropped only from 23% preoperatively to 13% and 9% at 6 and 12 months, respectively. There was no significant difference between both treatment arms (Table 4).Quality of Life and Long-term Follow-upAt the time of operation, EORTC QLQ-C30 and PAN26 scores were balanced between the treatment groups except for the physical functioning scale scores, which were higher in the PG group (P = 0.002). The patients assigned the lowest scores to role functioning and body image. Other major reported problems were fatigue, insomnia, pain, and digestive symptoms such as altered bowel habit. At 6 and 12 months after the operation, the most severe impairments were observed in role functioning, altered bowel habit, and fatigue. On the contrary, appetite, nausea, and hepatic symptoms improved. At 6 months, a reduced score on the financial problems scale could be observed (P = 0.044) in PG compared with PJ, which persisted at 12-month follow-up. Furthermore, emotional and social functioning scale scores were significantly better after PG than after PJ (P = 0.039 and 0.019) (see Supplemental Digital Content Table S5, available at).DISCUSSIONWe report the currently largest RCT to compare PG and PJ in terms of POPF and perioperative complications and long-term outcome including quality of life. Of note, this multicenter trial was independently monitored. In contrast to previous RCTs, PG or PJ was not restricted to a specific subtype. The results of this trial have several implications for clinical practice. First, although it was designed to confirm the hypothesis of a reduction of clinically relevant POPF in patients with PG, the results show similar rates of grade B/C POPF regardless of the reconstruction method with an overall rate of 21%. This is higher than the reported range of 4% to 18% from large retrospective benchmark series (see Supplemental Digital Content Table S1, available at). The previous RCTs report fistula rates between 12% and 24% (see Supplemental Digital Content Table S1, available at). In comparison with the other RCTs, RECOPANC included the oldest patients (average 68 years vs 56–67 years in other RCTs) with the highest body mass index (average 25 vs 21–25 in other RCTs). Of note, RECOPANC is also the first RCT to report independent monitoring. Taken together, the observed POPF rate must be considered valid in view of an ageing general population with increased operative risk.Also, overall in-hospital mortality of 6% and the 90-day mortality of 7% in this trial do not meet the usually cited 5% benchmark for pancreatoduodenectomy. It is above the reported range of 0.7% to 3.7% from current large-scale retrospective series (see Supplemental Digital Content Table S1, available at), whereas some RCTs report comparable perioperative mortality rates of 0% to 11% (see Supplemental Digital Content Table S1, available at). In agreement with a current study,41 our data highlight the relevance of 90-day mortality figures in pancreatic surgery. It seems appropriate to accept that clinically relevant fistula rates of 20% and perioperative mortality of more than 5% mirror clinical reality even in high-volume pancreatic surgery. A similar effect was observed in the distal pancreatectomy trial, which reported a pancreatic fistula rate after distal pancreatic resection more than twice as high as previously reported in several retrospective series.42,43Meta-analysis of the available RCTs19–26 incorporating data from this trial suggests no significant reduction in POPF rates (odds ratio: 0.66; 95% confidence interval: 0.43–1.01; P = 0.056) (see Supplemental Digital Content Table S6, available at for details). This stands in contrast to current meta-analysis.44In a multivariate analysis, the single most important factor influencing POPF rates was the quality and texture of the organ. Soft pancreatic texture, as judged intraoperatively by the surgeon, has been demonstrated to bear a higher risk for secondary complications, erosion bleeding, and mortality in previous studies.6,9,11,24,37,38,40 It has been shown that subjective evaluation of the pancreatic hardness and texture strongly correlates with the histopathological degree of fibrosis.40 On the one hand, pancreatic cancer and chronic pancreatitis are usually associated with hardening of the whole organ including the pancreatic remnant; on the other hand, prophylactic surgery for benign lesions such as cystic neoplasms or small tumors such as ampullary cancer is usually associated with soft pancreatic tissue.9,19,40As outlined, all participating clinics were high-volume academic centers for pancreatic surgery, and there was no statistically significant center effect regarding POPF rate. Nevertheless, a high odds ratio for POPF in the low-volume surgeons indicates that besides center volume, individual surgeon volume is a relevant factor influencing complication rates in pancreatoduodenectomy.Furthermore, from our data, it might be speculated that PG offers an easier-to-learn technique suited for less experienced surgeons, but this effect did not reach statistical significance. This opinion has also been expressed by other authors of previous RCTs19,20,24,26 on the basis of the assumption that it is technically easier to achieve secure invagination of the pancreatic remnant with PG, especially in case of a bulky soft pancreas. Reasons given for conversion to PG instead of PJ (soft pancreas in 11 of 12 cases) in the current trial may reflect this assumption. However, operation time was not reduced with PG in the current trial, and only 2 previous RCTs23,26 found a shorter operation time with PG.The incidence of grade A and B postpancreatectomy hemorrhages was increased after PG. By ISGPS definition, grade A bleeding has no therapeutic consequence, but grade B events require conservative or even invasive therapy and may be sentinels of later grade C hemorrhage. The feared life-threatening (grade\u200aC) bleeding events were not increased with PG. These findings confirm previous retrospective and prospective observations, which showed increased bleeding events from PGs.23,45,46 Meticulous hemostatic measures at the pancreatic cut surface are, therefore, advised. There was a higher rate of perioperative stroke events in patients with PGs that were not associated with the bleeding events, however. For lack of a rational explanation, this might be interpreted as an artifact of exploratory data analysis.Our reported length of hospital stay (median, 16 days) is about twice as long as that usually reported from high-volume North American centers (see Supplemental Digital Content Table S1, available at). Our explanations are that due to law-enforced universal health care insurance in Germany, patients usually do not experience financial pressure to be discharged early, and the common practice is to discharge patients home after full recovery. Even in a fast-track surgery program applied to major pancreatic resections in a German center,47 patients were discharged at median on day 10, with a 30-day readmission rate of only 3.5%, whereas readmission rates of 15% to 20% after pancreatoduodenectomy are currently reported from the United States.48,49 In consequence, readmission has been highlighted as a significant problem by American scientific studies and is financially penalized in the United States but not in Germany.47–51The results of long-term pancreatic function follow-up in the current trial may be interpreted as suggestive of better exocrine function in patients with PG. However, pancreatic function was not measured directly but by means of the surrogate parameters oral enzyme supplementation and steatorrhea, and the drawback of exploratory data analysis must be kept in mind. Previous RCTs with smaller case numbers have reported inconsistent outcomes.25,26 The current study represents the largest prospective evaluation of this issue and will be followed by a prospective long-term observation of the included patients. Regarding the usually encountered opinion that pancreatic function is worse after PG compared with PJ, our results suggest that this is not the case.Only one previous retrospective study compared quality of life after pancreatoduodenectomy with PG and PJ and found no difference, but it was unbalanced with regard to the preoperative patient status.52 Follow-up in the present trial did not reveal differences between the treatment groups in most aspects covered by the EORTC QLQ-C30/PAN26 questionnaires. On the contrary, the few detected that differences are not large enough to be considered clinically relevant. We also interpret these as an artifact of explorative analysis of the many quality-of-life aspects. Our results, however, provide valuable data to identify major problems that impair the quality of life of patients before and after pancreatoduodenectomy: role functioning, altered bowel habit, and fatigue.CONCLUSIONSIn summary, this trial demonstrated several salient findings. Reconstruction by PG, when not restricted to a specific subtype and evaluated in a multicenter setting, did not reduce perioperative complications. Soft pancreatic tissue quality remains the most influential factor for POPF rate. PG may offer a technically less demanding but safe anastomotic technique. However, a higher rate of postoperative grade A/B hemorrhage was observed, advocating increased awareness toward hemostatic measures with PG. The rate of POPF remains substantial and is currently underestimated. Perioperative mortality can surpass the 5% margin even in the high-volume academic pancreatic surgery setting. Both may be attributed to extended indications for pancreatoduodenectomy in an ageing population. Quality of life in pancreatoduodenectomy patients is most severely impaired regarding role functioning and body image. The operation seems to ameliorate gastrointestinal and hepatic symptoms but does not improve fatigue and role functioning. Long-term exocrine pancreatic function after PG does not seem to be inferior to PJ.Supplementary MaterialSupplemental Digital ContentSupplementary MaterialSupplemental Digital ContentSupplementary MaterialSupplemental Digital ContentSupplementary MaterialSupplemental Digital ContentSupplementary MaterialSupplemental Digital ContentSupplementary MaterialSupplemental Digital ContentSupplementary MaterialSupplemental Digital ContentSupplementary MaterialSupplemental Digital ContentSupplementary MaterialSupplemental Digital ContentSupplementary MaterialSupplemental Digital ContentAcknowledgmentsT. Keck and U. F. 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Ann Surg\n2012; 256:529–537.2286837351.KristensenSRBechMQuentinW\nA roadmap for comparing readmission policies with application to Denmark, England and the United States. Health Policy\n2015; 119:264–273.2554740152.SchmidtUSimunecDPisoP\nQuality of life and functional long-term outcome after partial pancreatoduodenectomy: pancreatogastrostomy versus pancreatojejunostomy. Ann Surg Oncol\n2005; 12:467–472.15886907TABLE 1Patients, Baseline Parameters, and OperationsPJPGTotalParameterN or Median% or RangeN or Median% or RangeN or Median% or RangePTotal149171320—Baseline DataAge, yr6629–876835–866829–870.787Sex\u2003Male9362%9556%18859%0.214\u2003Female5638%6744%13241%BMI (kg/m2)2515–432516–392515–430.706Chronic pancreatitis149%148%289%Pancreatic adenocarcinoma9866%10461%20263%Ampullary adenocarcinoma117%106%217%Indications0.695\u2003CNP43%85%124%\u2003NET21%32%52%\u2003Other2013%3219%5216%\u2003Weight loss8960%9757%18658%0.587Symptoms\u2003Pain7953%8449%16351%0.487\u2003Jaundice7248%8852%16050%0.575Preop biliary drainage\u2003ERD6040%6136%12138%0.396\u2003PTD43%74%113%0.488History of acute pancreatitis2013%1710%3712%0.331Chronic pancreatitis4027%4526%8527%0.915Prior abdominal surgery6946%8047%14947%0.932Cardiac5839%6840%12639%0.878pulmonary149%1911%3310%0.615Comorbidities\u2003Renal1510%159%309%0.692\u2003Hepatic96%106%196%0.942\u2003Ex-smoker4027%3319%7323%0.074\u2003Active smoker4430%4225%8627%\u2003Ex-alcohol abuse1711%1911%3611%0.673\u2003Active alcohol abuse1611%2414%4013%ASA\u2003I1410%1811%3210%\u2003II8156%8652%16753%\u2003III5034%6137%11136%0.881\u2003IV11%21%31%\u2003NA32%42%72%Medication\u2003Glucocorticoids43%32%72%0.570\u2003Immunosuppressives21%11%31%0.483\u2003Analgesics2920%4526%7423%0.147\u2003Somatostatin analog21%00%21%0.129\u2003Neoadjuvant cx43%32%72%0.570\u2003Neoadjuvant rx21%11%31%0.483Laboratory\u2003Amylase [U/L]5113–360589–536569–5360.168\u2003Creatinine (μmol/L)6115–3286237–51962156–5190.581\u2003Bilirubin (μmol/L)123–598152–371142–5980.951\u2003C-reactive protein (mg/L)60–11160–17760–1770.618\u2003Total protein (g/L)7044–5587155–857044–5580.442\u2003CA 19–9 (U/mL)421–11,000481–4,491471–11,0000.503\u2003Hemoglobin (mmol/L)84–1084–1084–100.418\u2003Leukocytes (1000/mL)73–1873–1973–190.436\u2003Thrombocytes (1000/mL)26095–56927037–62526837–6250.926OperationsSurgeon experience*\u2003<52920%2414%5317%\u20035–105034%5432%10433%0.301\u2003>106947%9254%16151%\u2003NA11%11%21%\u2003<10139%159%289%Surgeon volume†\u200310–254329%4929%9229%\u2003>259262%10662%19862%0.999\u2003NA11%11%21%Technique\u2003PPPD12181%13478%25580%0.528\u2003Classic Whipple2819%3722%6520%\u2003NA53%116%165%LAD\u2003Standard10671%12473%23072%0.331\u2003Extended3826%3621%7423%\u2003Portal venous resection3020%2917%5918%0.465\u2003Additional organ resection3926%3923%7824%0.484Blood loss5000–4,8005000–3,5005000–4,8000.581Intraoperative red blood cell transfusion\u2003No13289%14685%27887%\u2003132%64%93%0.708\u2003285%138%217%\u2003>266%66%1212%Pancreatic texture\u2003Hard6243%6641%12842%\u2003Soft8357%9559%17858%0.755\u2003NA43%106%144%MPD diameter\u2003Normal (≤3 mm)7855%9458%17256%\u2003Dilated (>3 mm)6445%6942%13344%0.630\u2003NA75%85%155%P values derived from 2-sided χ2 test and Student t test.*Years of pancreatic surgery.†Pancreatoduodenectomies per year.ASA indicates American Society of Anesthesiologists; BMI, body mass index; CA, 19-9, Carbohydrate antigen 19-9; CNP, cystic neoplasm of the pancreas; cx, chemotherapy; ERD, endoscopic retrograde drainage; LAD, lymphadenectomy; MPD, main pancreatic duct; NA, not assessed; NET, neuroendocrine tumor; PPPD, pylorus preserving pancreatoduodenectomy; PTD, percutaneous transhepatic drainage; rx, radiotherapy.TABLE 2Primary Endpoint AnalysisUnivariate AnalysisTotalNo/POPF APOPF B/CParameternn (%)n (%)PAll patients320253 (79%)67 (21%)—PJ149116 (78%)33 (22%)0.617PG171137 (80%)34 (20%)Multivariate AnalysisParameterOdds RatioLower CIUpper CIPPG vs PJ0.8640.4951.5070.607Age, yr0.9880.9661.0110.318Soft vs hard pancreatic texture2.0941.1453.8270.016Center location (north vs south)1.0480.581.8960.876Surgeon volume 10–25 vs >25 PD/yr1.5780.8223.0290.863Surgeon volume <10 vs >25 PD/yr2.8011.1556.7940.064P values derived from 2-sided χ2 test (univariate) and binary logistic regression (multivariate). CI indicates 95% confidence interval; PD, pancreatoduodenectomy; POPF, postoperative pancreatic fistula grade according to the International Study Group for Pancreatic Surgery definition.TABLE 3Perioperative Secondary Endpoint AnalysisPJPGTotalParameterN or Median% or RangeN or Median% or RangeN or Median% or RangePTotal149171320—Operation time337165–565332165–600332165–6000.706DGE* (delayed gastric emptying)\u2003No8759%10763%19461%\u2003Grade A3927%4426%8326%\u2003Grade B96%148%237%0.301\u2003Grade C128%64%186%\u2003Missing202PPH* (postpancreatectomy hemorrhage)\u2003No13289%13579%16783%\u2003Grade A11%95%103%\u2003Grade B64%169%227%0.023\u2003Grade C107%116%217%IA with IPC drainage1913%1811%3712%IA with OP drainage128%159%278%0.814Other surgical complications\u2003Relaparotomy completion2718%2012%4715%0.100\u2003Pancreatectomy96%64%155%0.285\u2003Hepaticoenterostomy leak53%32%83%0.480\u2003Gastroenterostomy leak32%64%93%0.511\u2003SSI1812%2012%2812%1.000Systemic complications\u2003Septic shock43%64%103%0.672\u2003Respiratory failure86%127%207%0.542\u2003Deep vein thrombosis11%00%10%0.283\u2003Lung embolism21%32%52%0.766\u2003Myocardial infarction11%11%21%0.923\u2003Stroke00%53%52%0.035\u2003Missing6713—Postoperative hospital stay (d)163–129155–208163–2080.404In-house mortality†8/1485%10/1696%18/3176%0.96390-d mortality‡7/1435%16/16510%23/3087%0.167P values derived from 2-sided χ2 test, Student t test.*According to the International Study Group for Pancreatic Surgery (ISGPS) definition.†Missing data (n = 3) excluded.‡Censored cases (n = 12) excluded.DGE indicates delayed gastric emptying; IA, intra-abdominal abscess; IPC, interventional percutaneous; OP, operative; PPH, postpancreatectomy hemorrhage; SSI, surgical site infection requiring invasive treatment.TABLE 4Long-term Pancreatic FunctionPancreatic FunctionPJPGTotalTimeParameterN or Median% or RangeN or Median% or RangeN or Median% or RangePOPTotal patients in follow-up149171320—Steatorrhea2315%2112%4414%0.414OES139%148%278%0.863DM3524%4526%8025%0.5606 moTotal patients in follow-up122143265—Steatorrhea2117%2820%4919%0.621OES10889%10372%21180%<0.001DM3831%4028%7829%0.57212 moTotal patients in follow-up101122223—Steatorrhea2222%1613%3817%0.092OES8281%8872%17076%0.114DM3424%3529%6931%0.424Therapy DetailsPJPGTotalTimePatient GroupParameterN or Median% or RangeN or Median% or RangeN or Median% or RangePOPOESEnzyme per day (kU)12075–1959860–17012060–1950.375Dietary therapy only7/3520%11/4524%18/8023%0.637DMOral antidiabetics15/2854%20/3459%35/6257%0.678Insulin therapy15/2854%17/3450%32/6252%0.678Insulin units per day188–43246–50196–500.6256 moOESEnzyme per day (kU)9525–3207825–3208025–3200.751Dietary therapy only4/3811%6/4015%10/7813%0.555DMOral antidiabetics13/3538%12/3435%25/6837%0.801Insulin therapy24/3471%24/3471%48/6871%1.000Insulin units per day254–48258–130254–1300.58312 moOESEnzyme per day (kU)9025–3009540–2509025–3000.678Dietary therapy only2/346%4/3511%6/699%0.414DMOral antidiabetics12/3238%13/3142%25/6340%0.719Insulin therapy23/3272%19/3161%42/6367%0.373Insulin units per day282–45224–64252–640.739P values derived from 2-sided χ2 test and Student t test. DM indicates diabetes mellitus; OES, oral enzyme supplementation; OP, operation.", 'title': 'Pancreatogastrostomy Versus Pancreatojejunostomy for RECOnstruction After PANCreatoduodenectomy (RECOPANC, DRKS 00000767): Perioperative and Long-term Results of a Multicenter Randomized Controlled Trial.', 'date': '2015-07-03'}, '23643139': {'article_id': '23643139', 'content': 'Postoperative pancreatic fistula is the leading cause of death and morbidity after pancreaticoduodenectomy. However, the best reconstruction method to reduce occurrence of fistula is debated. We did a multicentre, randomised superiority trial to compare the outcomes of different reconstructive techniques in patients undergoing pancreaticoduodenectomy for pancreatic or periampullary tumours.\nPatients aged 18-85 years with confirmed or suspected neoplasms of the pancreas, distal bile duct, ampulla vateri, duodenum, or periampullary tumours were eligible for inclusion. An internet-based platform was used to randomly assign patients to either pancreaticojejunostomy or pancreaticogastrostomy as reconstruction after pancreaticoduodenectomy, using permuted blocks with six patients per block. Within each centre the randomisation was stratified on the pancreatic duct diameter (≤3 mm vs >3 mm) measured at the time of surgery. The primary endpoint was the occurrence of clinical postoperative pancreatic fistula (grade B or C) as defined by the International Study Group on Pancreatic Fistula. The study was not masked and analyses were done by intention to treat. Patient follow-up was closed 2 months after discharge from the hospital. This study is registered with ClinicalTrials.gov, number NCT00830778.\nBetween June, 2009, and August, 2012, we randomly allocated 167 patients to receive pancreaticojejunostomy and 162 to receive pancreaticogastrostomy. 33 (19.8%) patients in the pancreaticojejunostomy group and 13 (8.0%) in the pancreaticogastrostomy group had clinical postoperative pancreatic fistula (OR 2.86, 95% CI 1.38-6.17; p=0.002). The overall incidence of postoperative complications did not differ significantly between the groups (99 in the pancreaticojejunostomy group vs 100 in the pancreaticogastrostomy group), although more events in the pancreaticojejunostomy group were of grade ≥3a than in the pancreaticogastrostomy group (39 vs 35).\nIn patients undergoing pancreaticoduodenectomy for pancreatic head or periampullary tumours, pancreaticogastrostomy is more efficient than pancreaticojejunostomy in reducing the incidence of postoperative pancreatic fistula.\nFunding Johnson & Johnson Medical Devices, Belgium.', 'title': 'Pancreaticojejunostomy versus pancreaticogastrostomy reconstruction after pancreaticoduodenectomy for pancreatic or periampullary tumours: a multicentre randomised trial.', 'date': '2013-05-07'}, '7574936': {'article_id': '7574936', 'content': 'The authors hypothesized that pancreaticogastrostomy is safer than pancreaticojejunostomy after pancreaticoduodenectomy and less likely to be associated with a postoperative pancreatic fistula.\nPancreatic fistula is a leading cause of morbidity and mortality after pancreaticoduodenectomy, occurring in 10% to 20% of patients. Nonrandomized reports have suggested that pancreaticogastrostomy is less likely than pancreaticojejunostomy to be associated with postoperative complications.\nBetween May 1993 and January 1995, the findings for 145 patients were analyzed in this prospective trial at The Johns Hopkins Hospital. After giving their appropriate preoperative informed consent, patients were randomly assigned to pancreaticogastrostomy or pancreaticojejunostomy after completion of the pancreaticoduodenal resection. All pancreatic anastomoses were performed in two layers without pancreatic duct stents and with closed suction drainage. Pancreatic fistula was defined as drainage of greater than 50 mL of amylase-rich fluid on or after postoperative day 10.\nThe pancreaticogastrostomy (n = 73) and pancreaticojejunostomy (n = 72) groups were comparable with regard to multiple parameters, including demographics, medical history, preoperative laboratory values, and intraoperative factors, such as operative time, blood transfusions, pancreatic texture, length of pancreatic remnant mobilized, and pancreatic duct diameter. The overall incidence of pancreatic fistula after pancreaticoduodenectomy was 11.7% (17/145). The incidence of pancreatic fistula was similar for the pancreaticogastrostomy (12.3%) and pancreaticojejunostomy (11.1%) groups. Pancreatic fistula was associated with a significant prolongation of postoperative hospital stay (36 +/- 5 vs. 15 +/- 1 days) (p < 0.001). Factors significantly increasing the risk of pancreatic fistula by univariate logistic regression analysis included ampullary or duodenal disease, soft pancreatic texture, longer operative time, greater intraoperative red blood cell transfusions, and lower surgical volume (p < 0.05). A multivariate logistic regression analysis revealed the factors most highly associated with pancreatic fistula to be lower surgical volume and ampullary or duodenal disease in the resected specimen.\nPancreatic fistula is a common complication after pancreaticoduodenectomy, with an incidence most strongly associated with surgical volume and underlying disease. These data do not support the hypothesis that pancreaticogastrostomy is safer than pancreaticojejunostomy or is associated with a lower incidence of pancreatic fistula.', 'title': 'A prospective randomized trial of pancreaticogastrostomy versus pancreaticojejunostomy after pancreaticoduodenectomy.', 'date': '1995-10-01'}}
| 0.666667
|
Surgery
|
10
|
Is the breast cancer detection rate in women with dense breasts higher, lower, or the same when comparing screening with a combination of mammography and ultrasonography to screening with mammography alone?
|
higher
|
high
|
no
|
['34406400', '29571797', '23116728', '26549432']
| 36,999,589
| 2,023
|
{'34406400': {'article_id': '34406400', 'content': 'JAMA Netw OpenJAMA Netw OpenJAMA Netw OpenJAMA Network Open2574-3805American Medical Association34406400837460610.1001/jamanetworkopen.2021.21505zoi210636ResearchOriginal InvestigationFeaturedOnline OnlyOncologyEvaluation of Adjunctive Ultrasonography for Breast Cancer Detection Among Women Aged 40-49 Years With Varying Breast Density Undergoing Screening MammographyA Secondary Analysis of a Randomized Clinical TrialAdjunctive Ultrasonography for Breast Cancer Detection Among Women With Varying Breast DensityAdjunctive Ultrasonography for Breast Cancer Detection Among Women With Varying Breast DensityHarada-ShojiNarumiMDPhD\n1\nSuzukiAkihikoMDPhD\n2\nIshidaTakanoriMDPhD\n1\nZhengYing-FangMDPhD\n1\nNarikawa-ShionoYokoPhD\n1\nSato-TadanoAkikoMDPhD\n1\nOhtaRie\n1\nOhuchiNoriakiMDPhD\n1\n1Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan2Department of Breast and Endocrine Surgery, Tohoku Medical and Pharmaceutical University, Sendai, JapanArticle InformationAccepted for Publication: May 26, 2021.Published: August 18, 2021. doi:10.1001/jamanetworkopen.2021.21505Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Harada-Shoji N et al. JAMA Network Open.Corresponding Author: Noriaki Ohuchi, MD, PhD, Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan (noriaki-ohuchi@med.tohoku.ac.jp).Author Contributions: Dr. Ohuchi had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Harada-Shoji and Suzuki contributed equally to this work.Concept and design: Harada-Shoji, Suzuki, Ishida, Zheng, Narikawa-Shiono, Sato-Tadano, Ohuchi.Acquisition, analysis, or interpretation of data: Harada-Shoji, Suzuki, Ishida, Zheng, Sato-Tadano, Ohta, Ohuchi.Drafting of the manuscript: Harada-Shoji, Suzuki, Ishida, Zheng, Sato-Tadano, Ohuchi.Critical revision of the manuscript for important intellectual content: All authors.Statistical analysis: Harada-Shoji, Suzuki, Zheng, Sato-Tadano, Ohuchi.Obtained funding: Shiono, Ohuchi.Administrative, technical, or material support: Harada-Shoji, Suzuki, Ishida, Narikawa-Shiono, Sato-Tadano, Ohta, Ohuchi.Supervision: Suzuki, Ishida, Ohuchi.Conflict of Interest Disclosures: None reported.Funding/Support: The J-START study was funded by the third Comprehensive Control Research for Cancer, the Ministry of Health, Labor and Welfare of Japan (grants H18-Senryaku-001, H23-Shitei-002, and H25-Shitei-005), and Japan Agency for Medical Research and Development (grants JP17ck0106278h0001, JP18ck0106278h0002, JP19ck0106278h0003, and JPck0106563h0001).Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.Data Sharing Statement: See Supplement 3.Additional Contributions: We thank all those involved in the J-START study, including the participants and the research associates at all the research sites.188202182021188202148e212150516320212652021Copyright 2021 Harada-Shoji N et al. JAMA Network Open.https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the CC-BY License.jamanetwopen-e2121505.pdfKey PointsQuestionDoes the performance of adjunctive ultrasonography for breast cancer detection among women undergoing screening mammography change according to breast tissue density?FindingsIn this secondary analysis of a randomized clinical trial, screening mammography alone demonstrated low sensitivity, whereas adjunctive ultrasonography improved sensitivity both in dense and nondense breasts.MeaningThese findings suggest that adjunctive ultrasonography has the potential to improve the detection of early-stage and invasive cancers across both dense and nondense breasts and to mitigate the flaws of mammographic screening.This secondary analysis of a randomized clinical trial evaluates the performance of adjunctive ultrasonography for breast cancer screening in asymptomatic women aged 40 to 49 years undergoing screening mammography according to differences in breast density.ImportanceMammography has limited accuracy in breast cancer screening. Ultrasonography, when used in conjunction with mammography screening, is helpful to detect early-stage and invasive cancers for asymptomatic women with dense and nondense breasts.ObjectiveTo evaluate the performance of adjunctive ultrasonography with mammography for breast cancer screening, according to differences in breast density.Design, Setting, and ParticipantsThis study is a secondary analysis of the Japan Strategic Anti-cancer Randomized Trial. Between July 2007 and March 2011, asymptomatic women aged 40 to 49 years were enrolled in Japan. The present study used data from cases enrolled from the screening center in Miyagi prefecture during 2007 to 2020. Participants were randomly assigned in a 1:1 ratio to undergo either mammography with ultrasonography (intervention group) or mammography alone (control group). Data analysis was performed from February to March 2020.ExposuresUltrasonography adjunctive to mammography for breast cancer screening regardless of breast density.Main Outcomes and MeasuresSensitivity, specificity, recall rates, biopsy rates, and characteristics of screen-detected cancers and interval breast cancers were evaluated between study groups and for each modality according to breast density.ResultsA total of 76\u2009119 women were enrolled, and data for 19\u2009213 women (mean [SD] age, 44.5 [2.8] years) from the Miyagi prefecture were analyzed; 9705 were randomized to the intervention group and 9508 were randomized to the control group. A total of 11\u2009390 women (59.3%) had heterogeneously or extremely dense breasts. Among the overall group, 130 cancers were found. Sensitivity was significantly higher in the intervention group than the control group (93.2% [95% CI, 87.4%-99.0%] vs 66.7% [95% CI, 54.4%-78.9%]; P\u2009<\u2009.001). Similar trends were observed in women with dense breasts (sensitivity in intervention vs control groups, 93.2% [95% CI, 85.7%-100.0%] vs 70.6% [95% CI, 55.3%-85.9%]; P\u2009<\u2009.001) and nondense breasts (sensitivity in intervention vs control groups, 93.1% [95% CI, 83.9%-102.3%] vs 60.9% [95% CI, 40.9%-80.8%]; P\u2009<\u2009.001). The rate of interval cancers per 1000 screenings was lower in the intervention group compared with the control group (0.5 cancers [95% CI, 0.1-1.0 cancers] vs 2.0 cancers [95% CI, 1.1-2.9 cancers]; P\u2009=\u2009.004). Within the intervention group, the rate of invasive cancers detected by ultrasonography alone was significantly higher than that for mammography alone in both dense (82.4% [95% CI, 56.6%-96.2%] vs 41.7% [95% CI, 15.2%-72.3%]; P\u2009=\u2009.02) and nondense (85.7% [95% CI, 42.1%-99.6%] vs 25.0% [95% CI, 5.5%-57.2%]; P\u2009=\u2009.02) breasts. However, sensitivity of mammography or ultrasonography alone did not exceed 80% across all breast densities in the 2 groups. Compared with the control group, specificity was significantly lower in the intervention group (91.8% [95% CI, 91.2%-92.3%] vs 86.8% [95% CI, 86.2%-87.5%]; P\u2009<\u2009.001). Recall rates (13.8% [95% CI, 13.1%-14.5%] vs 8.6% [95% CI, 8.0%-9.1%]; P\u2009<\u2009.001) and biopsy rates (5.5% [95% CI, 5.1%-6.0%] vs 2.1% [95% CI, 1.8%-2.4%]; P\u2009<\u2009.001) were significantly higher in the intervention group than the control group.Conclusions and RelevanceIn this secondary analysis of a randomized clinical trial, screening mammography alone demonstrated low sensitivity, whereas adjunctive ultrasonography was associated with increased sensitivity. These findings suggest that adjunctive ultrasonography has the potential to improve detection of early-stage and invasive cancers across both dense and nondense breasts. Supplemental ultrasonography should be considered as an appropriate imaging modality for breast cancer screening in asymptomatic women aged 40 to 49 years regardless of breast density.Trial RegistrationNIPH Clinical Trial Identifier: UMIN000000757IntroductionGlobally, breast cancer is the most frequently diagnosed cancer and is the leading cause of cancer-related death in women.1 In Japan, breast cancer is also the leading cancer in women, with breast cancer incidence rates peaking among women aged 45 to 49 years.2 Mammography is the only screening modality that has been shown to be associated with reduced deaths caused by breast cancer. However, the sensitivity of mammography is variable and ranges from as high as 80% to 98% in women with fatty breast tissue to as low as 30% to 48% in women with dense breast tissue.3,4 Because of the limitations of mammography and increase in breast cancer awareness, a few study groups have investigated the performance characteristics of supplementary screening tools, including breast ultrasonography, tomosynthesis, and magnetic resonance imaging.5,6,7,8Breast density has been shown to be independently associated with increased risk of the incidence of and mortality attributable to breast cancer in younger women compared with older women,9,10 with increased risk of interval cancers between screening.6,11,12 Multiple studies6,11,13 have demonstrated that supplemental screening using ultrasonography generates an incremental cancer detection rate at the expense of lower specificity and lower positive predictive values. However, because most studies have focused on women at high risk3,6,7 or those with dense breast tissue but negative mammography findings,3,8,14,15 the performance of ultrasonography as an adjunct to mammography according to differences in breast density classification or among women at average risk remains unknown.4,11,13,16 Consequently, the effect of supplemental screening on breast cancer outcomes is still unclear.17To our knowledge, the Japan Strategic Anti-cancer Randomized Trial (J-START) is the only multicenter randomized clinical trial (RCT) to date to directly compare adjunctive ultrasonography with standard mammography to screen asymptomatic women aged 40 to 49 years.18,19,20 The primary analysis in the original report18 revealed that sensitivity was significantly higher in the intervention group (mammography with ultrasonography) than in the control group (mammography alone), whereas specificity was significantly lower. More cancers were detected in the intervention group than in the control group and were more frequently stages 0 and I. Furthermore, there was a significant reduction in interval cancers.20 However, results according to breast density were not described in detail,21,22 and further studies investigating specific breast density groups have been solicited.21,23 This secondary analysis of the J-START RCT aimed to address issues related to performance of each modality according to differences in breast density.MethodsStudy Design and ParticipantsThe J-START research design of has been published in detail elsewhere.18,19,20 Participants were randomly assigned in a 1:1 ratio to undergo screening by either mammography plus ultrasonography (intervention group) or mammography alone (control group), with or without clinical breast examination, once a year for 2 years.Following a planned protocol (Supplement 1), randomization was centrally conducted by the Japan Clinical Research Support Unit, which is responsible for data management and support for trial operations and independently from Tohoku University. An independent data safety and monitoring board was established to monitor the progress of the trial, which met every 6 months. The study protocol was developed in accordance with the principles of the Declaration of Helsinki. Ethics guidelines for clinical studies issued by the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labor and Welfare of Japan were followed. Ethics approval was granted by Tohoku University School of Medicine Research Ethics Committee and the Japan Cancer Society. Written informed consent was obtained from all participants. This study follows the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline for RCTs.Participants who had a personal history of breast cancer, including in situ cancer, or other cancers in the previous 5 years, or life expectancy of no more than 5 years, were ineligible for the study. Between July 2007 and March 2011, 76\u2009119 asymptomatic women aged 40 to 49 years were enrolled from 42 study sites in 23 of 47 prefectures in Japan. In this study, we used cases enrolled from the screening center in Miyagi prefecture, because we could examine and confirm the breast density.Screening Method and AssessmentStandard mammography and ultrasonography techniques were used at all participating facilities. The physicians and technicians involved in J-START completed a 2-day, 16-hour education program for the standardization of ultrasonography screening for breast cancer.24 Handheld ultrasonography was performed by a technician or by a physician, and later, the ultrasonography image was interpreted by another physician. The ultrasonography examination was performed, on average, in 10 minutes. Mammography acquisition, practice, apparatus, and interpretation were certified by the Japan Central Organization on Quality Assurance of Breast Cancer Screening. Ultrasonography acquisition, practice, apparatus, and interpretation were certified by the Japan Association of Breast and Thyroid Sonology.18Mammography, ultrasonography, and clinical breast examination were performed and interpreted independently from one another, and images were interpreted with double reading by 2 authorized physicians.18,19 The independently assessed findings of mammography, ultrasonography, and clinical examination were classified into 5 categories that are used locally and internationally: 1, no findings; 2, benign; 3, probably benign but further assessment needed; 4, probably malignant; and 5, malignant.19,25,26 Further assessment was considered test-positive if any of the findings were categorized as 3 or higher.For the purpose of this secondary analysis, which was conducted from March to September 2019, 3 expert physicians revaluated mammographic density of the first screening image. All information on screening results, medical interview record, and follow-up data were blinded. By use of the fifth edition of the Breast Imaging Reporting and Data System (BI-RADS),27 we classified visual judgment data as follows: almost entirely fatty; scattered areas of fibroglandular density; heterogeneously dense, which may obscure detection of small masses; and extremely dense, which lowers the sensitivity of mammography screening. In the present article, fatty and scattered are referred to as nondense, and heterogeneously dense and extremely dense are referred to as dense.Follow-upBreast cancers were ascertained by diagnostic assessment of first and second screening results or by a mail survey questionnaire to patients who did not attend the second screening. If data were not available, resident registers were used to identify the patient’s living status. In addition, date linkage with both hospital discharge records and cancer registry databases was used to identify breast cancer diagnosis information. Miyagi prefecture has a sophisticated system of local registration for cancer that contains data on virtually all patients with breast cancer in Miyagi prefecture. Therefore, it was possible to identify interval cancers exactly, and follow-up for this study was updated in February 2020.Screen-detected breast cancers were defined as those categorized as categories 3 to 5 at the first-round screening, and interval cancers were defined as those diagnosed between the first round and the second round of screening for which the initial category had been 1 or 2. Recall was defined as the need for any additional diagnostic testing after screening, including imaging and/or biopsy. The clinical stage and histopathological data were classified by the seventh edition of the TNM classification system.28 The outcome definitions and measure methods were prespecified before data release. Breast cancers diagnosed by the second-round screening were not counted for this study analysis.Statistical AnalysisThe preliminary sample size determination in J-START has been published in detail elsewhere.19,20 We used data from the participants at screening center in Miyagi prefecture. The special feature of the present study was not only to clarify differences between the intervention and control groups, but also differences in breast density composition. Sensitivity, specificity, recall rates, cancer detection rates, interval cancer rates, biopsy rates, and characteristics of screen-detected and interval breast cancers of the first-round screening were examined.All outcomes were analyzed according to the intention-to-treat principle. Performance outcomes were assessed with generalized estimating equations with an exchangeable working correlation matrix and robust SEs. Fisher exact test was used to detect significant differences in the clinical stage and histological findings between cancers detected by ultrasonography and mammography within the intervention group. All tests were 2-sided, and significance was set at P < .05. All statistical analyses were done with SAS statistical software version 9.\u20094 (SAS Institute). Data analysis was performed from February to March 2020.ResultsParticipant CharacteristicsThe baseline characteristics of study participants are shown in Table 1. Of 72\u2009998 asymptomatic women aged 40 to 49 years enrolled in J-START, 19\u2009213 women (9705 in the intervention group and 9508 in the control group) were analyzed in this study because they were residents in Miyagi Prefecture where the cancer registry had been established.Table 1. Baseline Characteristics of Study ParticipantsCharacteristicParticipants, No. (%) (N\u2009=\u200919\u2009213)aTotal intervention group (n\u2009=\u20099705)Total control group (n\u2009=\u20099508)Intervention group by breast densityControl group by breast densityDense (n\u2009=\u20095797)Nondense (n\u2009=\u20093908)bDense (n\u2009=\u20095593)bNondense (n\u2009=\u20093915)bAge, mean (SD), y44.5 (2.9)44.6 (2.9)44.5 (2.9)44.7 (2.9)44.5 (2.9)44.6 (2.9)Ever undergo breast cancer screening No1687 (17.4)1895 (19.9)995 (17.2)692 (17.7)1094 (19.6)801 (20.5) Yes8018 (82.6)7613 (80.1)4802 (82.8)3216 (82.3)4499 (80.4)3114 (79.5)Time since most recent breast cancer screening, mo <12716 (8.9)681 (9.0)441 (9.2)275 (8.6)424 (9.4)257 (8.3) 12-242942 (36.7)2773 (36.4)1759 (36.6)1183 (36.8)1620 (36.0)1153 (37.0) 25-362916 (36.4)2806 (36.9)1710 (35.6)1206 (37.5)1667 (37.1)1139 (36.6) >361391 (17.4)1308 (17.2)859 (17.9)532 (16.5)762 (16.9)546 (17.5) Unknown or data missing53 (0.7)45 (0.6)33 (0.7)20 (0.6)26 (0.6)19 (0.6)Method of most recent breast cancer screening Mammography No2342 (29.2)2191 (28.8)1419 (29.6)923 (28.7)1308 (29.1)883 (28.4) Yes5676 (70.8)5422 (71.2)3383 (70.5)2293 (71.3)3191 (70.9)2231 (71.6) Ultrasonography No6406 (79.9)6221 (81.7)3800 (79.1)2606 (81.0)3647 (81.1)2574 (82.7) Yes1612 (20.1)1392 (18.3)1002 (20.9)610 (19.0)852 (18.9)540 (17.3) Clinical breast examination No356 (4.4)332 (4.4)215 (4.5)141 (4.4)194 (4.3)138 (4.4) Yes7662 (95.6)7281 (95.6)4587 (95.5)3075 (95.6)4305 (95.7)2976 (95.6)Age at menarche, y ≤925 (0.3)25 (0.3)12 (0.2)13 (0.3)9 (0.2)16 (0.4) 10-159559 (98.5)9383 (98.7)5709 (98.5)3850 (98.5)5517 (98.6)3866 (98.8) ≥16121 (1.3)100 (1.1)76 (1.3)45 (1.2)67 (1.2)33 (0.8)Menopausal status Premenopausal7353 (75.8)7285 (76.6)4502 (77.7)2851 (73.0)4399 (78.7)2886 (73.7) Perimenopausal1699 (17.5)1615 (17.0)948 (16.4)751 (19.2)876 (15.7)739 (18.9) Postmenopausal652 (6.7)603 (6.3)347 (6.0)305 (7.8)315 (5.6)288 (7.4) Unknown or data missing1 (<0.1)5 (<0.1)01 (<0.1)3 (<0.1)2 (<0.1)Pregnancies, No. 0813 (8.4)742 (7.8)606 (10.5)207 (5.3)520 (9.3)222 (5.7) 11192 (12.3)1170 (12.3)768 (13.3)424 (36.5)762 (13.6)408 (10.4) 23659 (37.7)3603 (37.9)2233 (38.5)1426 (36.5)2154 (38.5)1449 (37.0) 3-43425 (35.3)3328 (35.0)1875 (38.5)1550 (39.7)1757 (31.4)1571 (40.1) 5-10372 (3.8)400 (4.2)159 (2.7)213 (5.5)212 (3.8)188 (4.8) Unknown or data missing244 (2.5)265 (2.8)156 (2.7)88 (2.3)188 (3.4)77 (2.0)Pregnancies delivered, No. Nulliparous130 (1.5)124 (1.5)96 (1.9)34 (0.9)85 (1.7)39 (1.1) 11427 (16.5)1423 (16.7)924 (18.4)503 (13.9)929 (19.0)494 (13.7) 24499 (52.0)4448 (52.3)2690 (18.4)1809 (50.1)2625 (53.7)1823 (50.4) 32270 (26.3)2202 (25.9)1191 (23.7)1079 (29.9)1113 (22.8)1089 (30.1) 4-8291 (3.4)257 (3.0)118 (2.3)173 (4.8)105 (2.2)152 (4.2) Unknown or data missing31 (0.4)47 (0.6)16 (2.3)15 (0.4)28 (0.6)19 (0.5)Age at first parturition, y <20102 (1.2)80 (0.9)58 (1.2)44 (1.2)44 (0.9)36 (1.0) 20-241626 (18.8)1470 (17.3)897 (17.8)729 (20.2)783 (16.0)687 (19.0) 25-293245 (37.5)3184 (37.5)1901 (37.8)1344 (37.2)1811 (37.1)1373 (38.0) 30-391882 (21.8)2022 (23.8)1132 (22.5)750 (20.8)1239 (25.4)783 (21.7) 40-4948 (0.6)47 (0.6)36 (0.7)12 (0.3)27 (0.6)20 (0.6) Unknown or data missing1745 (20.2)1698 (20.0)1011 (20.1)734 (20.3)981 (20.1)717 (19.8)Ever breastfed children Yes7754 (90.9)7570 (90.4)4507 (91.1)3247 (90.6)4338 (90.4)3232 (90.4) No758 (8.9)792 (9.5)428 (8.7)330 (9.2)455 (9.5)337 (9.4) Unknown or data missing21 (0.3)16 (0.2)15 (0.3)6 (0.2)8 (0.2)8 (0.2)First-degree female relatives with breast cancer, No. 09214 (94.9)9024 (94.9)5503 (94.9)3711 (95.0)5299 (94.7)3725 (95.2) 1485 (5.0)477 (5.0)291 (5.0)194 (5.0)289 (5.2)188 (4.8) >16 (<0.1)7 (<0.1)3 (<0.1)3 (<0.1)5 (<0.1)2 (<0.1)Ever had breast surgery227 (1.2)214 (1.1)170 (1.8)57 (0.6)140 (1.5)74 (0.8)Ever had benign neoplasm154 (0.8)143 (0.7)121 (1.3)33 (0.3)97 (1.0)46 (0.5)Ever had breast inflammation71 (0.4)70 (0.4)46 (0.5)25 (0.3)45 (0.5)25 (0.3)aPercentages might not total 100% because of rounding.bThe 2 least dense categories (almost entirely fatty and scattered fibroglandular tissues) are referred to as nondense, conventionally, the 2 most dense categories (heterogeneously dense and extremely dense) are referred to as dense.An overview of participant flow is shown in the eFigure in Supplement 2. A total of 19\u2009280 participants were enrolled and randomly allocated either study arms. Eligibility was assessed for inclusion in the analyses; 26 participants in the intervention group and 41 participants in the control group were excluded because of ineligibility and were withdrawn. Of 19\u2009213 participants, 11\u2009390 (59.3%) were categorized as having dense breast tissue (ie, heterogeneously or extremely dense) (eTable in Supplement 2).The mean (SD) age of participants was 44.5 (2.8) years (Table 1). A total of 975 participants (5.0%) reported a history of breast cancer in first-degree female relatives, and 297 participants (1.5%) reported having ever had benign breast diseases. There were no differences in demographic characteristics or risk factors between the intervention and control groups. On the other hand, the percentages of participants who had never been pregnant were significantly higher among women with dense breasts than among women with nondense breasts in both the intervention group (10.5% [95% CI, 9.9%-11.6%] vs 5.3% [95% CI, 4.7%-6.1%]; P\u2009<\u2009.001) and control group (9.3% [95% CI, 8.8%-10.4%] vs 5.7% [95% CI, 5.1%-6.5%] P\u2009<\u2009.001).Screening PerformanceTable 2 and Table 3 summarize the screening performance. In 19\u2009213 women, 130 cancers were found. More screen-detected cancers were found in the intervention group than in the control group (68 cancers [7.0 cancers per 1000 screenings; 95% CI, 5.3 to 8.7 cancers per 1000 screenings] vs 38 cancers [4.0 cancers per 1000 screenings; [95% CI, 2.7 to 5.3 cancers per 1000 screenings]; P\u2009=\u2009.004). Among women with dense breasts, there were more screen-detected cancer in the intervention group than the control group (41 cancers [7.1 cancers per 1000 screenings; 95% CI, 4.9 to 9.2 cancers per 1000 screenings] vs 24 cancers [4.3 cancers per 1000 screenings; 95% CI, 2.6 to 6.0 cancers per 1000 screenings]; P\u2009=\u2009.04). A similar tendency is seen in women with nondense breasts (27 cancers [6.9 cancers per 1000 screenings; 95% CI, 4.3 to 9.5 cancers per 1000 screenings] in the intervention group vs 14 cancers [3.6 cancers per 1000 screenings; 95% CI, 1.7 to 5.4 cancers per 1000 screenings] in the control group; P\u2009=\u2009.04). Five interval cancers (0.5 cancers per 1000 screenings; 95% CI, 0.1 to 1.0 cancers per 1000 screenings) were detected in the intervention group compared with 19 (2.0 cancers per 1000 screenings; 95% CI, 1.1 to 2.9 cancers per 1000 screenings) in the control group (P\u2009=\u2009.004), with a significant difference between the 2 groups among women with dense breasts (3 cancers [0.5 cancers per 1000 screenings; 95% CI, −0.1 to 1.1 cancers per 1000 screenings] vs 10 cancers [1.8 cancers per 1000 screenings; 95% CI, 0.7 to 2.9 cancers per 1000 screenings]; P\u2009=\u2009.04) as well as women with nondense breasts (2 cancers [0.5 cancers per 1000 screenings; 95% CI, −0.2 to 1.2 cancers per 1000 screenings] vs 9 cancers [2.3 cancers per 1000 screenings; 95% CI, 0.8 to 3.8 cancers per 1000 screenings]; P\u2009=\u2009.03). Sensitivity in the intervention group was higher than that in the control group (93.2% [95% CI, 87.4% to 99.0%] vs 66.7% [95% CI, 54.4% to 78.9%]; P\u2009<\u2009.001) for both dense breasts and nondense breasts. In contrast, specificity was significantly lower in the intervention group than the control group (86.8% [95% CI, 86.2% to 87.5%] vs 91.8% [95% CI, 91.2% to 92.3%]; P\u2009<\u2009.001) regardless of breast tissue density (Table 2).Table 2. Performance According to Breast Density CategoryVariableTotal participants (N\u2009=\u200919 213)Dense breastsaNondense breastsaIntervention group (n\u2009=\u20099705)Control group (n\u2009=\u20099508)P valueIntervention group (n\u2009=\u20095797)Control group (n\u2009=\u20095593)P valueIntervention group (n\u2009=\u20093908)Control group (n\u2009=\u20093915)P valueScreen-detected cancers No. of cancers/total No.68/970538/9508.00441/579724/5593.0427/390814/3915.04 No. of cancers per 1000 screenings (95% CI)7 (5.3 to 8.7)4 (2.7 to 5.3)7.1 (4.9 to 9.2)4.3 (2.6 to 6.0)6.9 (4.3 to 9.5)3.6 (1.7 to 5.4)Interval cancers No. of cancers/total No.5/970519/9508.0043/579710/5593.042/39089/3915.03 No. of cancers per 1000 screenings (95% CI)0.5 (0.1 to 1.0)2.0 (1.1 to 2.9)0.5 (−0.1 to 1.1)1.8 (0.7 to 2.9)0.5 (−0.2 to 1.2)2.3 (0.8 to 3.8)Sensitivity, % (95% CI)93.2 (87.4 to 99.0)66.7 (54.4 to 78.9)<.00193.2 (85.7 to 100)70.6 (55.3 to 85.9)<.00193.1 (83.9 to 102.3)60.9 (40.9 to 80.8)<.001Specificity, % (95% CI)86.8 (86.2 to 87.5)91.8 (91.2 to 92.3)<.00185.4 (84.5 to 86.3)91.7 (91.0 to 92.4)<.00189.0 (88.0 to 90.0)91.9 (91.1 to 92.8)<.001aThe 2 least dense categories (almost entirely fatty and scattered fibroglandular tissues) are referred to as nondense, and the 2 most dense categories (heterogeneously dense and extremely dense) are referred to as dense.Table 3. Sensitivity of Each Modality According to Breast Densities and Study GroupsGroup and modalityCancers, No. (%) [95% CI]P valueDense breastsaNondense breastsaIntervention group (n\u2009=\u20099705) Screen-detected cancers (n\u2009=\u200968) Mammography positive, ultrasonography positive or negative, CBE positive or negative24 (54.6) [39.8-69.3]20 (69.0) [52.1-85.8].20 Mammography positive or negative, ultrasonography positive, CBE positive or negative29 (65.9) [51.9-79.9]15 (51.7) [33.5-69.9].22 Mammography positive, ultrasonography positive, CBE positive or negative12 (27.3) [14.1-40.3]8 (27.6) [11.3-43.9].98 Mammography positive or negative, US positive or negative, CBE positive10 (22.7) [10.3-35.1]10 (34.5) [17.2-51.8].28 Only mammography positive12 (27.3) [14.1-40.3]12 (41.4) [23.5-59.3].21 Only ultrasonography positive17 (38.6) [24.3-53.0]7 (24.1) [8.6-39.7].18 Only CBE positive0 (NA)0 (NA)NA Any positive41 (93.2) [85.7-100.0]27 (93.1) [83.9-102.3].98 Interval cancers (n\u2009=\u20095), all modalities negative3 (NA)2 (NA)NAControl group (n\u2009=\u20099508) Screen-detected cancers (n\u2009=\u200938) Mammography positive, CBE positive or negative22 (64.7) [48.6-80.8]14 (60.9) [40.9-80.8].77 Mammography positive or negative, CBE positive9 (26.5) [11.6-41.3]6 (26.1) [8.1-44.0].97 Only mammography positive15 (44.1) [27.3-60.8]8 (34.8) [15.3-54.3].48 Only CBE positive2 (NA)0 (NA)NA Either mammography or CBE positive24 (70.6) [55.3-85.9]14 (60.9) [40.9-80.8].45 Interval cancers (n\u2009=\u200919), all modalities negative10 (NA)9 (NA)NAAbbreviations: CBE, clinical breast examination; NA, not applicable.aThe 2 least dense categories (almost entirely fatty and scattered fibroglandular tissues) are referred to as nondense, and the 2 most dense categories (heterogeneously dense and extremely dense) are referred to as dense.Table 3 summarizes sensitivity of each modality according to density. Neither modality exceeded 80% sensitivity alone (Table 3). In the intervention group, sensitivity of mammography was 69.0% (95% CI, 52.1%-85.8%) in nondense breasts and 54.6% (95% CI, 39.8%-69.3%) in dense breasts, whereas the sensitivity of mammography with adjunct ultrasonography was 93.1% (95% CI, 83.9%-102.3%) in nondense breasts and 93.2% (95% CI, 85.7%-100.0%) in dense breasts. The sensitivity of mammography was higher in women with dense breasts than those with nondense breasts (70.6% [95% CI, 55.3%-85.9%] vs 60.9% [95% CI, 40.9%-80.8%]).The frequency of clinical stage 0 and I breast cancer was 85.4% in dense breasts and 88.9% in nondense breasts within the intervention group, whereas in the control group, the frequency was 79.2% for dense breasts and 64.3% for nondense breasts. The differences in stage between the 2 groups were similar for dense and nondense breasts (Table 4). Within the intervention group, the rate of invasive cancers detected by ultrasonography alone was significantly higher than that for mammography alone, in both dense breasts (82.4% [95% CI, 56.6%-96.2%] vs 41.7% [95% CI, 15.2%-72.3%]; P = .02) and nondense breasts (85.7% [95% CI, 42.1%-99.6%] vs 25% [95% CI, 5.5%-57.2%]; P = .02). In the control group, however, the clinical stage and each pathological finding of invasive cancers detected by mammography alone were not meaningfully different between dense and nondense breasts (Table 4).Table 4. Clinical Stage and Histological Findings of Screen-Detected Cancers and Interval Cancers According to Breast DensityPatients, No. (%)aIntervention groupControl groupScreen-detected cancers (n\u2009=\u200968)Interval cancers (n\u2009=\u20095)Screen-detected cancers (n\u2009=\u200938)Interval cancers (n\u2009=\u200919)Any modality positive (n\u2009=\u200968)Only mammography positive (n\u2009=\u200924)Only US positive (n\u2009=\u200924)Only CBE positive (n\u2009=\u20090)Either positive (n\u2009=\u200938)Only mammography positive (n\u2009=\u200923)Only CBE positive (n\u2009=\u20092)Extremely and heterogeneously denseb Breast cancers, No.411217032415210 Clinical stagec 0 and I35 (85.4)12 (100)2 (76.5)01 (33.3)19 (79.2)15 (100)1 (50)9 (90) II or higher6 (14.6)04 (23.5)02 (66.7)5 (20.8)01 (50)1 (10) Histopathological cancer type Noninvasived13 (31.7)7 (58.3)3 (17.7)006 (25)6 (40)03 (30) Invasivee28 (68.3)5 (41.7)14 (82.4)03 (100)18 (75)9 (60)2 (100)7 (70) Size of invasive tumors on histological examination, mm <1011 (39.3)5 (100)4 (28.6)01 (33.3)9 (50)6 (66.7)1 (50)1 (14.3) 11-2015 (53.6)08 (57.1)004 (22.2)2 (22.2)1 (50)4 (57.1) >202 (7.1)02 (14.3)02 (66.7)4 (22.2)000 Data missing000001 (5.6)1 (11.1)02 (28.6) Node status of invasive cancers Negative23 (82.1)5 (100)11 (78.6)01 (33.3)15 (83.3)8 (88.9)2 (100)6 (85.7) Positive5 (17.9)03 (21.4)02 (66.7)2 (11.1)000 Data missing000001 (5.6)1 (11.1)01 (14.3)Scattered fibroglandular tissue and almost entirely fattyb Breast cancers, No.271270214809 Clinical stagec 0 and I24 (88.9)11 (91.7)6 (86.7)01 (50)9 (64.3)5 (62.5)09 (100) II or higher3 (11.1)1 (8.3)1 (14.3)01 (50)5 (35.7)3 (37.5)00 Histopathological cancer type Noninvasived13 (48.2)9 (75)1 (14.3)003 (21.4)3 (37.5)02 (22.2) Invasivee14 (51.9)3 (25)6 (85.7)02 (100)11 (78.6)5 (62.5)07 (77.8) Size of invasive tumors on histological examination, mm ≤105 (35.7)04 (66.7)01 (50)4 (36.4)3 (60)02 (28.6) 11-209 (64.3)3 (100)2 (33.3)005 (45.5)1 (20)04 (57.1) >2000001 (50)2 (18.2)1 (20)00 Data missing000000001 (14.3) Node status of invasive cancers Negative11 (78.6)2 (66.7)5 (83.3)02 (100)6 (54.6)3 (60)06 (85.7) Positive3 (21.4)1 (33.3)1 (16.7)005 (45.5)2 (40)00 Data missing000000001 (14.3)Abbreviations: CBE, clinical breast examination; US, ultrasonography.aPercentages might not total 100% because of rounding.bNo cancer was found in the category of almost entirely fatty.cBased on the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision.dIncludes ductal carcinoma in situ and lobular carcinoma in situ.eIncludes invasive ductal carcinoma and special type.Data of screening recalls and biopsy are presented in Table 5. Of 2147 participants who were recalled, 734 underwent biopsies. The recall rates (13.8% [95% CI, 13.1%-14.5%] vs 8.6% [95% CI, 8.0%-9.1%]; P\u2009<\u2009.001) and biopsy rates (5.5% [95% CI, 5.1%-6.0%] vs 2.1% [95% CI, 1.8%-2.4%]; P\u2009<\u2009.001) were significantly greater in the intervention group vs the control group. Recall rates for mammography alone were similar in the 2 groups regardless of breast density. In the intervention group, the recall rate by ultrasonography alone was higher for women with dense breasts than for women with nondense breasts (7.0% vs 3.9%), and the same was true for the biopsy rate (4.4% vs 2.6%).Table 5. Recall Rate and Biopsy Rate of Each Modality According to Study GroupVariableParticipants, No. (%)Intervention groupControl groupTotal (n\u2009=\u20099705)Dense breastsaTotal (n\u2009=\u20099508)Dense breastsaYes (n\u2009=\u20095797)No (n\u2009=\u20093908)Yes (n\u2009=\u20095593)No (n\u2009=\u20093915)Recalled after first-round screening Any modality positive1334 (13.8)880 (15.2)454 (11.6)813 (8.6)485 (8.7)328 (8.4) Only mammography positive606 (6.2)356 (6.1)250 (6.4)663 (7.0)374 (6.7)290 (7.4) Only ultrasonography positive558 (5.8)404 (7.0)154 (3.9)NANANA Only CBE positive59 (0.6)44 (0.8)15 (0.4)85 (0.9)69 (1.2)16 (0.4)Biopsy rateb Biopsy done538 (5.5)360 (6.2)178 (4.6)196 (2.1)127 (2.3)69 (1.8) Only mammography positive107 (1.1)56 (1.0)51 (1.3)128 (1.4)77 (1.4)51 (1.3) Only ultrasonography positive355 (3.7)255 (4.4)100 (2.6)NANANA Only CBE positive7 (<0.1)4 (<0.1)3 (<0.1)27 (0.3)22 (0.4)5 (<0.1)Abbreviations: CBE, clinical breast examination; NA, not applicable.aThe 2 least dense categories (almost entirely fatty and scattered fibroglandular tissues) are referred to as nondense, and the 2 most dense categories (heterogeneously dense and extremely dense) are referred to as dense.bIndicates a need for biopsy on first-round screening. When clinically indicated, participants might have undergone 2 or more types of biopsy.DiscussionTo our knowledge, J-START is the first large-scale RCT to assess the performance of ultrasonography screening in combination with mammography for breast cancer in women aged 40 to 49 years with average risk. Now, the question is raised as to whether adjunctive ultrasonography improves the balance of breast cancer screening in women with different breast densities. In the present secondary analysis, we further evaluated the performance of each screening modality (ie, mammography and ultrasonography) according to breast density, which has been shown to be a factor independently associated with increased risk of breast cancer across age group.9 Heterogeneity of tissue density is associated with not only increased cancer risk but also complications of mammographic interpretation; even small amounts of dense tissue can mask cancer. The fifth edition of the BI-RADS lexicon for breast density27 recommends that breast imagers assign breast composition descriptors that better convey whether there are dense areas of tissue that could mask or obscure cancer. In this respect, a major strength of this study is that we used the fifth edition of the BI-RADS lexicon to assess breast density and conducted double readings to reduce variation, which provided reproducible estimates and verification of density assessment quality. With awareness of these issues (breast density and lower screening sensitivity of mammography) as the starting point, we analyzed the performance of adjunctive ultrasonography compared with mammography in breasts with different densities. The principal findings between the intervention and control groups were consistent with those of the J-START,20 as adjunct ultrasonography to mammography exhibited higher sensitivity and lower specificity than mammography alone, with more cancers detected, more cancers that were stages 0 and I, and lower numbers of interval cancers than in the control group.20 Adjunct ultrasonography improved the sensitivity and detection rate of small, early-stage (stage 0 and stage I) and invasive cancers, consistent with other studies.3,7,11In addition, this study revealed that adjunctive ultrasonography improved the detection of early invasive cancers not only in dense breasts but also in nondense breasts. Moreover, we found ultrasonography to be potentially superior to mammography in detecting early and node-negative invasive cancers in both dense and nondense breasts.It should be noted that sensitivity of mammography alone and that of ultrasonography alone were both lower than the sensitivity of the combination of these modalities. In this study, the sensitivity of mammography was higher in women with dense breasts than those with nondense breasts (70.6% vs 60.9%). One of the explanations is that the sensitivity of mammography did not depend on breast density, because even nondense tissue might hide or mask cancer in women aged 40 to 49 years. However, sensitivity was improved when ultrasonography was used as an adjunct to mammography, suggesting that adjunctive ultrasonography has an advantage in breast cancer screening for young women regardless of dense breasts. Taking these results into account, we can conclude that breast density should not be the sole criterion for deciding whether supplemental imaging is justified. Because of the limitations of mammography in breast density, studies have investigated performance of supplementary screening tools, including tomosynthesis and magnetic resonance imaging.5,6,7,8 Tomosynthesis is unlikely to be an optimal solution, and magnetic resonance imaging is expensive and not easy to access for screening.With regard to the harms associated with breast cancer screening, supplemental ultrasonography had lower specificity and higher recall and biopsy rates than mammography alone, which are major limitations of screening ultrasonography.14,29 Ultrasonography and mammography findings were interpreted independently according to the J-START protocol, which consequently increased recall and biopsy rates and decreased specificity. In addition, ultrasonography-guided histological examination using core-needle biopsy is easy to perform and more accurate for diagnosing the lesion, which suggests that it is the main reason for the increased biopsy rate. A study30 of the European mammography screening programs showed overall further assessment rates to be 9.3% and 4.0% for initial and subsequent mammography screening tests, respectively. The overall rates of needle biopsy rates were 2.2% and 1.1%, respectively.30 A previous study31 in Japan reported that recall rate of mammography screening among 33\u2009924 women in their 40s was 9.9%. The recall rate of the first round in J-START31 was 8.8% in the control group (mammography only), which is within the accepted range.LimitationsThe sensitivity and specificity in this study were calculated with the data from the first-round screening. Our findings cannot be extended beyond the first round, because characteristics of breast cancer would differ between the first and later rounds of screening.7,12 Except for women at increased and high risk, estimates indicate a nearly 40% breast cancer mortality reduction when screening women annually starting at age 40 years.32 Improving cancer detection in younger and middle-aged women is crucial for increasing the effectiveness of breast cancer screening.23 To evaluate screening benefits avoiding lead time bias, and to determine balance of benefits and harms, further investigation providing hard evidence about the contributions of adjunctive ultrasonography screening to breast cancer mortality is necessary.ConclusionsIn this secondary analysis of an RCT, adjunctive ultrasonography had good screening balance with mammography regardless of breast density, detecting early-stage and invasive malignant lesions for asymptomatic women with average risk of breast cancer. Thus, adjunctive ultrasonography should be considered as an optimal solution in young women with average risk.References1TorreLA, BrayF, SiegelRL, FerlayJ, Lortet-TieulentJ, JemalA. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87-108. doi:10.3322/caac.21262256517872HoriM, MatsudaT, ShibataA, KatanodaK, SobueT, NishimotoH; Japan Cancer Surveillance Research Group. Cancer incidence and incidence rates in Japan in 2009: a study of 32 population-based cancer registries for the Monitoring of Cancer Incidence in Japan (MCIJ) project. Jpn J Clin Oncol. 2015;45(9):884-891. doi:10.1093/jjco/hyv088261424373KolbTM, LichyJ, NewhouseJH. Comparison of the performance of screening mammography, physical examination, and breast US and evaluation of factors that influence them: an analysis of 27,825 patient evaluations. Radiology. 2002;225(1):165-175. doi:10.1148/radiol.2251011667123550014BuchbergerW, Geiger-GritschS, KnappR, GautschK, OberaignerW. Combined screening with mammography and ultrasound in a population-based screening program. Eur J Radiol. 2018;101:24-29. doi:10.1016/j.ejrad.2018.01.022295717975TagliaficoAS, CalabreseM, MariscottiG, . Adjunct screening with tomosynthesis or ultrasound in women with mammography-negative dense breasts: interim report of a prospective comparative trial. J Clin Oncol. 2016;34(16):1882-1888. doi:10.1200/JCO.2015.63.4147269620976BergWA, BlumeJD, CormackJB, ; ACRIN 6666 Investigators. Combined screening with ultrasound and mammography vs mammography alone in women at elevated risk of breast cancer. JAMA. 2008;299(18):2151-2163. doi:10.1001/jama.299.18.2151184777827BergWA, BandosAI, MendelsonEB, LehrerD, JongRA, PisanoED. Ultrasound as the primary screening test for breast cancer: analysis from ACRIN 6666. J Natl Cancer Inst. 2015;108(4):djv367. doi:10.1093/jnci/djv367267121108MelnikowJ, FentonJJ, WhitlockEP, . Supplemental screening for breast cancer in women with dense breasts: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2016;164(4):268-278. doi:10.7326/M15-1789267570219BoydNF, GuoH, MartinLJ, . Mammographic density and the risk and detection of breast cancer. N Engl J Med. 2007;356(3):227-236. doi:10.1056/NEJMoa0627901722995010CheckaCM, ChunJE, SchnabelFR, LeeJ, TothH. The relationship of mammographic density and age: implications for breast cancer screening. AJR Am J Roentgenol. 2012;198(3):W292-W295. doi:10.2214/AJR.10.60492235802811CorsettiV, HoussamiN, GhirardiM, . Evidence of the effect of adjunct ultrasound screening in women with mammography-negative dense breasts: interval breast cancers at 1 year follow-up. Eur J Cancer. 2011;47(7):1021-1026. doi:10.1016/j.ejca.2010.12.0022121196212BergWA, ZhangZ, LehrerD, ; ACRIN 6666 Investigators. Detection of breast cancer with addition of annual screening ultrasound or a single screening MRI to mammography in women with elevated breast cancer risk. JAMA. 2012;307(13):1394-1404. doi:10.1001/jama.2012.3882247420313DongH, HuangY, SongF, . Improved performance of adjunctive ultrasonography after mammography screening for breast cancer among Chinese females. Clin Breast Cancer. 2018;18(3):e353-e361. doi:10.1016/j.clbc.2017.07.0142888701014CorsettiV, HoussamiN, FerrariA, . Breast screening with ultrasound in women with mammography-negative dense breasts: evidence on incremental cancer detection and false positives, and associated cost. Eur J Cancer. 2008;44(4):539-544. doi:10.1016/j.ejca.2008.01.0091826735715YoukJH, KimEK, KimMJ, KwakJY, SonEJ. Performance of hand-held whole-breast ultrasound based on BI-RADS in women with mammographically negative dense breast. Eur Radiol. 2011;21(4):667-675. doi:10.1007/s00330-010-1955-82085310816HooleyRJ, GreenbergKL, StackhouseRM, GeiselJL, ButlerRS, PhilpottsLE. Screening US in patients with mammographically dense breasts: initial experience with Connecticut Public Act 09-41. Radiology. 2012;265(1):59-69. doi:10.1148/radiol.121206212272350117SiuAL; US Preventive Services Task Force. Screening for breast cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2016;164(4):279-296. doi:10.7326/M15-28862675717018IshidaT, SuzukiA, KawaiM, . A randomized controlled trial to verify the efficacy of the use of ultrasonography in breast cancer screening aged 40-49 (J-START): 76 196 women registered. Jpn J Clin Oncol. 2014;44(2):134-140. doi:10.1093/jjco/hyt1992440783519OhuchiN, IshidaT, KawaiM, NarikawaY, YamamotoS, SobueT. Randomized controlled trial on effectiveness of ultrasonography screening for breast cancer in women aged 40-49 (J-START): research design. Jpn J Clin Oncol. 2011;41(2):275-277. doi:10.1093/jjco/hyq2142113129520OhuchiN, SuzukiA, SobueT, ; J-START investigator groups. Sensitivity and specificity of mammography and adjunctive ultrasonography to screen for breast cancer in the Japan Strategic Anti-cancer Randomized Trial (J-START): a randomised controlled trial. Lancet. 2016;387(10016):341-348. doi:10.1016/S0140-6736(15)00774-62654710121BergWA. Current status of supplemental screening in dense breasts. J Clin Oncol. 2016;34(16):1840-1843. doi:10.1200/JCO.2015.65.86742696209622UematsuT. The need for supplemental breast cancer screening modalities: a perspective of population-based breast cancer screening programs in Japan. Breast Cancer. 2017;24(1):26-31. doi:10.1007/s12282-016-0707-22725934223ThigpenD, KapplerA, BremR. The role of ultrasound in screening dense breasts: a review of the literature and practical solutions for implementation. Diagnostics (Basel). 2018;8(1):E20. doi:10.3390/diagnostics80100202954753224TohnoE, TakahashiH, TamadaT, FujimotoY, YasudaH, OhuchiN. Educational program and testing using images for the standardization of breast cancer screening by ultrasonography. Breast Cancer. 2012;19(2):138-146. doi:10.1007/s12282-010-0221-x2092473325OhuchiN, YoshidaK, KimuraM, . Improved detection rate of early breast cancer in mass screening combined with mammography. Jpn J Cancer Res. 1993;84(7):807-812. doi:10.1111/j.1349-7006.1993.tb02048.x839656926OhuchiN, YoshidaK, KimuraM, . Comparison of false negative rates among breast cancer screening modalities with or without mammography: Miyagi trial. Jpn J Cancer Res. 1995;86(5):501-506. doi:10.1111/j.1349-7006.1995.tb03084.x779032327American College of Radiology. ACR BI-RADS fifth edition. Published 2013. Accessed July 15, 2021. https://www.acr.org/-/media/ACR/Files/RADS/BI-RADS/BIRADS-Reference-Card.pdf28SobinLH, GospodarowiczML, WittekindC, eds. TNM Classification of Malignant Tumours. 7th ed. Wiley;2011.29SpragueBL, StoutNK, SchechterC, . Benefits, harms, and cost-effectiveness of supplemental ultrasonography screening for women with dense breasts. Ann Intern Med. 2015;162(3):157-166. doi:10.7326/M14-06922548655030HofvindS, PontiA, PatnickJ, ; EUNICE Project and Euroscreen Working Groups. False-positive results in mammographic screening for breast cancer in Europe: a literature review and survey of service screening programmes. J Med Screen. 2012;19(1)(suppl):57-66. doi:10.1258/jms.2012.0120832297281131KasaharaY, KawaiM, TsujiI, . Harms of screening mammography for breast cancer in Japanese women. Breast Cancer. 2013;20(4):310-315. doi:10.1007/s12282-012-0333-62228216432ArleoEK, HendrickRE, HelvieMA, SicklesEA. Comparison of recommendations for screening mammography using CISNET models. Cancer. 2017;123(19):3673-3680. doi:10.1002/cncr.3084228832983Supplement 1.\nTrial Protocol and Statistical Analysis Plan\nClick here for additional data file.Supplement 2.eFigure. Trial ProfileeTable. Distribution of Mammography Density Based on 5th Edition BI-RADS Density CategoriesClick here for additional data file.Supplement 3.\nData Sharing Statement\nClick here for additional data file.', 'title': 'Evaluation of Adjunctive Ultrasonography for Breast Cancer Detection Among Women Aged 40-49 Years With Varying Breast Density Undergoing Screening Mammography: A Secondary Analysis of a Randomized Clinical Trial.', 'date': '2021-08-19'}, '29571797': {'article_id': '29571797', 'content': 'To compare the performance of screening with mammography combined with ultrasound versus mammography alone in women at average risk for breast cancer.\n66,680 women underwent physician-performed ultrasound as an adjunct to screening mammography. Histological results and follow-up at one year were used as reference standard for sensitivity. Main outcome measures were cancer detection rate, sensitivity, recall rate, biopsy rate, and positive predictive value of biopsy for combined screening with mammography plus ultrasound versus mammography alone.\nThe overall sensitivity of mammography only was 61.5% in women with dense breasts and 86.6% in women with non-dense breasts. The sensitivity of mammography plus ultrasound combined was 81.3% in women with dense breasts and 95.0% in women with non-dense breasts. Adjunctive ultrasound increased the recall rate from 10.5 to 16.5 per 1000 women screened, and increased the biopsy rate from 6.3 to 9.3 per 1000 women screened. The positive predictive value of biopsy was 55.5% (95% CI 50.6%-60.3%) for mammography alone and 43.3 (95% CI 39.4%-47.3%) for combined mammography plus ultrasound.\nSupplemental ultrasound improves cancer detection in screening of women at average risk for breast cancer. Recall rates and biopsy rates can be kept within acceptable limits.', 'title': 'Combined screening with mammography and ultrasound in a population-based screening program.', 'date': '2018-03-25'}, '23116728': {'article_id': '23116728', 'content': 'Automated breast ultrasound (ABUS)was performed in 3418 asymptomatic women with mammographically dense breasts. The addition of ABUS to mammography in women with greater than 50% breast density resulted in the detection of 12.3 per 1,000 breast cancers, compared to 4.6 per 1,000 by mammography alone. The mean tumor size was 14.3 mm and overall attributable risk of breast cancer was 19.92 (95% confidence level, 16.75 - 23.61) in our screened population. These preliminary results may justify the cost-benefit of implementing the judicious us of ABUS in conjunction with mammography in the dense breast screening population.', 'title': 'Improved breast cancer detection in asymptomatic women using 3D-automated breast ultrasound in mammographically dense breasts.', 'date': '2012-11-03'}, '26549432': {'article_id': '26549432', 'content': 'To determine which modalities [2D mammography (2D), digital breast tomosynthesis (DBT), whole breast sonography (WBS)] are optimal for screening depending on breast density.\nInstitutional retrospective cohort study of 2013 screening mammograms (16,789), sorted by modalities and density.\nCancer detection is increased by adding WBS to 2D (P=.02) for the overall study population. Recall rate was lowest with 2D+DBT (10.2%, P<.001) and highest with 2D+DBT+WBS (23.6%, P<.001) for the overall study population as well.\nWomen with dense and nondense breasts benefit from reduced recall rate with the addition of DBT; however, this benefit is negated with the addition of WBS.', 'title': '2D mammography, digital breast tomosynthesis, and ultrasound: which should be used for the different breast densities in breast cancer screening?', 'date': '2015-11-10'}}
| 1
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Oncology & Hematology
|
11
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Is the frequency of interval carcinoma occurence higher, lower, or the same when comparing screening with a combination of mammography and ultrasonography to screening with mammography alone?
|
lower
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high
|
no
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['34406400', '30882843']
| 36,999,589
| 2,023
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{'34406400': {'article_id': '34406400', 'content': 'JAMA Netw OpenJAMA Netw OpenJAMA Netw OpenJAMA Network Open2574-3805American Medical Association34406400837460610.1001/jamanetworkopen.2021.21505zoi210636ResearchOriginal InvestigationFeaturedOnline OnlyOncologyEvaluation of Adjunctive Ultrasonography for Breast Cancer Detection Among Women Aged 40-49 Years With Varying Breast Density Undergoing Screening MammographyA Secondary Analysis of a Randomized Clinical TrialAdjunctive Ultrasonography for Breast Cancer Detection Among Women With Varying Breast DensityAdjunctive Ultrasonography for Breast Cancer Detection Among Women With Varying Breast DensityHarada-ShojiNarumiMDPhD\n1\nSuzukiAkihikoMDPhD\n2\nIshidaTakanoriMDPhD\n1\nZhengYing-FangMDPhD\n1\nNarikawa-ShionoYokoPhD\n1\nSato-TadanoAkikoMDPhD\n1\nOhtaRie\n1\nOhuchiNoriakiMDPhD\n1\n1Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan2Department of Breast and Endocrine Surgery, Tohoku Medical and Pharmaceutical University, Sendai, JapanArticle InformationAccepted for Publication: May 26, 2021.Published: August 18, 2021. doi:10.1001/jamanetworkopen.2021.21505Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Harada-Shoji N et al. JAMA Network Open.Corresponding Author: Noriaki Ohuchi, MD, PhD, Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan (noriaki-ohuchi@med.tohoku.ac.jp).Author Contributions: Dr. Ohuchi had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Harada-Shoji and Suzuki contributed equally to this work.Concept and design: Harada-Shoji, Suzuki, Ishida, Zheng, Narikawa-Shiono, Sato-Tadano, Ohuchi.Acquisition, analysis, or interpretation of data: Harada-Shoji, Suzuki, Ishida, Zheng, Sato-Tadano, Ohta, Ohuchi.Drafting of the manuscript: Harada-Shoji, Suzuki, Ishida, Zheng, Sato-Tadano, Ohuchi.Critical revision of the manuscript for important intellectual content: All authors.Statistical analysis: Harada-Shoji, Suzuki, Zheng, Sato-Tadano, Ohuchi.Obtained funding: Shiono, Ohuchi.Administrative, technical, or material support: Harada-Shoji, Suzuki, Ishida, Narikawa-Shiono, Sato-Tadano, Ohta, Ohuchi.Supervision: Suzuki, Ishida, Ohuchi.Conflict of Interest Disclosures: None reported.Funding/Support: The J-START study was funded by the third Comprehensive Control Research for Cancer, the Ministry of Health, Labor and Welfare of Japan (grants H18-Senryaku-001, H23-Shitei-002, and H25-Shitei-005), and Japan Agency for Medical Research and Development (grants JP17ck0106278h0001, JP18ck0106278h0002, JP19ck0106278h0003, and JPck0106563h0001).Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.Data Sharing Statement: See Supplement 3.Additional Contributions: We thank all those involved in the J-START study, including the participants and the research associates at all the research sites.188202182021188202148e212150516320212652021Copyright 2021 Harada-Shoji N et al. JAMA Network Open.https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the CC-BY License.jamanetwopen-e2121505.pdfKey PointsQuestionDoes the performance of adjunctive ultrasonography for breast cancer detection among women undergoing screening mammography change according to breast tissue density?FindingsIn this secondary analysis of a randomized clinical trial, screening mammography alone demonstrated low sensitivity, whereas adjunctive ultrasonography improved sensitivity both in dense and nondense breasts.MeaningThese findings suggest that adjunctive ultrasonography has the potential to improve the detection of early-stage and invasive cancers across both dense and nondense breasts and to mitigate the flaws of mammographic screening.This secondary analysis of a randomized clinical trial evaluates the performance of adjunctive ultrasonography for breast cancer screening in asymptomatic women aged 40 to 49 years undergoing screening mammography according to differences in breast density.ImportanceMammography has limited accuracy in breast cancer screening. Ultrasonography, when used in conjunction with mammography screening, is helpful to detect early-stage and invasive cancers for asymptomatic women with dense and nondense breasts.ObjectiveTo evaluate the performance of adjunctive ultrasonography with mammography for breast cancer screening, according to differences in breast density.Design, Setting, and ParticipantsThis study is a secondary analysis of the Japan Strategic Anti-cancer Randomized Trial. Between July 2007 and March 2011, asymptomatic women aged 40 to 49 years were enrolled in Japan. The present study used data from cases enrolled from the screening center in Miyagi prefecture during 2007 to 2020. Participants were randomly assigned in a 1:1 ratio to undergo either mammography with ultrasonography (intervention group) or mammography alone (control group). Data analysis was performed from February to March 2020.ExposuresUltrasonography adjunctive to mammography for breast cancer screening regardless of breast density.Main Outcomes and MeasuresSensitivity, specificity, recall rates, biopsy rates, and characteristics of screen-detected cancers and interval breast cancers were evaluated between study groups and for each modality according to breast density.ResultsA total of 76\u2009119 women were enrolled, and data for 19\u2009213 women (mean [SD] age, 44.5 [2.8] years) from the Miyagi prefecture were analyzed; 9705 were randomized to the intervention group and 9508 were randomized to the control group. A total of 11\u2009390 women (59.3%) had heterogeneously or extremely dense breasts. Among the overall group, 130 cancers were found. Sensitivity was significantly higher in the intervention group than the control group (93.2% [95% CI, 87.4%-99.0%] vs 66.7% [95% CI, 54.4%-78.9%]; P\u2009<\u2009.001). Similar trends were observed in women with dense breasts (sensitivity in intervention vs control groups, 93.2% [95% CI, 85.7%-100.0%] vs 70.6% [95% CI, 55.3%-85.9%]; P\u2009<\u2009.001) and nondense breasts (sensitivity in intervention vs control groups, 93.1% [95% CI, 83.9%-102.3%] vs 60.9% [95% CI, 40.9%-80.8%]; P\u2009<\u2009.001). The rate of interval cancers per 1000 screenings was lower in the intervention group compared with the control group (0.5 cancers [95% CI, 0.1-1.0 cancers] vs 2.0 cancers [95% CI, 1.1-2.9 cancers]; P\u2009=\u2009.004). Within the intervention group, the rate of invasive cancers detected by ultrasonography alone was significantly higher than that for mammography alone in both dense (82.4% [95% CI, 56.6%-96.2%] vs 41.7% [95% CI, 15.2%-72.3%]; P\u2009=\u2009.02) and nondense (85.7% [95% CI, 42.1%-99.6%] vs 25.0% [95% CI, 5.5%-57.2%]; P\u2009=\u2009.02) breasts. However, sensitivity of mammography or ultrasonography alone did not exceed 80% across all breast densities in the 2 groups. Compared with the control group, specificity was significantly lower in the intervention group (91.8% [95% CI, 91.2%-92.3%] vs 86.8% [95% CI, 86.2%-87.5%]; P\u2009<\u2009.001). Recall rates (13.8% [95% CI, 13.1%-14.5%] vs 8.6% [95% CI, 8.0%-9.1%]; P\u2009<\u2009.001) and biopsy rates (5.5% [95% CI, 5.1%-6.0%] vs 2.1% [95% CI, 1.8%-2.4%]; P\u2009<\u2009.001) were significantly higher in the intervention group than the control group.Conclusions and RelevanceIn this secondary analysis of a randomized clinical trial, screening mammography alone demonstrated low sensitivity, whereas adjunctive ultrasonography was associated with increased sensitivity. These findings suggest that adjunctive ultrasonography has the potential to improve detection of early-stage and invasive cancers across both dense and nondense breasts. Supplemental ultrasonography should be considered as an appropriate imaging modality for breast cancer screening in asymptomatic women aged 40 to 49 years regardless of breast density.Trial RegistrationNIPH Clinical Trial Identifier: UMIN000000757IntroductionGlobally, breast cancer is the most frequently diagnosed cancer and is the leading cause of cancer-related death in women.1 In Japan, breast cancer is also the leading cancer in women, with breast cancer incidence rates peaking among women aged 45 to 49 years.2 Mammography is the only screening modality that has been shown to be associated with reduced deaths caused by breast cancer. However, the sensitivity of mammography is variable and ranges from as high as 80% to 98% in women with fatty breast tissue to as low as 30% to 48% in women with dense breast tissue.3,4 Because of the limitations of mammography and increase in breast cancer awareness, a few study groups have investigated the performance characteristics of supplementary screening tools, including breast ultrasonography, tomosynthesis, and magnetic resonance imaging.5,6,7,8Breast density has been shown to be independently associated with increased risk of the incidence of and mortality attributable to breast cancer in younger women compared with older women,9,10 with increased risk of interval cancers between screening.6,11,12 Multiple studies6,11,13 have demonstrated that supplemental screening using ultrasonography generates an incremental cancer detection rate at the expense of lower specificity and lower positive predictive values. However, because most studies have focused on women at high risk3,6,7 or those with dense breast tissue but negative mammography findings,3,8,14,15 the performance of ultrasonography as an adjunct to mammography according to differences in breast density classification or among women at average risk remains unknown.4,11,13,16 Consequently, the effect of supplemental screening on breast cancer outcomes is still unclear.17To our knowledge, the Japan Strategic Anti-cancer Randomized Trial (J-START) is the only multicenter randomized clinical trial (RCT) to date to directly compare adjunctive ultrasonography with standard mammography to screen asymptomatic women aged 40 to 49 years.18,19,20 The primary analysis in the original report18 revealed that sensitivity was significantly higher in the intervention group (mammography with ultrasonography) than in the control group (mammography alone), whereas specificity was significantly lower. More cancers were detected in the intervention group than in the control group and were more frequently stages 0 and I. Furthermore, there was a significant reduction in interval cancers.20 However, results according to breast density were not described in detail,21,22 and further studies investigating specific breast density groups have been solicited.21,23 This secondary analysis of the J-START RCT aimed to address issues related to performance of each modality according to differences in breast density.MethodsStudy Design and ParticipantsThe J-START research design of has been published in detail elsewhere.18,19,20 Participants were randomly assigned in a 1:1 ratio to undergo screening by either mammography plus ultrasonography (intervention group) or mammography alone (control group), with or without clinical breast examination, once a year for 2 years.Following a planned protocol (Supplement 1), randomization was centrally conducted by the Japan Clinical Research Support Unit, which is responsible for data management and support for trial operations and independently from Tohoku University. An independent data safety and monitoring board was established to monitor the progress of the trial, which met every 6 months. The study protocol was developed in accordance with the principles of the Declaration of Helsinki. Ethics guidelines for clinical studies issued by the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labor and Welfare of Japan were followed. Ethics approval was granted by Tohoku University School of Medicine Research Ethics Committee and the Japan Cancer Society. Written informed consent was obtained from all participants. This study follows the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline for RCTs.Participants who had a personal history of breast cancer, including in situ cancer, or other cancers in the previous 5 years, or life expectancy of no more than 5 years, were ineligible for the study. Between July 2007 and March 2011, 76\u2009119 asymptomatic women aged 40 to 49 years were enrolled from 42 study sites in 23 of 47 prefectures in Japan. In this study, we used cases enrolled from the screening center in Miyagi prefecture, because we could examine and confirm the breast density.Screening Method and AssessmentStandard mammography and ultrasonography techniques were used at all participating facilities. The physicians and technicians involved in J-START completed a 2-day, 16-hour education program for the standardization of ultrasonography screening for breast cancer.24 Handheld ultrasonography was performed by a technician or by a physician, and later, the ultrasonography image was interpreted by another physician. The ultrasonography examination was performed, on average, in 10 minutes. Mammography acquisition, practice, apparatus, and interpretation were certified by the Japan Central Organization on Quality Assurance of Breast Cancer Screening. Ultrasonography acquisition, practice, apparatus, and interpretation were certified by the Japan Association of Breast and Thyroid Sonology.18Mammography, ultrasonography, and clinical breast examination were performed and interpreted independently from one another, and images were interpreted with double reading by 2 authorized physicians.18,19 The independently assessed findings of mammography, ultrasonography, and clinical examination were classified into 5 categories that are used locally and internationally: 1, no findings; 2, benign; 3, probably benign but further assessment needed; 4, probably malignant; and 5, malignant.19,25,26 Further assessment was considered test-positive if any of the findings were categorized as 3 or higher.For the purpose of this secondary analysis, which was conducted from March to September 2019, 3 expert physicians revaluated mammographic density of the first screening image. All information on screening results, medical interview record, and follow-up data were blinded. By use of the fifth edition of the Breast Imaging Reporting and Data System (BI-RADS),27 we classified visual judgment data as follows: almost entirely fatty; scattered areas of fibroglandular density; heterogeneously dense, which may obscure detection of small masses; and extremely dense, which lowers the sensitivity of mammography screening. In the present article, fatty and scattered are referred to as nondense, and heterogeneously dense and extremely dense are referred to as dense.Follow-upBreast cancers were ascertained by diagnostic assessment of first and second screening results or by a mail survey questionnaire to patients who did not attend the second screening. If data were not available, resident registers were used to identify the patient’s living status. In addition, date linkage with both hospital discharge records and cancer registry databases was used to identify breast cancer diagnosis information. Miyagi prefecture has a sophisticated system of local registration for cancer that contains data on virtually all patients with breast cancer in Miyagi prefecture. Therefore, it was possible to identify interval cancers exactly, and follow-up for this study was updated in February 2020.Screen-detected breast cancers were defined as those categorized as categories 3 to 5 at the first-round screening, and interval cancers were defined as those diagnosed between the first round and the second round of screening for which the initial category had been 1 or 2. Recall was defined as the need for any additional diagnostic testing after screening, including imaging and/or biopsy. The clinical stage and histopathological data were classified by the seventh edition of the TNM classification system.28 The outcome definitions and measure methods were prespecified before data release. Breast cancers diagnosed by the second-round screening were not counted for this study analysis.Statistical AnalysisThe preliminary sample size determination in J-START has been published in detail elsewhere.19,20 We used data from the participants at screening center in Miyagi prefecture. The special feature of the present study was not only to clarify differences between the intervention and control groups, but also differences in breast density composition. Sensitivity, specificity, recall rates, cancer detection rates, interval cancer rates, biopsy rates, and characteristics of screen-detected and interval breast cancers of the first-round screening were examined.All outcomes were analyzed according to the intention-to-treat principle. Performance outcomes were assessed with generalized estimating equations with an exchangeable working correlation matrix and robust SEs. Fisher exact test was used to detect significant differences in the clinical stage and histological findings between cancers detected by ultrasonography and mammography within the intervention group. All tests were 2-sided, and significance was set at P < .05. All statistical analyses were done with SAS statistical software version 9.\u20094 (SAS Institute). Data analysis was performed from February to March 2020.ResultsParticipant CharacteristicsThe baseline characteristics of study participants are shown in Table 1. Of 72\u2009998 asymptomatic women aged 40 to 49 years enrolled in J-START, 19\u2009213 women (9705 in the intervention group and 9508 in the control group) were analyzed in this study because they were residents in Miyagi Prefecture where the cancer registry had been established.Table 1. Baseline Characteristics of Study ParticipantsCharacteristicParticipants, No. (%) (N\u2009=\u200919\u2009213)aTotal intervention group (n\u2009=\u20099705)Total control group (n\u2009=\u20099508)Intervention group by breast densityControl group by breast densityDense (n\u2009=\u20095797)Nondense (n\u2009=\u20093908)bDense (n\u2009=\u20095593)bNondense (n\u2009=\u20093915)bAge, mean (SD), y44.5 (2.9)44.6 (2.9)44.5 (2.9)44.7 (2.9)44.5 (2.9)44.6 (2.9)Ever undergo breast cancer screening No1687 (17.4)1895 (19.9)995 (17.2)692 (17.7)1094 (19.6)801 (20.5) Yes8018 (82.6)7613 (80.1)4802 (82.8)3216 (82.3)4499 (80.4)3114 (79.5)Time since most recent breast cancer screening, mo <12716 (8.9)681 (9.0)441 (9.2)275 (8.6)424 (9.4)257 (8.3) 12-242942 (36.7)2773 (36.4)1759 (36.6)1183 (36.8)1620 (36.0)1153 (37.0) 25-362916 (36.4)2806 (36.9)1710 (35.6)1206 (37.5)1667 (37.1)1139 (36.6) >361391 (17.4)1308 (17.2)859 (17.9)532 (16.5)762 (16.9)546 (17.5) Unknown or data missing53 (0.7)45 (0.6)33 (0.7)20 (0.6)26 (0.6)19 (0.6)Method of most recent breast cancer screening Mammography No2342 (29.2)2191 (28.8)1419 (29.6)923 (28.7)1308 (29.1)883 (28.4) Yes5676 (70.8)5422 (71.2)3383 (70.5)2293 (71.3)3191 (70.9)2231 (71.6) Ultrasonography No6406 (79.9)6221 (81.7)3800 (79.1)2606 (81.0)3647 (81.1)2574 (82.7) Yes1612 (20.1)1392 (18.3)1002 (20.9)610 (19.0)852 (18.9)540 (17.3) Clinical breast examination No356 (4.4)332 (4.4)215 (4.5)141 (4.4)194 (4.3)138 (4.4) Yes7662 (95.6)7281 (95.6)4587 (95.5)3075 (95.6)4305 (95.7)2976 (95.6)Age at menarche, y ≤925 (0.3)25 (0.3)12 (0.2)13 (0.3)9 (0.2)16 (0.4) 10-159559 (98.5)9383 (98.7)5709 (98.5)3850 (98.5)5517 (98.6)3866 (98.8) ≥16121 (1.3)100 (1.1)76 (1.3)45 (1.2)67 (1.2)33 (0.8)Menopausal status Premenopausal7353 (75.8)7285 (76.6)4502 (77.7)2851 (73.0)4399 (78.7)2886 (73.7) Perimenopausal1699 (17.5)1615 (17.0)948 (16.4)751 (19.2)876 (15.7)739 (18.9) Postmenopausal652 (6.7)603 (6.3)347 (6.0)305 (7.8)315 (5.6)288 (7.4) Unknown or data missing1 (<0.1)5 (<0.1)01 (<0.1)3 (<0.1)2 (<0.1)Pregnancies, No. 0813 (8.4)742 (7.8)606 (10.5)207 (5.3)520 (9.3)222 (5.7) 11192 (12.3)1170 (12.3)768 (13.3)424 (36.5)762 (13.6)408 (10.4) 23659 (37.7)3603 (37.9)2233 (38.5)1426 (36.5)2154 (38.5)1449 (37.0) 3-43425 (35.3)3328 (35.0)1875 (38.5)1550 (39.7)1757 (31.4)1571 (40.1) 5-10372 (3.8)400 (4.2)159 (2.7)213 (5.5)212 (3.8)188 (4.8) Unknown or data missing244 (2.5)265 (2.8)156 (2.7)88 (2.3)188 (3.4)77 (2.0)Pregnancies delivered, No. Nulliparous130 (1.5)124 (1.5)96 (1.9)34 (0.9)85 (1.7)39 (1.1) 11427 (16.5)1423 (16.7)924 (18.4)503 (13.9)929 (19.0)494 (13.7) 24499 (52.0)4448 (52.3)2690 (18.4)1809 (50.1)2625 (53.7)1823 (50.4) 32270 (26.3)2202 (25.9)1191 (23.7)1079 (29.9)1113 (22.8)1089 (30.1) 4-8291 (3.4)257 (3.0)118 (2.3)173 (4.8)105 (2.2)152 (4.2) Unknown or data missing31 (0.4)47 (0.6)16 (2.3)15 (0.4)28 (0.6)19 (0.5)Age at first parturition, y <20102 (1.2)80 (0.9)58 (1.2)44 (1.2)44 (0.9)36 (1.0) 20-241626 (18.8)1470 (17.3)897 (17.8)729 (20.2)783 (16.0)687 (19.0) 25-293245 (37.5)3184 (37.5)1901 (37.8)1344 (37.2)1811 (37.1)1373 (38.0) 30-391882 (21.8)2022 (23.8)1132 (22.5)750 (20.8)1239 (25.4)783 (21.7) 40-4948 (0.6)47 (0.6)36 (0.7)12 (0.3)27 (0.6)20 (0.6) Unknown or data missing1745 (20.2)1698 (20.0)1011 (20.1)734 (20.3)981 (20.1)717 (19.8)Ever breastfed children Yes7754 (90.9)7570 (90.4)4507 (91.1)3247 (90.6)4338 (90.4)3232 (90.4) No758 (8.9)792 (9.5)428 (8.7)330 (9.2)455 (9.5)337 (9.4) Unknown or data missing21 (0.3)16 (0.2)15 (0.3)6 (0.2)8 (0.2)8 (0.2)First-degree female relatives with breast cancer, No. 09214 (94.9)9024 (94.9)5503 (94.9)3711 (95.0)5299 (94.7)3725 (95.2) 1485 (5.0)477 (5.0)291 (5.0)194 (5.0)289 (5.2)188 (4.8) >16 (<0.1)7 (<0.1)3 (<0.1)3 (<0.1)5 (<0.1)2 (<0.1)Ever had breast surgery227 (1.2)214 (1.1)170 (1.8)57 (0.6)140 (1.5)74 (0.8)Ever had benign neoplasm154 (0.8)143 (0.7)121 (1.3)33 (0.3)97 (1.0)46 (0.5)Ever had breast inflammation71 (0.4)70 (0.4)46 (0.5)25 (0.3)45 (0.5)25 (0.3)aPercentages might not total 100% because of rounding.bThe 2 least dense categories (almost entirely fatty and scattered fibroglandular tissues) are referred to as nondense, conventionally, the 2 most dense categories (heterogeneously dense and extremely dense) are referred to as dense.An overview of participant flow is shown in the eFigure in Supplement 2. A total of 19\u2009280 participants were enrolled and randomly allocated either study arms. Eligibility was assessed for inclusion in the analyses; 26 participants in the intervention group and 41 participants in the control group were excluded because of ineligibility and were withdrawn. Of 19\u2009213 participants, 11\u2009390 (59.3%) were categorized as having dense breast tissue (ie, heterogeneously or extremely dense) (eTable in Supplement 2).The mean (SD) age of participants was 44.5 (2.8) years (Table 1). A total of 975 participants (5.0%) reported a history of breast cancer in first-degree female relatives, and 297 participants (1.5%) reported having ever had benign breast diseases. There were no differences in demographic characteristics or risk factors between the intervention and control groups. On the other hand, the percentages of participants who had never been pregnant were significantly higher among women with dense breasts than among women with nondense breasts in both the intervention group (10.5% [95% CI, 9.9%-11.6%] vs 5.3% [95% CI, 4.7%-6.1%]; P\u2009<\u2009.001) and control group (9.3% [95% CI, 8.8%-10.4%] vs 5.7% [95% CI, 5.1%-6.5%] P\u2009<\u2009.001).Screening PerformanceTable 2 and Table 3 summarize the screening performance. In 19\u2009213 women, 130 cancers were found. More screen-detected cancers were found in the intervention group than in the control group (68 cancers [7.0 cancers per 1000 screenings; 95% CI, 5.3 to 8.7 cancers per 1000 screenings] vs 38 cancers [4.0 cancers per 1000 screenings; [95% CI, 2.7 to 5.3 cancers per 1000 screenings]; P\u2009=\u2009.004). Among women with dense breasts, there were more screen-detected cancer in the intervention group than the control group (41 cancers [7.1 cancers per 1000 screenings; 95% CI, 4.9 to 9.2 cancers per 1000 screenings] vs 24 cancers [4.3 cancers per 1000 screenings; 95% CI, 2.6 to 6.0 cancers per 1000 screenings]; P\u2009=\u2009.04). A similar tendency is seen in women with nondense breasts (27 cancers [6.9 cancers per 1000 screenings; 95% CI, 4.3 to 9.5 cancers per 1000 screenings] in the intervention group vs 14 cancers [3.6 cancers per 1000 screenings; 95% CI, 1.7 to 5.4 cancers per 1000 screenings] in the control group; P\u2009=\u2009.04). Five interval cancers (0.5 cancers per 1000 screenings; 95% CI, 0.1 to 1.0 cancers per 1000 screenings) were detected in the intervention group compared with 19 (2.0 cancers per 1000 screenings; 95% CI, 1.1 to 2.9 cancers per 1000 screenings) in the control group (P\u2009=\u2009.004), with a significant difference between the 2 groups among women with dense breasts (3 cancers [0.5 cancers per 1000 screenings; 95% CI, −0.1 to 1.1 cancers per 1000 screenings] vs 10 cancers [1.8 cancers per 1000 screenings; 95% CI, 0.7 to 2.9 cancers per 1000 screenings]; P\u2009=\u2009.04) as well as women with nondense breasts (2 cancers [0.5 cancers per 1000 screenings; 95% CI, −0.2 to 1.2 cancers per 1000 screenings] vs 9 cancers [2.3 cancers per 1000 screenings; 95% CI, 0.8 to 3.8 cancers per 1000 screenings]; P\u2009=\u2009.03). Sensitivity in the intervention group was higher than that in the control group (93.2% [95% CI, 87.4% to 99.0%] vs 66.7% [95% CI, 54.4% to 78.9%]; P\u2009<\u2009.001) for both dense breasts and nondense breasts. In contrast, specificity was significantly lower in the intervention group than the control group (86.8% [95% CI, 86.2% to 87.5%] vs 91.8% [95% CI, 91.2% to 92.3%]; P\u2009<\u2009.001) regardless of breast tissue density (Table 2).Table 2. Performance According to Breast Density CategoryVariableTotal participants (N\u2009=\u200919 213)Dense breastsaNondense breastsaIntervention group (n\u2009=\u20099705)Control group (n\u2009=\u20099508)P valueIntervention group (n\u2009=\u20095797)Control group (n\u2009=\u20095593)P valueIntervention group (n\u2009=\u20093908)Control group (n\u2009=\u20093915)P valueScreen-detected cancers No. of cancers/total No.68/970538/9508.00441/579724/5593.0427/390814/3915.04 No. of cancers per 1000 screenings (95% CI)7 (5.3 to 8.7)4 (2.7 to 5.3)7.1 (4.9 to 9.2)4.3 (2.6 to 6.0)6.9 (4.3 to 9.5)3.6 (1.7 to 5.4)Interval cancers No. of cancers/total No.5/970519/9508.0043/579710/5593.042/39089/3915.03 No. of cancers per 1000 screenings (95% CI)0.5 (0.1 to 1.0)2.0 (1.1 to 2.9)0.5 (−0.1 to 1.1)1.8 (0.7 to 2.9)0.5 (−0.2 to 1.2)2.3 (0.8 to 3.8)Sensitivity, % (95% CI)93.2 (87.4 to 99.0)66.7 (54.4 to 78.9)<.00193.2 (85.7 to 100)70.6 (55.3 to 85.9)<.00193.1 (83.9 to 102.3)60.9 (40.9 to 80.8)<.001Specificity, % (95% CI)86.8 (86.2 to 87.5)91.8 (91.2 to 92.3)<.00185.4 (84.5 to 86.3)91.7 (91.0 to 92.4)<.00189.0 (88.0 to 90.0)91.9 (91.1 to 92.8)<.001aThe 2 least dense categories (almost entirely fatty and scattered fibroglandular tissues) are referred to as nondense, and the 2 most dense categories (heterogeneously dense and extremely dense) are referred to as dense.Table 3. Sensitivity of Each Modality According to Breast Densities and Study GroupsGroup and modalityCancers, No. (%) [95% CI]P valueDense breastsaNondense breastsaIntervention group (n\u2009=\u20099705) Screen-detected cancers (n\u2009=\u200968) Mammography positive, ultrasonography positive or negative, CBE positive or negative24 (54.6) [39.8-69.3]20 (69.0) [52.1-85.8].20 Mammography positive or negative, ultrasonography positive, CBE positive or negative29 (65.9) [51.9-79.9]15 (51.7) [33.5-69.9].22 Mammography positive, ultrasonography positive, CBE positive or negative12 (27.3) [14.1-40.3]8 (27.6) [11.3-43.9].98 Mammography positive or negative, US positive or negative, CBE positive10 (22.7) [10.3-35.1]10 (34.5) [17.2-51.8].28 Only mammography positive12 (27.3) [14.1-40.3]12 (41.4) [23.5-59.3].21 Only ultrasonography positive17 (38.6) [24.3-53.0]7 (24.1) [8.6-39.7].18 Only CBE positive0 (NA)0 (NA)NA Any positive41 (93.2) [85.7-100.0]27 (93.1) [83.9-102.3].98 Interval cancers (n\u2009=\u20095), all modalities negative3 (NA)2 (NA)NAControl group (n\u2009=\u20099508) Screen-detected cancers (n\u2009=\u200938) Mammography positive, CBE positive or negative22 (64.7) [48.6-80.8]14 (60.9) [40.9-80.8].77 Mammography positive or negative, CBE positive9 (26.5) [11.6-41.3]6 (26.1) [8.1-44.0].97 Only mammography positive15 (44.1) [27.3-60.8]8 (34.8) [15.3-54.3].48 Only CBE positive2 (NA)0 (NA)NA Either mammography or CBE positive24 (70.6) [55.3-85.9]14 (60.9) [40.9-80.8].45 Interval cancers (n\u2009=\u200919), all modalities negative10 (NA)9 (NA)NAAbbreviations: CBE, clinical breast examination; NA, not applicable.aThe 2 least dense categories (almost entirely fatty and scattered fibroglandular tissues) are referred to as nondense, and the 2 most dense categories (heterogeneously dense and extremely dense) are referred to as dense.Table 3 summarizes sensitivity of each modality according to density. Neither modality exceeded 80% sensitivity alone (Table 3). In the intervention group, sensitivity of mammography was 69.0% (95% CI, 52.1%-85.8%) in nondense breasts and 54.6% (95% CI, 39.8%-69.3%) in dense breasts, whereas the sensitivity of mammography with adjunct ultrasonography was 93.1% (95% CI, 83.9%-102.3%) in nondense breasts and 93.2% (95% CI, 85.7%-100.0%) in dense breasts. The sensitivity of mammography was higher in women with dense breasts than those with nondense breasts (70.6% [95% CI, 55.3%-85.9%] vs 60.9% [95% CI, 40.9%-80.8%]).The frequency of clinical stage 0 and I breast cancer was 85.4% in dense breasts and 88.9% in nondense breasts within the intervention group, whereas in the control group, the frequency was 79.2% for dense breasts and 64.3% for nondense breasts. The differences in stage between the 2 groups were similar for dense and nondense breasts (Table 4). Within the intervention group, the rate of invasive cancers detected by ultrasonography alone was significantly higher than that for mammography alone, in both dense breasts (82.4% [95% CI, 56.6%-96.2%] vs 41.7% [95% CI, 15.2%-72.3%]; P = .02) and nondense breasts (85.7% [95% CI, 42.1%-99.6%] vs 25% [95% CI, 5.5%-57.2%]; P = .02). In the control group, however, the clinical stage and each pathological finding of invasive cancers detected by mammography alone were not meaningfully different between dense and nondense breasts (Table 4).Table 4. Clinical Stage and Histological Findings of Screen-Detected Cancers and Interval Cancers According to Breast DensityPatients, No. (%)aIntervention groupControl groupScreen-detected cancers (n\u2009=\u200968)Interval cancers (n\u2009=\u20095)Screen-detected cancers (n\u2009=\u200938)Interval cancers (n\u2009=\u200919)Any modality positive (n\u2009=\u200968)Only mammography positive (n\u2009=\u200924)Only US positive (n\u2009=\u200924)Only CBE positive (n\u2009=\u20090)Either positive (n\u2009=\u200938)Only mammography positive (n\u2009=\u200923)Only CBE positive (n\u2009=\u20092)Extremely and heterogeneously denseb Breast cancers, No.411217032415210 Clinical stagec 0 and I35 (85.4)12 (100)2 (76.5)01 (33.3)19 (79.2)15 (100)1 (50)9 (90) II or higher6 (14.6)04 (23.5)02 (66.7)5 (20.8)01 (50)1 (10) Histopathological cancer type Noninvasived13 (31.7)7 (58.3)3 (17.7)006 (25)6 (40)03 (30) Invasivee28 (68.3)5 (41.7)14 (82.4)03 (100)18 (75)9 (60)2 (100)7 (70) Size of invasive tumors on histological examination, mm <1011 (39.3)5 (100)4 (28.6)01 (33.3)9 (50)6 (66.7)1 (50)1 (14.3) 11-2015 (53.6)08 (57.1)004 (22.2)2 (22.2)1 (50)4 (57.1) >202 (7.1)02 (14.3)02 (66.7)4 (22.2)000 Data missing000001 (5.6)1 (11.1)02 (28.6) Node status of invasive cancers Negative23 (82.1)5 (100)11 (78.6)01 (33.3)15 (83.3)8 (88.9)2 (100)6 (85.7) Positive5 (17.9)03 (21.4)02 (66.7)2 (11.1)000 Data missing000001 (5.6)1 (11.1)01 (14.3)Scattered fibroglandular tissue and almost entirely fattyb Breast cancers, No.271270214809 Clinical stagec 0 and I24 (88.9)11 (91.7)6 (86.7)01 (50)9 (64.3)5 (62.5)09 (100) II or higher3 (11.1)1 (8.3)1 (14.3)01 (50)5 (35.7)3 (37.5)00 Histopathological cancer type Noninvasived13 (48.2)9 (75)1 (14.3)003 (21.4)3 (37.5)02 (22.2) Invasivee14 (51.9)3 (25)6 (85.7)02 (100)11 (78.6)5 (62.5)07 (77.8) Size of invasive tumors on histological examination, mm ≤105 (35.7)04 (66.7)01 (50)4 (36.4)3 (60)02 (28.6) 11-209 (64.3)3 (100)2 (33.3)005 (45.5)1 (20)04 (57.1) >2000001 (50)2 (18.2)1 (20)00 Data missing000000001 (14.3) Node status of invasive cancers Negative11 (78.6)2 (66.7)5 (83.3)02 (100)6 (54.6)3 (60)06 (85.7) Positive3 (21.4)1 (33.3)1 (16.7)005 (45.5)2 (40)00 Data missing000000001 (14.3)Abbreviations: CBE, clinical breast examination; US, ultrasonography.aPercentages might not total 100% because of rounding.bNo cancer was found in the category of almost entirely fatty.cBased on the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision.dIncludes ductal carcinoma in situ and lobular carcinoma in situ.eIncludes invasive ductal carcinoma and special type.Data of screening recalls and biopsy are presented in Table 5. Of 2147 participants who were recalled, 734 underwent biopsies. The recall rates (13.8% [95% CI, 13.1%-14.5%] vs 8.6% [95% CI, 8.0%-9.1%]; P\u2009<\u2009.001) and biopsy rates (5.5% [95% CI, 5.1%-6.0%] vs 2.1% [95% CI, 1.8%-2.4%]; P\u2009<\u2009.001) were significantly greater in the intervention group vs the control group. Recall rates for mammography alone were similar in the 2 groups regardless of breast density. In the intervention group, the recall rate by ultrasonography alone was higher for women with dense breasts than for women with nondense breasts (7.0% vs 3.9%), and the same was true for the biopsy rate (4.4% vs 2.6%).Table 5. Recall Rate and Biopsy Rate of Each Modality According to Study GroupVariableParticipants, No. (%)Intervention groupControl groupTotal (n\u2009=\u20099705)Dense breastsaTotal (n\u2009=\u20099508)Dense breastsaYes (n\u2009=\u20095797)No (n\u2009=\u20093908)Yes (n\u2009=\u20095593)No (n\u2009=\u20093915)Recalled after first-round screening Any modality positive1334 (13.8)880 (15.2)454 (11.6)813 (8.6)485 (8.7)328 (8.4) Only mammography positive606 (6.2)356 (6.1)250 (6.4)663 (7.0)374 (6.7)290 (7.4) Only ultrasonography positive558 (5.8)404 (7.0)154 (3.9)NANANA Only CBE positive59 (0.6)44 (0.8)15 (0.4)85 (0.9)69 (1.2)16 (0.4)Biopsy rateb Biopsy done538 (5.5)360 (6.2)178 (4.6)196 (2.1)127 (2.3)69 (1.8) Only mammography positive107 (1.1)56 (1.0)51 (1.3)128 (1.4)77 (1.4)51 (1.3) Only ultrasonography positive355 (3.7)255 (4.4)100 (2.6)NANANA Only CBE positive7 (<0.1)4 (<0.1)3 (<0.1)27 (0.3)22 (0.4)5 (<0.1)Abbreviations: CBE, clinical breast examination; NA, not applicable.aThe 2 least dense categories (almost entirely fatty and scattered fibroglandular tissues) are referred to as nondense, and the 2 most dense categories (heterogeneously dense and extremely dense) are referred to as dense.bIndicates a need for biopsy on first-round screening. When clinically indicated, participants might have undergone 2 or more types of biopsy.DiscussionTo our knowledge, J-START is the first large-scale RCT to assess the performance of ultrasonography screening in combination with mammography for breast cancer in women aged 40 to 49 years with average risk. Now, the question is raised as to whether adjunctive ultrasonography improves the balance of breast cancer screening in women with different breast densities. In the present secondary analysis, we further evaluated the performance of each screening modality (ie, mammography and ultrasonography) according to breast density, which has been shown to be a factor independently associated with increased risk of breast cancer across age group.9 Heterogeneity of tissue density is associated with not only increased cancer risk but also complications of mammographic interpretation; even small amounts of dense tissue can mask cancer. The fifth edition of the BI-RADS lexicon for breast density27 recommends that breast imagers assign breast composition descriptors that better convey whether there are dense areas of tissue that could mask or obscure cancer. In this respect, a major strength of this study is that we used the fifth edition of the BI-RADS lexicon to assess breast density and conducted double readings to reduce variation, which provided reproducible estimates and verification of density assessment quality. With awareness of these issues (breast density and lower screening sensitivity of mammography) as the starting point, we analyzed the performance of adjunctive ultrasonography compared with mammography in breasts with different densities. The principal findings between the intervention and control groups were consistent with those of the J-START,20 as adjunct ultrasonography to mammography exhibited higher sensitivity and lower specificity than mammography alone, with more cancers detected, more cancers that were stages 0 and I, and lower numbers of interval cancers than in the control group.20 Adjunct ultrasonography improved the sensitivity and detection rate of small, early-stage (stage 0 and stage I) and invasive cancers, consistent with other studies.3,7,11In addition, this study revealed that adjunctive ultrasonography improved the detection of early invasive cancers not only in dense breasts but also in nondense breasts. Moreover, we found ultrasonography to be potentially superior to mammography in detecting early and node-negative invasive cancers in both dense and nondense breasts.It should be noted that sensitivity of mammography alone and that of ultrasonography alone were both lower than the sensitivity of the combination of these modalities. In this study, the sensitivity of mammography was higher in women with dense breasts than those with nondense breasts (70.6% vs 60.9%). One of the explanations is that the sensitivity of mammography did not depend on breast density, because even nondense tissue might hide or mask cancer in women aged 40 to 49 years. However, sensitivity was improved when ultrasonography was used as an adjunct to mammography, suggesting that adjunctive ultrasonography has an advantage in breast cancer screening for young women regardless of dense breasts. Taking these results into account, we can conclude that breast density should not be the sole criterion for deciding whether supplemental imaging is justified. Because of the limitations of mammography in breast density, studies have investigated performance of supplementary screening tools, including tomosynthesis and magnetic resonance imaging.5,6,7,8 Tomosynthesis is unlikely to be an optimal solution, and magnetic resonance imaging is expensive and not easy to access for screening.With regard to the harms associated with breast cancer screening, supplemental ultrasonography had lower specificity and higher recall and biopsy rates than mammography alone, which are major limitations of screening ultrasonography.14,29 Ultrasonography and mammography findings were interpreted independently according to the J-START protocol, which consequently increased recall and biopsy rates and decreased specificity. In addition, ultrasonography-guided histological examination using core-needle biopsy is easy to perform and more accurate for diagnosing the lesion, which suggests that it is the main reason for the increased biopsy rate. A study30 of the European mammography screening programs showed overall further assessment rates to be 9.3% and 4.0% for initial and subsequent mammography screening tests, respectively. The overall rates of needle biopsy rates were 2.2% and 1.1%, respectively.30 A previous study31 in Japan reported that recall rate of mammography screening among 33\u2009924 women in their 40s was 9.9%. The recall rate of the first round in J-START31 was 8.8% in the control group (mammography only), which is within the accepted range.LimitationsThe sensitivity and specificity in this study were calculated with the data from the first-round screening. Our findings cannot be extended beyond the first round, because characteristics of breast cancer would differ between the first and later rounds of screening.7,12 Except for women at increased and high risk, estimates indicate a nearly 40% breast cancer mortality reduction when screening women annually starting at age 40 years.32 Improving cancer detection in younger and middle-aged women is crucial for increasing the effectiveness of breast cancer screening.23 To evaluate screening benefits avoiding lead time bias, and to determine balance of benefits and harms, further investigation providing hard evidence about the contributions of adjunctive ultrasonography screening to breast cancer mortality is necessary.ConclusionsIn this secondary analysis of an RCT, adjunctive ultrasonography had good screening balance with mammography regardless of breast density, detecting early-stage and invasive malignant lesions for asymptomatic women with average risk of breast cancer. Thus, adjunctive ultrasonography should be considered as an optimal solution in young women with average risk.References1TorreLA, BrayF, SiegelRL, FerlayJ, Lortet-TieulentJ, JemalA. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87-108. doi:10.3322/caac.21262256517872HoriM, MatsudaT, ShibataA, KatanodaK, SobueT, NishimotoH; Japan Cancer Surveillance Research Group. Cancer incidence and incidence rates in Japan in 2009: a study of 32 population-based cancer registries for the Monitoring of Cancer Incidence in Japan (MCIJ) project. Jpn J Clin Oncol. 2015;45(9):884-891. doi:10.1093/jjco/hyv088261424373KolbTM, LichyJ, NewhouseJH. Comparison of the performance of screening mammography, physical examination, and breast US and evaluation of factors that influence them: an analysis of 27,825 patient evaluations. Radiology. 2002;225(1):165-175. doi:10.1148/radiol.2251011667123550014BuchbergerW, Geiger-GritschS, KnappR, GautschK, OberaignerW. Combined screening with mammography and ultrasound in a population-based screening program. Eur J Radiol. 2018;101:24-29. doi:10.1016/j.ejrad.2018.01.022295717975TagliaficoAS, CalabreseM, MariscottiG, . Adjunct screening with tomosynthesis or ultrasound in women with mammography-negative dense breasts: interim report of a prospective comparative trial. J Clin Oncol. 2016;34(16):1882-1888. doi:10.1200/JCO.2015.63.4147269620976BergWA, BlumeJD, CormackJB, ; ACRIN 6666 Investigators. Combined screening with ultrasound and mammography vs mammography alone in women at elevated risk of breast cancer. JAMA. 2008;299(18):2151-2163. doi:10.1001/jama.299.18.2151184777827BergWA, BandosAI, MendelsonEB, LehrerD, JongRA, PisanoED. Ultrasound as the primary screening test for breast cancer: analysis from ACRIN 6666. J Natl Cancer Inst. 2015;108(4):djv367. doi:10.1093/jnci/djv367267121108MelnikowJ, FentonJJ, WhitlockEP, . Supplemental screening for breast cancer in women with dense breasts: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2016;164(4):268-278. doi:10.7326/M15-1789267570219BoydNF, GuoH, MartinLJ, . Mammographic density and the risk and detection of breast cancer. N Engl J Med. 2007;356(3):227-236. doi:10.1056/NEJMoa0627901722995010CheckaCM, ChunJE, SchnabelFR, LeeJ, TothH. The relationship of mammographic density and age: implications for breast cancer screening. AJR Am J Roentgenol. 2012;198(3):W292-W295. doi:10.2214/AJR.10.60492235802811CorsettiV, HoussamiN, GhirardiM, . Evidence of the effect of adjunct ultrasound screening in women with mammography-negative dense breasts: interval breast cancers at 1 year follow-up. Eur J Cancer. 2011;47(7):1021-1026. doi:10.1016/j.ejca.2010.12.0022121196212BergWA, ZhangZ, LehrerD, ; ACRIN 6666 Investigators. Detection of breast cancer with addition of annual screening ultrasound or a single screening MRI to mammography in women with elevated breast cancer risk. JAMA. 2012;307(13):1394-1404. doi:10.1001/jama.2012.3882247420313DongH, HuangY, SongF, . Improved performance of adjunctive ultrasonography after mammography screening for breast cancer among Chinese females. Clin Breast Cancer. 2018;18(3):e353-e361. doi:10.1016/j.clbc.2017.07.0142888701014CorsettiV, HoussamiN, FerrariA, . Breast screening with ultrasound in women with mammography-negative dense breasts: evidence on incremental cancer detection and false positives, and associated cost. Eur J Cancer. 2008;44(4):539-544. doi:10.1016/j.ejca.2008.01.0091826735715YoukJH, KimEK, KimMJ, KwakJY, SonEJ. Performance of hand-held whole-breast ultrasound based on BI-RADS in women with mammographically negative dense breast. Eur Radiol. 2011;21(4):667-675. doi:10.1007/s00330-010-1955-82085310816HooleyRJ, GreenbergKL, StackhouseRM, GeiselJL, ButlerRS, PhilpottsLE. Screening US in patients with mammographically dense breasts: initial experience with Connecticut Public Act 09-41. Radiology. 2012;265(1):59-69. doi:10.1148/radiol.121206212272350117SiuAL; US Preventive Services Task Force. Screening for breast cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2016;164(4):279-296. doi:10.7326/M15-28862675717018IshidaT, SuzukiA, KawaiM, . A randomized controlled trial to verify the efficacy of the use of ultrasonography in breast cancer screening aged 40-49 (J-START): 76 196 women registered. Jpn J Clin Oncol. 2014;44(2):134-140. doi:10.1093/jjco/hyt1992440783519OhuchiN, IshidaT, KawaiM, NarikawaY, YamamotoS, SobueT. Randomized controlled trial on effectiveness of ultrasonography screening for breast cancer in women aged 40-49 (J-START): research design. Jpn J Clin Oncol. 2011;41(2):275-277. doi:10.1093/jjco/hyq2142113129520OhuchiN, SuzukiA, SobueT, ; J-START investigator groups. Sensitivity and specificity of mammography and adjunctive ultrasonography to screen for breast cancer in the Japan Strategic Anti-cancer Randomized Trial (J-START): a randomised controlled trial. Lancet. 2016;387(10016):341-348. doi:10.1016/S0140-6736(15)00774-62654710121BergWA. Current status of supplemental screening in dense breasts. J Clin Oncol. 2016;34(16):1840-1843. doi:10.1200/JCO.2015.65.86742696209622UematsuT. The need for supplemental breast cancer screening modalities: a perspective of population-based breast cancer screening programs in Japan. Breast Cancer. 2017;24(1):26-31. doi:10.1007/s12282-016-0707-22725934223ThigpenD, KapplerA, BremR. The role of ultrasound in screening dense breasts: a review of the literature and practical solutions for implementation. Diagnostics (Basel). 2018;8(1):E20. doi:10.3390/diagnostics80100202954753224TohnoE, TakahashiH, TamadaT, FujimotoY, YasudaH, OhuchiN. Educational program and testing using images for the standardization of breast cancer screening by ultrasonography. Breast Cancer. 2012;19(2):138-146. doi:10.1007/s12282-010-0221-x2092473325OhuchiN, YoshidaK, KimuraM, . Improved detection rate of early breast cancer in mass screening combined with mammography. Jpn J Cancer Res. 1993;84(7):807-812. doi:10.1111/j.1349-7006.1993.tb02048.x839656926OhuchiN, YoshidaK, KimuraM, . Comparison of false negative rates among breast cancer screening modalities with or without mammography: Miyagi trial. Jpn J Cancer Res. 1995;86(5):501-506. doi:10.1111/j.1349-7006.1995.tb03084.x779032327American College of Radiology. ACR BI-RADS fifth edition. Published 2013. Accessed July 15, 2021. https://www.acr.org/-/media/ACR/Files/RADS/BI-RADS/BIRADS-Reference-Card.pdf28SobinLH, GospodarowiczML, WittekindC, eds. TNM Classification of Malignant Tumours. 7th ed. Wiley;2011.29SpragueBL, StoutNK, SchechterC, . Benefits, harms, and cost-effectiveness of supplemental ultrasonography screening for women with dense breasts. Ann Intern Med. 2015;162(3):157-166. doi:10.7326/M14-06922548655030HofvindS, PontiA, PatnickJ, ; EUNICE Project and Euroscreen Working Groups. False-positive results in mammographic screening for breast cancer in Europe: a literature review and survey of service screening programmes. J Med Screen. 2012;19(1)(suppl):57-66. doi:10.1258/jms.2012.0120832297281131KasaharaY, KawaiM, TsujiI, . Harms of screening mammography for breast cancer in Japanese women. Breast Cancer. 2013;20(4):310-315. doi:10.1007/s12282-012-0333-62228216432ArleoEK, HendrickRE, HelvieMA, SicklesEA. Comparison of recommendations for screening mammography using CISNET models. Cancer. 2017;123(19):3673-3680. doi:10.1002/cncr.3084228832983Supplement 1.\nTrial Protocol and Statistical Analysis Plan\nClick here for additional data file.Supplement 2.eFigure. Trial ProfileeTable. Distribution of Mammography Density Based on 5th Edition BI-RADS Density CategoriesClick here for additional data file.Supplement 3.\nData Sharing Statement\nClick here for additional data file.', 'title': 'Evaluation of Adjunctive Ultrasonography for Breast Cancer Detection Among Women Aged 40-49 Years With Varying Breast Density Undergoing Screening Mammography: A Secondary Analysis of a Randomized Clinical Trial.', 'date': '2021-08-19'}, '30882843': {'article_id': '30882843', 'content': 'Whole-breast ultrasonography has been advocated to supplement screening mammography to improve outcomes in women with dense breasts.\nTo determine the performance of screening mammography plus screening ultrasonography compared with screening mammography alone in community practice.\nObservational cohort study. Two Breast Cancer Surveillance Consortium registries provided prospectively collected data on screening mammography with vs without same-day breast ultrasonography from January 1, 2000, to December 31, 2013. The dates of analysis were March 2014 to December 2018. A total of 6081 screening mammography plus same-day screening ultrasonography examinations in 3386 women were propensity score matched 1:5 to 30\u202f062 screening mammograms without screening ultrasonography in 15\u202f176 women from a sample of 113\u202f293 mammograms. Exclusion criteria included a personal history of breast cancer and self-reported breast symptoms.\nScreening mammography with vs without screening ultrasonography.\nCancer detection rate and rates of interval cancer, false-positive biopsy recommendation, short-interval follow-up, and positive predictive value of biopsy recommendation were estimated and compared using log binomial regression.\nScreening mammography with vs without ultrasonography examinations was performed more often in women with dense breasts (74.3% [n\u2009=\u20094317 of 5810] vs 35.9% [n\u2009=\u200939\u202f928 of 111\u202f306] in the overall sample), in women who were younger than 50 years (49.7% [n\u2009=\u20093022 of 6081] vs 31.7% [n\u2009=\u200916\u202f897 of 112\u202f462]), and in women with a family history of breast cancer (42.9% [n\u2009=\u20092595 of 6055] vs 15.0% [n\u2009=\u200916\u202f897 of 112\u202f462]). While 21.4% (n\u2009=\u20091154 of 5392) of screening ultrasonography examinations were performed in women with high or very high (≥2.50%) Breast Cancer Surveillance Consortium 5-year risk scores, 53.6% (n\u2009=\u20092889 of 5392) had low or average (<1.67%) risk. Comparing mammography plus ultrasonography with mammography alone, the cancer detection rate was similar at 5.4 vs 5.5 per 1000 screens (adjusted relative risk [RR], 1.14; 95% CI, 0.76-1.68), as were interval cancer rates at 1.5 vs 1.9 per 1000 screens (RR, 0.67; 95% CI, 0.33-1.37). The false-positive biopsy rates were significantly higher at 52.0 vs 22.2 per 1000 screens (RR, 2.23; 95% CI, 1.93-2.58), as was short-interval follow-up at 3.9% vs 1.1% (RR, 3.10; 95% CI, 2.60-3.70). The positive predictive value of biopsy recommendation was significantly lower at 9.5% vs 21.4% (RR, 0.50; 95% CI, 0.35-0.71).\nIn a relatively young population of women at low, intermediate, and high breast cancer risk, these results suggest that the benefits of supplemental ultrasonography screening may not outweigh associated harms.', 'title': 'Performance of Screening Ultrasonography as an Adjunct to Screening Mammography in Women Across the Spectrum of Breast Cancer Risk.', 'date': '2019-03-19'}}
| 0.5
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Oncology & Hematology
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12
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Is the breast cancer detection rate higher, lower, or the same when comparing screening with a combination of mammography and ultrasonography to screening with mammography alone?
|
higher
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high
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no
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['34406400', '29571797', '26549432', '23465737', '30882843']
| 36,999,589
| 2,023
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{'34406400': {'article_id': '34406400', 'content': 'JAMA Netw OpenJAMA Netw OpenJAMA Netw OpenJAMA Network Open2574-3805American Medical Association34406400837460610.1001/jamanetworkopen.2021.21505zoi210636ResearchOriginal InvestigationFeaturedOnline OnlyOncologyEvaluation of Adjunctive Ultrasonography for Breast Cancer Detection Among Women Aged 40-49 Years With Varying Breast Density Undergoing Screening MammographyA Secondary Analysis of a Randomized Clinical TrialAdjunctive Ultrasonography for Breast Cancer Detection Among Women With Varying Breast DensityAdjunctive Ultrasonography for Breast Cancer Detection Among Women With Varying Breast DensityHarada-ShojiNarumiMDPhD\n1\nSuzukiAkihikoMDPhD\n2\nIshidaTakanoriMDPhD\n1\nZhengYing-FangMDPhD\n1\nNarikawa-ShionoYokoPhD\n1\nSato-TadanoAkikoMDPhD\n1\nOhtaRie\n1\nOhuchiNoriakiMDPhD\n1\n1Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan2Department of Breast and Endocrine Surgery, Tohoku Medical and Pharmaceutical University, Sendai, JapanArticle InformationAccepted for Publication: May 26, 2021.Published: August 18, 2021. doi:10.1001/jamanetworkopen.2021.21505Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Harada-Shoji N et al. JAMA Network Open.Corresponding Author: Noriaki Ohuchi, MD, PhD, Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan (noriaki-ohuchi@med.tohoku.ac.jp).Author Contributions: Dr. Ohuchi had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Harada-Shoji and Suzuki contributed equally to this work.Concept and design: Harada-Shoji, Suzuki, Ishida, Zheng, Narikawa-Shiono, Sato-Tadano, Ohuchi.Acquisition, analysis, or interpretation of data: Harada-Shoji, Suzuki, Ishida, Zheng, Sato-Tadano, Ohta, Ohuchi.Drafting of the manuscript: Harada-Shoji, Suzuki, Ishida, Zheng, Sato-Tadano, Ohuchi.Critical revision of the manuscript for important intellectual content: All authors.Statistical analysis: Harada-Shoji, Suzuki, Zheng, Sato-Tadano, Ohuchi.Obtained funding: Shiono, Ohuchi.Administrative, technical, or material support: Harada-Shoji, Suzuki, Ishida, Narikawa-Shiono, Sato-Tadano, Ohta, Ohuchi.Supervision: Suzuki, Ishida, Ohuchi.Conflict of Interest Disclosures: None reported.Funding/Support: The J-START study was funded by the third Comprehensive Control Research for Cancer, the Ministry of Health, Labor and Welfare of Japan (grants H18-Senryaku-001, H23-Shitei-002, and H25-Shitei-005), and Japan Agency for Medical Research and Development (grants JP17ck0106278h0001, JP18ck0106278h0002, JP19ck0106278h0003, and JPck0106563h0001).Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.Data Sharing Statement: See Supplement 3.Additional Contributions: We thank all those involved in the J-START study, including the participants and the research associates at all the research sites.188202182021188202148e212150516320212652021Copyright 2021 Harada-Shoji N et al. JAMA Network Open.https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the CC-BY License.jamanetwopen-e2121505.pdfKey PointsQuestionDoes the performance of adjunctive ultrasonography for breast cancer detection among women undergoing screening mammography change according to breast tissue density?FindingsIn this secondary analysis of a randomized clinical trial, screening mammography alone demonstrated low sensitivity, whereas adjunctive ultrasonography improved sensitivity both in dense and nondense breasts.MeaningThese findings suggest that adjunctive ultrasonography has the potential to improve the detection of early-stage and invasive cancers across both dense and nondense breasts and to mitigate the flaws of mammographic screening.This secondary analysis of a randomized clinical trial evaluates the performance of adjunctive ultrasonography for breast cancer screening in asymptomatic women aged 40 to 49 years undergoing screening mammography according to differences in breast density.ImportanceMammography has limited accuracy in breast cancer screening. Ultrasonography, when used in conjunction with mammography screening, is helpful to detect early-stage and invasive cancers for asymptomatic women with dense and nondense breasts.ObjectiveTo evaluate the performance of adjunctive ultrasonography with mammography for breast cancer screening, according to differences in breast density.Design, Setting, and ParticipantsThis study is a secondary analysis of the Japan Strategic Anti-cancer Randomized Trial. Between July 2007 and March 2011, asymptomatic women aged 40 to 49 years were enrolled in Japan. The present study used data from cases enrolled from the screening center in Miyagi prefecture during 2007 to 2020. Participants were randomly assigned in a 1:1 ratio to undergo either mammography with ultrasonography (intervention group) or mammography alone (control group). Data analysis was performed from February to March 2020.ExposuresUltrasonography adjunctive to mammography for breast cancer screening regardless of breast density.Main Outcomes and MeasuresSensitivity, specificity, recall rates, biopsy rates, and characteristics of screen-detected cancers and interval breast cancers were evaluated between study groups and for each modality according to breast density.ResultsA total of 76\u2009119 women were enrolled, and data for 19\u2009213 women (mean [SD] age, 44.5 [2.8] years) from the Miyagi prefecture were analyzed; 9705 were randomized to the intervention group and 9508 were randomized to the control group. A total of 11\u2009390 women (59.3%) had heterogeneously or extremely dense breasts. Among the overall group, 130 cancers were found. Sensitivity was significantly higher in the intervention group than the control group (93.2% [95% CI, 87.4%-99.0%] vs 66.7% [95% CI, 54.4%-78.9%]; P\u2009<\u2009.001). Similar trends were observed in women with dense breasts (sensitivity in intervention vs control groups, 93.2% [95% CI, 85.7%-100.0%] vs 70.6% [95% CI, 55.3%-85.9%]; P\u2009<\u2009.001) and nondense breasts (sensitivity in intervention vs control groups, 93.1% [95% CI, 83.9%-102.3%] vs 60.9% [95% CI, 40.9%-80.8%]; P\u2009<\u2009.001). The rate of interval cancers per 1000 screenings was lower in the intervention group compared with the control group (0.5 cancers [95% CI, 0.1-1.0 cancers] vs 2.0 cancers [95% CI, 1.1-2.9 cancers]; P\u2009=\u2009.004). Within the intervention group, the rate of invasive cancers detected by ultrasonography alone was significantly higher than that for mammography alone in both dense (82.4% [95% CI, 56.6%-96.2%] vs 41.7% [95% CI, 15.2%-72.3%]; P\u2009=\u2009.02) and nondense (85.7% [95% CI, 42.1%-99.6%] vs 25.0% [95% CI, 5.5%-57.2%]; P\u2009=\u2009.02) breasts. However, sensitivity of mammography or ultrasonography alone did not exceed 80% across all breast densities in the 2 groups. Compared with the control group, specificity was significantly lower in the intervention group (91.8% [95% CI, 91.2%-92.3%] vs 86.8% [95% CI, 86.2%-87.5%]; P\u2009<\u2009.001). Recall rates (13.8% [95% CI, 13.1%-14.5%] vs 8.6% [95% CI, 8.0%-9.1%]; P\u2009<\u2009.001) and biopsy rates (5.5% [95% CI, 5.1%-6.0%] vs 2.1% [95% CI, 1.8%-2.4%]; P\u2009<\u2009.001) were significantly higher in the intervention group than the control group.Conclusions and RelevanceIn this secondary analysis of a randomized clinical trial, screening mammography alone demonstrated low sensitivity, whereas adjunctive ultrasonography was associated with increased sensitivity. These findings suggest that adjunctive ultrasonography has the potential to improve detection of early-stage and invasive cancers across both dense and nondense breasts. Supplemental ultrasonography should be considered as an appropriate imaging modality for breast cancer screening in asymptomatic women aged 40 to 49 years regardless of breast density.Trial RegistrationNIPH Clinical Trial Identifier: UMIN000000757IntroductionGlobally, breast cancer is the most frequently diagnosed cancer and is the leading cause of cancer-related death in women.1 In Japan, breast cancer is also the leading cancer in women, with breast cancer incidence rates peaking among women aged 45 to 49 years.2 Mammography is the only screening modality that has been shown to be associated with reduced deaths caused by breast cancer. However, the sensitivity of mammography is variable and ranges from as high as 80% to 98% in women with fatty breast tissue to as low as 30% to 48% in women with dense breast tissue.3,4 Because of the limitations of mammography and increase in breast cancer awareness, a few study groups have investigated the performance characteristics of supplementary screening tools, including breast ultrasonography, tomosynthesis, and magnetic resonance imaging.5,6,7,8Breast density has been shown to be independently associated with increased risk of the incidence of and mortality attributable to breast cancer in younger women compared with older women,9,10 with increased risk of interval cancers between screening.6,11,12 Multiple studies6,11,13 have demonstrated that supplemental screening using ultrasonography generates an incremental cancer detection rate at the expense of lower specificity and lower positive predictive values. However, because most studies have focused on women at high risk3,6,7 or those with dense breast tissue but negative mammography findings,3,8,14,15 the performance of ultrasonography as an adjunct to mammography according to differences in breast density classification or among women at average risk remains unknown.4,11,13,16 Consequently, the effect of supplemental screening on breast cancer outcomes is still unclear.17To our knowledge, the Japan Strategic Anti-cancer Randomized Trial (J-START) is the only multicenter randomized clinical trial (RCT) to date to directly compare adjunctive ultrasonography with standard mammography to screen asymptomatic women aged 40 to 49 years.18,19,20 The primary analysis in the original report18 revealed that sensitivity was significantly higher in the intervention group (mammography with ultrasonography) than in the control group (mammography alone), whereas specificity was significantly lower. More cancers were detected in the intervention group than in the control group and were more frequently stages 0 and I. Furthermore, there was a significant reduction in interval cancers.20 However, results according to breast density were not described in detail,21,22 and further studies investigating specific breast density groups have been solicited.21,23 This secondary analysis of the J-START RCT aimed to address issues related to performance of each modality according to differences in breast density.MethodsStudy Design and ParticipantsThe J-START research design of has been published in detail elsewhere.18,19,20 Participants were randomly assigned in a 1:1 ratio to undergo screening by either mammography plus ultrasonography (intervention group) or mammography alone (control group), with or without clinical breast examination, once a year for 2 years.Following a planned protocol (Supplement 1), randomization was centrally conducted by the Japan Clinical Research Support Unit, which is responsible for data management and support for trial operations and independently from Tohoku University. An independent data safety and monitoring board was established to monitor the progress of the trial, which met every 6 months. The study protocol was developed in accordance with the principles of the Declaration of Helsinki. Ethics guidelines for clinical studies issued by the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labor and Welfare of Japan were followed. Ethics approval was granted by Tohoku University School of Medicine Research Ethics Committee and the Japan Cancer Society. Written informed consent was obtained from all participants. This study follows the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline for RCTs.Participants who had a personal history of breast cancer, including in situ cancer, or other cancers in the previous 5 years, or life expectancy of no more than 5 years, were ineligible for the study. Between July 2007 and March 2011, 76\u2009119 asymptomatic women aged 40 to 49 years were enrolled from 42 study sites in 23 of 47 prefectures in Japan. In this study, we used cases enrolled from the screening center in Miyagi prefecture, because we could examine and confirm the breast density.Screening Method and AssessmentStandard mammography and ultrasonography techniques were used at all participating facilities. The physicians and technicians involved in J-START completed a 2-day, 16-hour education program for the standardization of ultrasonography screening for breast cancer.24 Handheld ultrasonography was performed by a technician or by a physician, and later, the ultrasonography image was interpreted by another physician. The ultrasonography examination was performed, on average, in 10 minutes. Mammography acquisition, practice, apparatus, and interpretation were certified by the Japan Central Organization on Quality Assurance of Breast Cancer Screening. Ultrasonography acquisition, practice, apparatus, and interpretation were certified by the Japan Association of Breast and Thyroid Sonology.18Mammography, ultrasonography, and clinical breast examination were performed and interpreted independently from one another, and images were interpreted with double reading by 2 authorized physicians.18,19 The independently assessed findings of mammography, ultrasonography, and clinical examination were classified into 5 categories that are used locally and internationally: 1, no findings; 2, benign; 3, probably benign but further assessment needed; 4, probably malignant; and 5, malignant.19,25,26 Further assessment was considered test-positive if any of the findings were categorized as 3 or higher.For the purpose of this secondary analysis, which was conducted from March to September 2019, 3 expert physicians revaluated mammographic density of the first screening image. All information on screening results, medical interview record, and follow-up data were blinded. By use of the fifth edition of the Breast Imaging Reporting and Data System (BI-RADS),27 we classified visual judgment data as follows: almost entirely fatty; scattered areas of fibroglandular density; heterogeneously dense, which may obscure detection of small masses; and extremely dense, which lowers the sensitivity of mammography screening. In the present article, fatty and scattered are referred to as nondense, and heterogeneously dense and extremely dense are referred to as dense.Follow-upBreast cancers were ascertained by diagnostic assessment of first and second screening results or by a mail survey questionnaire to patients who did not attend the second screening. If data were not available, resident registers were used to identify the patient’s living status. In addition, date linkage with both hospital discharge records and cancer registry databases was used to identify breast cancer diagnosis information. Miyagi prefecture has a sophisticated system of local registration for cancer that contains data on virtually all patients with breast cancer in Miyagi prefecture. Therefore, it was possible to identify interval cancers exactly, and follow-up for this study was updated in February 2020.Screen-detected breast cancers were defined as those categorized as categories 3 to 5 at the first-round screening, and interval cancers were defined as those diagnosed between the first round and the second round of screening for which the initial category had been 1 or 2. Recall was defined as the need for any additional diagnostic testing after screening, including imaging and/or biopsy. The clinical stage and histopathological data were classified by the seventh edition of the TNM classification system.28 The outcome definitions and measure methods were prespecified before data release. Breast cancers diagnosed by the second-round screening were not counted for this study analysis.Statistical AnalysisThe preliminary sample size determination in J-START has been published in detail elsewhere.19,20 We used data from the participants at screening center in Miyagi prefecture. The special feature of the present study was not only to clarify differences between the intervention and control groups, but also differences in breast density composition. Sensitivity, specificity, recall rates, cancer detection rates, interval cancer rates, biopsy rates, and characteristics of screen-detected and interval breast cancers of the first-round screening were examined.All outcomes were analyzed according to the intention-to-treat principle. Performance outcomes were assessed with generalized estimating equations with an exchangeable working correlation matrix and robust SEs. Fisher exact test was used to detect significant differences in the clinical stage and histological findings between cancers detected by ultrasonography and mammography within the intervention group. All tests were 2-sided, and significance was set at P < .05. All statistical analyses were done with SAS statistical software version 9.\u20094 (SAS Institute). Data analysis was performed from February to March 2020.ResultsParticipant CharacteristicsThe baseline characteristics of study participants are shown in Table 1. Of 72\u2009998 asymptomatic women aged 40 to 49 years enrolled in J-START, 19\u2009213 women (9705 in the intervention group and 9508 in the control group) were analyzed in this study because they were residents in Miyagi Prefecture where the cancer registry had been established.Table 1. Baseline Characteristics of Study ParticipantsCharacteristicParticipants, No. (%) (N\u2009=\u200919\u2009213)aTotal intervention group (n\u2009=\u20099705)Total control group (n\u2009=\u20099508)Intervention group by breast densityControl group by breast densityDense (n\u2009=\u20095797)Nondense (n\u2009=\u20093908)bDense (n\u2009=\u20095593)bNondense (n\u2009=\u20093915)bAge, mean (SD), y44.5 (2.9)44.6 (2.9)44.5 (2.9)44.7 (2.9)44.5 (2.9)44.6 (2.9)Ever undergo breast cancer screening No1687 (17.4)1895 (19.9)995 (17.2)692 (17.7)1094 (19.6)801 (20.5) Yes8018 (82.6)7613 (80.1)4802 (82.8)3216 (82.3)4499 (80.4)3114 (79.5)Time since most recent breast cancer screening, mo <12716 (8.9)681 (9.0)441 (9.2)275 (8.6)424 (9.4)257 (8.3) 12-242942 (36.7)2773 (36.4)1759 (36.6)1183 (36.8)1620 (36.0)1153 (37.0) 25-362916 (36.4)2806 (36.9)1710 (35.6)1206 (37.5)1667 (37.1)1139 (36.6) >361391 (17.4)1308 (17.2)859 (17.9)532 (16.5)762 (16.9)546 (17.5) Unknown or data missing53 (0.7)45 (0.6)33 (0.7)20 (0.6)26 (0.6)19 (0.6)Method of most recent breast cancer screening Mammography No2342 (29.2)2191 (28.8)1419 (29.6)923 (28.7)1308 (29.1)883 (28.4) Yes5676 (70.8)5422 (71.2)3383 (70.5)2293 (71.3)3191 (70.9)2231 (71.6) Ultrasonography No6406 (79.9)6221 (81.7)3800 (79.1)2606 (81.0)3647 (81.1)2574 (82.7) Yes1612 (20.1)1392 (18.3)1002 (20.9)610 (19.0)852 (18.9)540 (17.3) Clinical breast examination No356 (4.4)332 (4.4)215 (4.5)141 (4.4)194 (4.3)138 (4.4) Yes7662 (95.6)7281 (95.6)4587 (95.5)3075 (95.6)4305 (95.7)2976 (95.6)Age at menarche, y ≤925 (0.3)25 (0.3)12 (0.2)13 (0.3)9 (0.2)16 (0.4) 10-159559 (98.5)9383 (98.7)5709 (98.5)3850 (98.5)5517 (98.6)3866 (98.8) ≥16121 (1.3)100 (1.1)76 (1.3)45 (1.2)67 (1.2)33 (0.8)Menopausal status Premenopausal7353 (75.8)7285 (76.6)4502 (77.7)2851 (73.0)4399 (78.7)2886 (73.7) Perimenopausal1699 (17.5)1615 (17.0)948 (16.4)751 (19.2)876 (15.7)739 (18.9) Postmenopausal652 (6.7)603 (6.3)347 (6.0)305 (7.8)315 (5.6)288 (7.4) Unknown or data missing1 (<0.1)5 (<0.1)01 (<0.1)3 (<0.1)2 (<0.1)Pregnancies, No. 0813 (8.4)742 (7.8)606 (10.5)207 (5.3)520 (9.3)222 (5.7) 11192 (12.3)1170 (12.3)768 (13.3)424 (36.5)762 (13.6)408 (10.4) 23659 (37.7)3603 (37.9)2233 (38.5)1426 (36.5)2154 (38.5)1449 (37.0) 3-43425 (35.3)3328 (35.0)1875 (38.5)1550 (39.7)1757 (31.4)1571 (40.1) 5-10372 (3.8)400 (4.2)159 (2.7)213 (5.5)212 (3.8)188 (4.8) Unknown or data missing244 (2.5)265 (2.8)156 (2.7)88 (2.3)188 (3.4)77 (2.0)Pregnancies delivered, No. Nulliparous130 (1.5)124 (1.5)96 (1.9)34 (0.9)85 (1.7)39 (1.1) 11427 (16.5)1423 (16.7)924 (18.4)503 (13.9)929 (19.0)494 (13.7) 24499 (52.0)4448 (52.3)2690 (18.4)1809 (50.1)2625 (53.7)1823 (50.4) 32270 (26.3)2202 (25.9)1191 (23.7)1079 (29.9)1113 (22.8)1089 (30.1) 4-8291 (3.4)257 (3.0)118 (2.3)173 (4.8)105 (2.2)152 (4.2) Unknown or data missing31 (0.4)47 (0.6)16 (2.3)15 (0.4)28 (0.6)19 (0.5)Age at first parturition, y <20102 (1.2)80 (0.9)58 (1.2)44 (1.2)44 (0.9)36 (1.0) 20-241626 (18.8)1470 (17.3)897 (17.8)729 (20.2)783 (16.0)687 (19.0) 25-293245 (37.5)3184 (37.5)1901 (37.8)1344 (37.2)1811 (37.1)1373 (38.0) 30-391882 (21.8)2022 (23.8)1132 (22.5)750 (20.8)1239 (25.4)783 (21.7) 40-4948 (0.6)47 (0.6)36 (0.7)12 (0.3)27 (0.6)20 (0.6) Unknown or data missing1745 (20.2)1698 (20.0)1011 (20.1)734 (20.3)981 (20.1)717 (19.8)Ever breastfed children Yes7754 (90.9)7570 (90.4)4507 (91.1)3247 (90.6)4338 (90.4)3232 (90.4) No758 (8.9)792 (9.5)428 (8.7)330 (9.2)455 (9.5)337 (9.4) Unknown or data missing21 (0.3)16 (0.2)15 (0.3)6 (0.2)8 (0.2)8 (0.2)First-degree female relatives with breast cancer, No. 09214 (94.9)9024 (94.9)5503 (94.9)3711 (95.0)5299 (94.7)3725 (95.2) 1485 (5.0)477 (5.0)291 (5.0)194 (5.0)289 (5.2)188 (4.8) >16 (<0.1)7 (<0.1)3 (<0.1)3 (<0.1)5 (<0.1)2 (<0.1)Ever had breast surgery227 (1.2)214 (1.1)170 (1.8)57 (0.6)140 (1.5)74 (0.8)Ever had benign neoplasm154 (0.8)143 (0.7)121 (1.3)33 (0.3)97 (1.0)46 (0.5)Ever had breast inflammation71 (0.4)70 (0.4)46 (0.5)25 (0.3)45 (0.5)25 (0.3)aPercentages might not total 100% because of rounding.bThe 2 least dense categories (almost entirely fatty and scattered fibroglandular tissues) are referred to as nondense, conventionally, the 2 most dense categories (heterogeneously dense and extremely dense) are referred to as dense.An overview of participant flow is shown in the eFigure in Supplement 2. A total of 19\u2009280 participants were enrolled and randomly allocated either study arms. Eligibility was assessed for inclusion in the analyses; 26 participants in the intervention group and 41 participants in the control group were excluded because of ineligibility and were withdrawn. Of 19\u2009213 participants, 11\u2009390 (59.3%) were categorized as having dense breast tissue (ie, heterogeneously or extremely dense) (eTable in Supplement 2).The mean (SD) age of participants was 44.5 (2.8) years (Table 1). A total of 975 participants (5.0%) reported a history of breast cancer in first-degree female relatives, and 297 participants (1.5%) reported having ever had benign breast diseases. There were no differences in demographic characteristics or risk factors between the intervention and control groups. On the other hand, the percentages of participants who had never been pregnant were significantly higher among women with dense breasts than among women with nondense breasts in both the intervention group (10.5% [95% CI, 9.9%-11.6%] vs 5.3% [95% CI, 4.7%-6.1%]; P\u2009<\u2009.001) and control group (9.3% [95% CI, 8.8%-10.4%] vs 5.7% [95% CI, 5.1%-6.5%] P\u2009<\u2009.001).Screening PerformanceTable 2 and Table 3 summarize the screening performance. In 19\u2009213 women, 130 cancers were found. More screen-detected cancers were found in the intervention group than in the control group (68 cancers [7.0 cancers per 1000 screenings; 95% CI, 5.3 to 8.7 cancers per 1000 screenings] vs 38 cancers [4.0 cancers per 1000 screenings; [95% CI, 2.7 to 5.3 cancers per 1000 screenings]; P\u2009=\u2009.004). Among women with dense breasts, there were more screen-detected cancer in the intervention group than the control group (41 cancers [7.1 cancers per 1000 screenings; 95% CI, 4.9 to 9.2 cancers per 1000 screenings] vs 24 cancers [4.3 cancers per 1000 screenings; 95% CI, 2.6 to 6.0 cancers per 1000 screenings]; P\u2009=\u2009.04). A similar tendency is seen in women with nondense breasts (27 cancers [6.9 cancers per 1000 screenings; 95% CI, 4.3 to 9.5 cancers per 1000 screenings] in the intervention group vs 14 cancers [3.6 cancers per 1000 screenings; 95% CI, 1.7 to 5.4 cancers per 1000 screenings] in the control group; P\u2009=\u2009.04). Five interval cancers (0.5 cancers per 1000 screenings; 95% CI, 0.1 to 1.0 cancers per 1000 screenings) were detected in the intervention group compared with 19 (2.0 cancers per 1000 screenings; 95% CI, 1.1 to 2.9 cancers per 1000 screenings) in the control group (P\u2009=\u2009.004), with a significant difference between the 2 groups among women with dense breasts (3 cancers [0.5 cancers per 1000 screenings; 95% CI, −0.1 to 1.1 cancers per 1000 screenings] vs 10 cancers [1.8 cancers per 1000 screenings; 95% CI, 0.7 to 2.9 cancers per 1000 screenings]; P\u2009=\u2009.04) as well as women with nondense breasts (2 cancers [0.5 cancers per 1000 screenings; 95% CI, −0.2 to 1.2 cancers per 1000 screenings] vs 9 cancers [2.3 cancers per 1000 screenings; 95% CI, 0.8 to 3.8 cancers per 1000 screenings]; P\u2009=\u2009.03). Sensitivity in the intervention group was higher than that in the control group (93.2% [95% CI, 87.4% to 99.0%] vs 66.7% [95% CI, 54.4% to 78.9%]; P\u2009<\u2009.001) for both dense breasts and nondense breasts. In contrast, specificity was significantly lower in the intervention group than the control group (86.8% [95% CI, 86.2% to 87.5%] vs 91.8% [95% CI, 91.2% to 92.3%]; P\u2009<\u2009.001) regardless of breast tissue density (Table 2).Table 2. Performance According to Breast Density CategoryVariableTotal participants (N\u2009=\u200919 213)Dense breastsaNondense breastsaIntervention group (n\u2009=\u20099705)Control group (n\u2009=\u20099508)P valueIntervention group (n\u2009=\u20095797)Control group (n\u2009=\u20095593)P valueIntervention group (n\u2009=\u20093908)Control group (n\u2009=\u20093915)P valueScreen-detected cancers No. of cancers/total No.68/970538/9508.00441/579724/5593.0427/390814/3915.04 No. of cancers per 1000 screenings (95% CI)7 (5.3 to 8.7)4 (2.7 to 5.3)7.1 (4.9 to 9.2)4.3 (2.6 to 6.0)6.9 (4.3 to 9.5)3.6 (1.7 to 5.4)Interval cancers No. of cancers/total No.5/970519/9508.0043/579710/5593.042/39089/3915.03 No. of cancers per 1000 screenings (95% CI)0.5 (0.1 to 1.0)2.0 (1.1 to 2.9)0.5 (−0.1 to 1.1)1.8 (0.7 to 2.9)0.5 (−0.2 to 1.2)2.3 (0.8 to 3.8)Sensitivity, % (95% CI)93.2 (87.4 to 99.0)66.7 (54.4 to 78.9)<.00193.2 (85.7 to 100)70.6 (55.3 to 85.9)<.00193.1 (83.9 to 102.3)60.9 (40.9 to 80.8)<.001Specificity, % (95% CI)86.8 (86.2 to 87.5)91.8 (91.2 to 92.3)<.00185.4 (84.5 to 86.3)91.7 (91.0 to 92.4)<.00189.0 (88.0 to 90.0)91.9 (91.1 to 92.8)<.001aThe 2 least dense categories (almost entirely fatty and scattered fibroglandular tissues) are referred to as nondense, and the 2 most dense categories (heterogeneously dense and extremely dense) are referred to as dense.Table 3. Sensitivity of Each Modality According to Breast Densities and Study GroupsGroup and modalityCancers, No. (%) [95% CI]P valueDense breastsaNondense breastsaIntervention group (n\u2009=\u20099705) Screen-detected cancers (n\u2009=\u200968) Mammography positive, ultrasonography positive or negative, CBE positive or negative24 (54.6) [39.8-69.3]20 (69.0) [52.1-85.8].20 Mammography positive or negative, ultrasonography positive, CBE positive or negative29 (65.9) [51.9-79.9]15 (51.7) [33.5-69.9].22 Mammography positive, ultrasonography positive, CBE positive or negative12 (27.3) [14.1-40.3]8 (27.6) [11.3-43.9].98 Mammography positive or negative, US positive or negative, CBE positive10 (22.7) [10.3-35.1]10 (34.5) [17.2-51.8].28 Only mammography positive12 (27.3) [14.1-40.3]12 (41.4) [23.5-59.3].21 Only ultrasonography positive17 (38.6) [24.3-53.0]7 (24.1) [8.6-39.7].18 Only CBE positive0 (NA)0 (NA)NA Any positive41 (93.2) [85.7-100.0]27 (93.1) [83.9-102.3].98 Interval cancers (n\u2009=\u20095), all modalities negative3 (NA)2 (NA)NAControl group (n\u2009=\u20099508) Screen-detected cancers (n\u2009=\u200938) Mammography positive, CBE positive or negative22 (64.7) [48.6-80.8]14 (60.9) [40.9-80.8].77 Mammography positive or negative, CBE positive9 (26.5) [11.6-41.3]6 (26.1) [8.1-44.0].97 Only mammography positive15 (44.1) [27.3-60.8]8 (34.8) [15.3-54.3].48 Only CBE positive2 (NA)0 (NA)NA Either mammography or CBE positive24 (70.6) [55.3-85.9]14 (60.9) [40.9-80.8].45 Interval cancers (n\u2009=\u200919), all modalities negative10 (NA)9 (NA)NAAbbreviations: CBE, clinical breast examination; NA, not applicable.aThe 2 least dense categories (almost entirely fatty and scattered fibroglandular tissues) are referred to as nondense, and the 2 most dense categories (heterogeneously dense and extremely dense) are referred to as dense.Table 3 summarizes sensitivity of each modality according to density. Neither modality exceeded 80% sensitivity alone (Table 3). In the intervention group, sensitivity of mammography was 69.0% (95% CI, 52.1%-85.8%) in nondense breasts and 54.6% (95% CI, 39.8%-69.3%) in dense breasts, whereas the sensitivity of mammography with adjunct ultrasonography was 93.1% (95% CI, 83.9%-102.3%) in nondense breasts and 93.2% (95% CI, 85.7%-100.0%) in dense breasts. The sensitivity of mammography was higher in women with dense breasts than those with nondense breasts (70.6% [95% CI, 55.3%-85.9%] vs 60.9% [95% CI, 40.9%-80.8%]).The frequency of clinical stage 0 and I breast cancer was 85.4% in dense breasts and 88.9% in nondense breasts within the intervention group, whereas in the control group, the frequency was 79.2% for dense breasts and 64.3% for nondense breasts. The differences in stage between the 2 groups were similar for dense and nondense breasts (Table 4). Within the intervention group, the rate of invasive cancers detected by ultrasonography alone was significantly higher than that for mammography alone, in both dense breasts (82.4% [95% CI, 56.6%-96.2%] vs 41.7% [95% CI, 15.2%-72.3%]; P = .02) and nondense breasts (85.7% [95% CI, 42.1%-99.6%] vs 25% [95% CI, 5.5%-57.2%]; P = .02). In the control group, however, the clinical stage and each pathological finding of invasive cancers detected by mammography alone were not meaningfully different between dense and nondense breasts (Table 4).Table 4. Clinical Stage and Histological Findings of Screen-Detected Cancers and Interval Cancers According to Breast DensityPatients, No. (%)aIntervention groupControl groupScreen-detected cancers (n\u2009=\u200968)Interval cancers (n\u2009=\u20095)Screen-detected cancers (n\u2009=\u200938)Interval cancers (n\u2009=\u200919)Any modality positive (n\u2009=\u200968)Only mammography positive (n\u2009=\u200924)Only US positive (n\u2009=\u200924)Only CBE positive (n\u2009=\u20090)Either positive (n\u2009=\u200938)Only mammography positive (n\u2009=\u200923)Only CBE positive (n\u2009=\u20092)Extremely and heterogeneously denseb Breast cancers, No.411217032415210 Clinical stagec 0 and I35 (85.4)12 (100)2 (76.5)01 (33.3)19 (79.2)15 (100)1 (50)9 (90) II or higher6 (14.6)04 (23.5)02 (66.7)5 (20.8)01 (50)1 (10) Histopathological cancer type Noninvasived13 (31.7)7 (58.3)3 (17.7)006 (25)6 (40)03 (30) Invasivee28 (68.3)5 (41.7)14 (82.4)03 (100)18 (75)9 (60)2 (100)7 (70) Size of invasive tumors on histological examination, mm <1011 (39.3)5 (100)4 (28.6)01 (33.3)9 (50)6 (66.7)1 (50)1 (14.3) 11-2015 (53.6)08 (57.1)004 (22.2)2 (22.2)1 (50)4 (57.1) >202 (7.1)02 (14.3)02 (66.7)4 (22.2)000 Data missing000001 (5.6)1 (11.1)02 (28.6) Node status of invasive cancers Negative23 (82.1)5 (100)11 (78.6)01 (33.3)15 (83.3)8 (88.9)2 (100)6 (85.7) Positive5 (17.9)03 (21.4)02 (66.7)2 (11.1)000 Data missing000001 (5.6)1 (11.1)01 (14.3)Scattered fibroglandular tissue and almost entirely fattyb Breast cancers, No.271270214809 Clinical stagec 0 and I24 (88.9)11 (91.7)6 (86.7)01 (50)9 (64.3)5 (62.5)09 (100) II or higher3 (11.1)1 (8.3)1 (14.3)01 (50)5 (35.7)3 (37.5)00 Histopathological cancer type Noninvasived13 (48.2)9 (75)1 (14.3)003 (21.4)3 (37.5)02 (22.2) Invasivee14 (51.9)3 (25)6 (85.7)02 (100)11 (78.6)5 (62.5)07 (77.8) Size of invasive tumors on histological examination, mm ≤105 (35.7)04 (66.7)01 (50)4 (36.4)3 (60)02 (28.6) 11-209 (64.3)3 (100)2 (33.3)005 (45.5)1 (20)04 (57.1) >2000001 (50)2 (18.2)1 (20)00 Data missing000000001 (14.3) Node status of invasive cancers Negative11 (78.6)2 (66.7)5 (83.3)02 (100)6 (54.6)3 (60)06 (85.7) Positive3 (21.4)1 (33.3)1 (16.7)005 (45.5)2 (40)00 Data missing000000001 (14.3)Abbreviations: CBE, clinical breast examination; US, ultrasonography.aPercentages might not total 100% because of rounding.bNo cancer was found in the category of almost entirely fatty.cBased on the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision.dIncludes ductal carcinoma in situ and lobular carcinoma in situ.eIncludes invasive ductal carcinoma and special type.Data of screening recalls and biopsy are presented in Table 5. Of 2147 participants who were recalled, 734 underwent biopsies. The recall rates (13.8% [95% CI, 13.1%-14.5%] vs 8.6% [95% CI, 8.0%-9.1%]; P\u2009<\u2009.001) and biopsy rates (5.5% [95% CI, 5.1%-6.0%] vs 2.1% [95% CI, 1.8%-2.4%]; P\u2009<\u2009.001) were significantly greater in the intervention group vs the control group. Recall rates for mammography alone were similar in the 2 groups regardless of breast density. In the intervention group, the recall rate by ultrasonography alone was higher for women with dense breasts than for women with nondense breasts (7.0% vs 3.9%), and the same was true for the biopsy rate (4.4% vs 2.6%).Table 5. Recall Rate and Biopsy Rate of Each Modality According to Study GroupVariableParticipants, No. (%)Intervention groupControl groupTotal (n\u2009=\u20099705)Dense breastsaTotal (n\u2009=\u20099508)Dense breastsaYes (n\u2009=\u20095797)No (n\u2009=\u20093908)Yes (n\u2009=\u20095593)No (n\u2009=\u20093915)Recalled after first-round screening Any modality positive1334 (13.8)880 (15.2)454 (11.6)813 (8.6)485 (8.7)328 (8.4) Only mammography positive606 (6.2)356 (6.1)250 (6.4)663 (7.0)374 (6.7)290 (7.4) Only ultrasonography positive558 (5.8)404 (7.0)154 (3.9)NANANA Only CBE positive59 (0.6)44 (0.8)15 (0.4)85 (0.9)69 (1.2)16 (0.4)Biopsy rateb Biopsy done538 (5.5)360 (6.2)178 (4.6)196 (2.1)127 (2.3)69 (1.8) Only mammography positive107 (1.1)56 (1.0)51 (1.3)128 (1.4)77 (1.4)51 (1.3) Only ultrasonography positive355 (3.7)255 (4.4)100 (2.6)NANANA Only CBE positive7 (<0.1)4 (<0.1)3 (<0.1)27 (0.3)22 (0.4)5 (<0.1)Abbreviations: CBE, clinical breast examination; NA, not applicable.aThe 2 least dense categories (almost entirely fatty and scattered fibroglandular tissues) are referred to as nondense, and the 2 most dense categories (heterogeneously dense and extremely dense) are referred to as dense.bIndicates a need for biopsy on first-round screening. When clinically indicated, participants might have undergone 2 or more types of biopsy.DiscussionTo our knowledge, J-START is the first large-scale RCT to assess the performance of ultrasonography screening in combination with mammography for breast cancer in women aged 40 to 49 years with average risk. Now, the question is raised as to whether adjunctive ultrasonography improves the balance of breast cancer screening in women with different breast densities. In the present secondary analysis, we further evaluated the performance of each screening modality (ie, mammography and ultrasonography) according to breast density, which has been shown to be a factor independently associated with increased risk of breast cancer across age group.9 Heterogeneity of tissue density is associated with not only increased cancer risk but also complications of mammographic interpretation; even small amounts of dense tissue can mask cancer. The fifth edition of the BI-RADS lexicon for breast density27 recommends that breast imagers assign breast composition descriptors that better convey whether there are dense areas of tissue that could mask or obscure cancer. In this respect, a major strength of this study is that we used the fifth edition of the BI-RADS lexicon to assess breast density and conducted double readings to reduce variation, which provided reproducible estimates and verification of density assessment quality. With awareness of these issues (breast density and lower screening sensitivity of mammography) as the starting point, we analyzed the performance of adjunctive ultrasonography compared with mammography in breasts with different densities. The principal findings between the intervention and control groups were consistent with those of the J-START,20 as adjunct ultrasonography to mammography exhibited higher sensitivity and lower specificity than mammography alone, with more cancers detected, more cancers that were stages 0 and I, and lower numbers of interval cancers than in the control group.20 Adjunct ultrasonography improved the sensitivity and detection rate of small, early-stage (stage 0 and stage I) and invasive cancers, consistent with other studies.3,7,11In addition, this study revealed that adjunctive ultrasonography improved the detection of early invasive cancers not only in dense breasts but also in nondense breasts. Moreover, we found ultrasonography to be potentially superior to mammography in detecting early and node-negative invasive cancers in both dense and nondense breasts.It should be noted that sensitivity of mammography alone and that of ultrasonography alone were both lower than the sensitivity of the combination of these modalities. In this study, the sensitivity of mammography was higher in women with dense breasts than those with nondense breasts (70.6% vs 60.9%). One of the explanations is that the sensitivity of mammography did not depend on breast density, because even nondense tissue might hide or mask cancer in women aged 40 to 49 years. However, sensitivity was improved when ultrasonography was used as an adjunct to mammography, suggesting that adjunctive ultrasonography has an advantage in breast cancer screening for young women regardless of dense breasts. Taking these results into account, we can conclude that breast density should not be the sole criterion for deciding whether supplemental imaging is justified. Because of the limitations of mammography in breast density, studies have investigated performance of supplementary screening tools, including tomosynthesis and magnetic resonance imaging.5,6,7,8 Tomosynthesis is unlikely to be an optimal solution, and magnetic resonance imaging is expensive and not easy to access for screening.With regard to the harms associated with breast cancer screening, supplemental ultrasonography had lower specificity and higher recall and biopsy rates than mammography alone, which are major limitations of screening ultrasonography.14,29 Ultrasonography and mammography findings were interpreted independently according to the J-START protocol, which consequently increased recall and biopsy rates and decreased specificity. In addition, ultrasonography-guided histological examination using core-needle biopsy is easy to perform and more accurate for diagnosing the lesion, which suggests that it is the main reason for the increased biopsy rate. A study30 of the European mammography screening programs showed overall further assessment rates to be 9.3% and 4.0% for initial and subsequent mammography screening tests, respectively. The overall rates of needle biopsy rates were 2.2% and 1.1%, respectively.30 A previous study31 in Japan reported that recall rate of mammography screening among 33\u2009924 women in their 40s was 9.9%. The recall rate of the first round in J-START31 was 8.8% in the control group (mammography only), which is within the accepted range.LimitationsThe sensitivity and specificity in this study were calculated with the data from the first-round screening. Our findings cannot be extended beyond the first round, because characteristics of breast cancer would differ between the first and later rounds of screening.7,12 Except for women at increased and high risk, estimates indicate a nearly 40% breast cancer mortality reduction when screening women annually starting at age 40 years.32 Improving cancer detection in younger and middle-aged women is crucial for increasing the effectiveness of breast cancer screening.23 To evaluate screening benefits avoiding lead time bias, and to determine balance of benefits and harms, further investigation providing hard evidence about the contributions of adjunctive ultrasonography screening to breast cancer mortality is necessary.ConclusionsIn this secondary analysis of an RCT, adjunctive ultrasonography had good screening balance with mammography regardless of breast density, detecting early-stage and invasive malignant lesions for asymptomatic women with average risk of breast cancer. Thus, adjunctive ultrasonography should be considered as an optimal solution in young women with average risk.References1TorreLA, BrayF, SiegelRL, FerlayJ, Lortet-TieulentJ, JemalA. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87-108. doi:10.3322/caac.21262256517872HoriM, MatsudaT, ShibataA, KatanodaK, SobueT, NishimotoH; Japan Cancer Surveillance Research Group. Cancer incidence and incidence rates in Japan in 2009: a study of 32 population-based cancer registries for the Monitoring of Cancer Incidence in Japan (MCIJ) project. Jpn J Clin Oncol. 2015;45(9):884-891. doi:10.1093/jjco/hyv088261424373KolbTM, LichyJ, NewhouseJH. Comparison of the performance of screening mammography, physical examination, and breast US and evaluation of factors that influence them: an analysis of 27,825 patient evaluations. Radiology. 2002;225(1):165-175. doi:10.1148/radiol.2251011667123550014BuchbergerW, Geiger-GritschS, KnappR, GautschK, OberaignerW. Combined screening with mammography and ultrasound in a population-based screening program. Eur J Radiol. 2018;101:24-29. doi:10.1016/j.ejrad.2018.01.022295717975TagliaficoAS, CalabreseM, MariscottiG, . Adjunct screening with tomosynthesis or ultrasound in women with mammography-negative dense breasts: interim report of a prospective comparative trial. J Clin Oncol. 2016;34(16):1882-1888. doi:10.1200/JCO.2015.63.4147269620976BergWA, BlumeJD, CormackJB, ; ACRIN 6666 Investigators. Combined screening with ultrasound and mammography vs mammography alone in women at elevated risk of breast cancer. JAMA. 2008;299(18):2151-2163. doi:10.1001/jama.299.18.2151184777827BergWA, BandosAI, MendelsonEB, LehrerD, JongRA, PisanoED. Ultrasound as the primary screening test for breast cancer: analysis from ACRIN 6666. J Natl Cancer Inst. 2015;108(4):djv367. doi:10.1093/jnci/djv367267121108MelnikowJ, FentonJJ, WhitlockEP, . Supplemental screening for breast cancer in women with dense breasts: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2016;164(4):268-278. doi:10.7326/M15-1789267570219BoydNF, GuoH, MartinLJ, . Mammographic density and the risk and detection of breast cancer. N Engl J Med. 2007;356(3):227-236. doi:10.1056/NEJMoa0627901722995010CheckaCM, ChunJE, SchnabelFR, LeeJ, TothH. The relationship of mammographic density and age: implications for breast cancer screening. AJR Am J Roentgenol. 2012;198(3):W292-W295. doi:10.2214/AJR.10.60492235802811CorsettiV, HoussamiN, GhirardiM, . Evidence of the effect of adjunct ultrasound screening in women with mammography-negative dense breasts: interval breast cancers at 1 year follow-up. Eur J Cancer. 2011;47(7):1021-1026. doi:10.1016/j.ejca.2010.12.0022121196212BergWA, ZhangZ, LehrerD, ; ACRIN 6666 Investigators. Detection of breast cancer with addition of annual screening ultrasound or a single screening MRI to mammography in women with elevated breast cancer risk. JAMA. 2012;307(13):1394-1404. doi:10.1001/jama.2012.3882247420313DongH, HuangY, SongF, . Improved performance of adjunctive ultrasonography after mammography screening for breast cancer among Chinese females. Clin Breast Cancer. 2018;18(3):e353-e361. doi:10.1016/j.clbc.2017.07.0142888701014CorsettiV, HoussamiN, FerrariA, . Breast screening with ultrasound in women with mammography-negative dense breasts: evidence on incremental cancer detection and false positives, and associated cost. Eur J Cancer. 2008;44(4):539-544. doi:10.1016/j.ejca.2008.01.0091826735715YoukJH, KimEK, KimMJ, KwakJY, SonEJ. Performance of hand-held whole-breast ultrasound based on BI-RADS in women with mammographically negative dense breast. Eur Radiol. 2011;21(4):667-675. doi:10.1007/s00330-010-1955-82085310816HooleyRJ, GreenbergKL, StackhouseRM, GeiselJL, ButlerRS, PhilpottsLE. Screening US in patients with mammographically dense breasts: initial experience with Connecticut Public Act 09-41. Radiology. 2012;265(1):59-69. doi:10.1148/radiol.121206212272350117SiuAL; US Preventive Services Task Force. Screening for breast cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2016;164(4):279-296. doi:10.7326/M15-28862675717018IshidaT, SuzukiA, KawaiM, . A randomized controlled trial to verify the efficacy of the use of ultrasonography in breast cancer screening aged 40-49 (J-START): 76 196 women registered. Jpn J Clin Oncol. 2014;44(2):134-140. doi:10.1093/jjco/hyt1992440783519OhuchiN, IshidaT, KawaiM, NarikawaY, YamamotoS, SobueT. Randomized controlled trial on effectiveness of ultrasonography screening for breast cancer in women aged 40-49 (J-START): research design. Jpn J Clin Oncol. 2011;41(2):275-277. doi:10.1093/jjco/hyq2142113129520OhuchiN, SuzukiA, SobueT, ; J-START investigator groups. Sensitivity and specificity of mammography and adjunctive ultrasonography to screen for breast cancer in the Japan Strategic Anti-cancer Randomized Trial (J-START): a randomised controlled trial. Lancet. 2016;387(10016):341-348. doi:10.1016/S0140-6736(15)00774-62654710121BergWA. Current status of supplemental screening in dense breasts. J Clin Oncol. 2016;34(16):1840-1843. doi:10.1200/JCO.2015.65.86742696209622UematsuT. The need for supplemental breast cancer screening modalities: a perspective of population-based breast cancer screening programs in Japan. Breast Cancer. 2017;24(1):26-31. doi:10.1007/s12282-016-0707-22725934223ThigpenD, KapplerA, BremR. The role of ultrasound in screening dense breasts: a review of the literature and practical solutions for implementation. Diagnostics (Basel). 2018;8(1):E20. doi:10.3390/diagnostics80100202954753224TohnoE, TakahashiH, TamadaT, FujimotoY, YasudaH, OhuchiN. Educational program and testing using images for the standardization of breast cancer screening by ultrasonography. Breast Cancer. 2012;19(2):138-146. doi:10.1007/s12282-010-0221-x2092473325OhuchiN, YoshidaK, KimuraM, . Improved detection rate of early breast cancer in mass screening combined with mammography. Jpn J Cancer Res. 1993;84(7):807-812. doi:10.1111/j.1349-7006.1993.tb02048.x839656926OhuchiN, YoshidaK, KimuraM, . Comparison of false negative rates among breast cancer screening modalities with or without mammography: Miyagi trial. Jpn J Cancer Res. 1995;86(5):501-506. doi:10.1111/j.1349-7006.1995.tb03084.x779032327American College of Radiology. ACR BI-RADS fifth edition. Published 2013. Accessed July 15, 2021. https://www.acr.org/-/media/ACR/Files/RADS/BI-RADS/BIRADS-Reference-Card.pdf28SobinLH, GospodarowiczML, WittekindC, eds. TNM Classification of Malignant Tumours. 7th ed. Wiley;2011.29SpragueBL, StoutNK, SchechterC, . Benefits, harms, and cost-effectiveness of supplemental ultrasonography screening for women with dense breasts. Ann Intern Med. 2015;162(3):157-166. doi:10.7326/M14-06922548655030HofvindS, PontiA, PatnickJ, ; EUNICE Project and Euroscreen Working Groups. False-positive results in mammographic screening for breast cancer in Europe: a literature review and survey of service screening programmes. J Med Screen. 2012;19(1)(suppl):57-66. doi:10.1258/jms.2012.0120832297281131KasaharaY, KawaiM, TsujiI, . Harms of screening mammography for breast cancer in Japanese women. Breast Cancer. 2013;20(4):310-315. doi:10.1007/s12282-012-0333-62228216432ArleoEK, HendrickRE, HelvieMA, SicklesEA. Comparison of recommendations for screening mammography using CISNET models. Cancer. 2017;123(19):3673-3680. doi:10.1002/cncr.3084228832983Supplement 1.\nTrial Protocol and Statistical Analysis Plan\nClick here for additional data file.Supplement 2.eFigure. Trial ProfileeTable. Distribution of Mammography Density Based on 5th Edition BI-RADS Density CategoriesClick here for additional data file.Supplement 3.\nData Sharing Statement\nClick here for additional data file.', 'title': 'Evaluation of Adjunctive Ultrasonography for Breast Cancer Detection Among Women Aged 40-49 Years With Varying Breast Density Undergoing Screening Mammography: A Secondary Analysis of a Randomized Clinical Trial.', 'date': '2021-08-19'}, '29571797': {'article_id': '29571797', 'content': 'To compare the performance of screening with mammography combined with ultrasound versus mammography alone in women at average risk for breast cancer.\n66,680 women underwent physician-performed ultrasound as an adjunct to screening mammography. Histological results and follow-up at one year were used as reference standard for sensitivity. Main outcome measures were cancer detection rate, sensitivity, recall rate, biopsy rate, and positive predictive value of biopsy for combined screening with mammography plus ultrasound versus mammography alone.\nThe overall sensitivity of mammography only was 61.5% in women with dense breasts and 86.6% in women with non-dense breasts. The sensitivity of mammography plus ultrasound combined was 81.3% in women with dense breasts and 95.0% in women with non-dense breasts. Adjunctive ultrasound increased the recall rate from 10.5 to 16.5 per 1000 women screened, and increased the biopsy rate from 6.3 to 9.3 per 1000 women screened. The positive predictive value of biopsy was 55.5% (95% CI 50.6%-60.3%) for mammography alone and 43.3 (95% CI 39.4%-47.3%) for combined mammography plus ultrasound.\nSupplemental ultrasound improves cancer detection in screening of women at average risk for breast cancer. Recall rates and biopsy rates can be kept within acceptable limits.', 'title': 'Combined screening with mammography and ultrasound in a population-based screening program.', 'date': '2018-03-25'}, '26549432': {'article_id': '26549432', 'content': 'To determine which modalities [2D mammography (2D), digital breast tomosynthesis (DBT), whole breast sonography (WBS)] are optimal for screening depending on breast density.\nInstitutional retrospective cohort study of 2013 screening mammograms (16,789), sorted by modalities and density.\nCancer detection is increased by adding WBS to 2D (P=.02) for the overall study population. Recall rate was lowest with 2D+DBT (10.2%, P<.001) and highest with 2D+DBT+WBS (23.6%, P<.001) for the overall study population as well.\nWomen with dense and nondense breasts benefit from reduced recall rate with the addition of DBT; however, this benefit is negated with the addition of WBS.', 'title': '2D mammography, digital breast tomosynthesis, and ultrasound: which should be used for the different breast densities in breast cancer screening?', 'date': '2015-11-10'}, '23465737': {'article_id': '23465737', 'content': 'To determine whether adding screening ultrasonography to screening mammography can reduce patient recall rates and increase cancer detection rates.\nWe analyzed the results of mammography and ultrasonography breast screenings performed at the Total Health Evaluation Center Tsukuba, Japan, between April 2011 and March 2012. We also reviewed the modalities and results of diagnostic examinations from women with mammographic abnormalities who visited the Tsukuba Medical Center Hospital for further testing.\nOf 11,753 women screened, cancer was diagnosed in 10 (0.22%) of the 4529 participants who underwent mammography alone, 23 (0.37%) of the 6250 participants who underwent ultrasonography alone, and 5 (0.51%) of the 974 participants who underwent mammography and ultrasonography. The recall rate due to mammographic abnormalities was 4.9% for women screened only with mammography and 2.6% for those screened with both modalities. The cancer detection rate was 0.22% for women screened only with mammography (positive predictive value, 4.5%) and 0.31% for those screened with both modalities (positive predictive value, 12.0%). Of the 211 lesions presenting as mammographic abnormalities investigated further, diagnostic ultrasonography found no abnormalities in 63 (29.9%) and benign findings in 69 (33.7%). The rest 36.4% needed mammography, cytological or histological examinations or follow-up in addition to diagnostic ultrasonography.\nIt is possible to reduce the recall rate in screening mammography by combining mammography and ultrasonography for breast screening.', 'title': 'Effect of adding screening ultrasonography to screening mammography on patient recall and cancer detection rates: a retrospective study in Japan.', 'date': '2013-03-08'}, '30882843': {'article_id': '30882843', 'content': 'Whole-breast ultrasonography has been advocated to supplement screening mammography to improve outcomes in women with dense breasts.\nTo determine the performance of screening mammography plus screening ultrasonography compared with screening mammography alone in community practice.\nObservational cohort study. Two Breast Cancer Surveillance Consortium registries provided prospectively collected data on screening mammography with vs without same-day breast ultrasonography from January 1, 2000, to December 31, 2013. The dates of analysis were March 2014 to December 2018. A total of 6081 screening mammography plus same-day screening ultrasonography examinations in 3386 women were propensity score matched 1:5 to 30\u202f062 screening mammograms without screening ultrasonography in 15\u202f176 women from a sample of 113\u202f293 mammograms. Exclusion criteria included a personal history of breast cancer and self-reported breast symptoms.\nScreening mammography with vs without screening ultrasonography.\nCancer detection rate and rates of interval cancer, false-positive biopsy recommendation, short-interval follow-up, and positive predictive value of biopsy recommendation were estimated and compared using log binomial regression.\nScreening mammography with vs without ultrasonography examinations was performed more often in women with dense breasts (74.3% [n\u2009=\u20094317 of 5810] vs 35.9% [n\u2009=\u200939\u202f928 of 111\u202f306] in the overall sample), in women who were younger than 50 years (49.7% [n\u2009=\u20093022 of 6081] vs 31.7% [n\u2009=\u200916\u202f897 of 112\u202f462]), and in women with a family history of breast cancer (42.9% [n\u2009=\u20092595 of 6055] vs 15.0% [n\u2009=\u200916\u202f897 of 112\u202f462]). While 21.4% (n\u2009=\u20091154 of 5392) of screening ultrasonography examinations were performed in women with high or very high (≥2.50%) Breast Cancer Surveillance Consortium 5-year risk scores, 53.6% (n\u2009=\u20092889 of 5392) had low or average (<1.67%) risk. Comparing mammography plus ultrasonography with mammography alone, the cancer detection rate was similar at 5.4 vs 5.5 per 1000 screens (adjusted relative risk [RR], 1.14; 95% CI, 0.76-1.68), as were interval cancer rates at 1.5 vs 1.9 per 1000 screens (RR, 0.67; 95% CI, 0.33-1.37). The false-positive biopsy rates were significantly higher at 52.0 vs 22.2 per 1000 screens (RR, 2.23; 95% CI, 1.93-2.58), as was short-interval follow-up at 3.9% vs 1.1% (RR, 3.10; 95% CI, 2.60-3.70). The positive predictive value of biopsy recommendation was significantly lower at 9.5% vs 21.4% (RR, 0.50; 95% CI, 0.35-0.71).\nIn a relatively young population of women at low, intermediate, and high breast cancer risk, these results suggest that the benefits of supplemental ultrasonography screening may not outweigh associated harms.', 'title': 'Performance of Screening Ultrasonography as an Adjunct to Screening Mammography in Women Across the Spectrum of Breast Cancer Risk.', 'date': '2019-03-19'}}
| 0.6
|
Oncology & Hematology
|
13
|
Is food intake higher, lower, or the same when comparing grehlin to placebo?
|
higher
|
very low
|
no
|
['15181065']
| 29,489,032
| 2,018
|
{'15181065': {'article_id': '15181065', 'content': 'There is a pressing need for more effective appetite-stimulatory therapies for many patient groups including those with cancer. We have previously demonstrated that the gastric hormone ghrelin potently enhances appetite in healthy volunteers. Here, we performed an acute, randomized, placebo-controlled, cross-over clinical trial to determine whether ghrelin stimulates appetite in cancer patients with anorexia. Seven cancer patients who reported loss of appetite were recruited from oncology clinics at Charing Cross Hospital. The main outcome measures were energy intake from a buffet meal during ghrelin or saline infusion and meal appreciation as assessed by visual analog scale. A marked increase in energy intake (31 +/- 7%; P = 0.005) was observed with ghrelin infusion compared with saline control, and every patient ate more. The meal appreciation score was greater by 28 +/- 8% (P = 0.02) with ghrelin treatment. No side effects were observed. The stimulatory effects of ghrelin on food intake and meal appreciation seen in this preliminary study suggest that ghrelin could be an effective treatment for cancer anorexia and possibly for appetite loss in other patient groups.', 'title': 'Ghrelin increases energy intake in cancer patients with impaired appetite: acute, randomized, placebo-controlled trial.', 'date': '2004-06-08'}}
| 1
|
Internal Medicine & Subspecialties
|
14
|
Is length gain higher, lower, or the same when comparing moderate protein concentration to low protein concentration?
|
higher
|
low
|
no
|
['27801753', '10838460', '8906139']
| 33,215,474
| 2,020
|
{'27801753': {'article_id': '27801753', 'content': 'The aim of the study was to determine whether higher enteral protein intake leads to improved head growth at 40 weeks postmenstrual age (PMA) in preterm infants <32 weeks or 1500 g.\nRandomized controlled trial in which 120 infants were assigned to either group A with higher enteral protein intake achieved by fortification with higher protein containing fortifier (1 g/100 mL expressed breast milk) or to group B with lower enteral protein intake where fortification was done with standard available protein fortifier (0.4 g /100 mL expressed breast milk).\nThe mean (standard deviation) protein intake was higher in group A as compared to group B; 4.2 (0.47) compared with 3.6 (0.37) g\u200a·\u200akg\u200a·\u200aday, P\u200a<\u200a0.001. At 40 weeks PMA, the mean (standard deviation) weekly occipitofrontal circumference gain was significantly higher in group A as compared to group B; 0.66 (0.16) compared with 0.60 (0.15) cm/week (mean difference 0.064, 95% confidence interval [0.004-0.123], [P\u200a=\u200a0.04]). Weight growth velocity in group A was 11.95 (2.2) g\u200a·\u200akg\u200a·\u200aday as compared to 10.78 (2.6) g\u200a·\u200akg\u200a·\u200aday in group B (mean difference 1.10, 95% confidence interval [0.25-2.07], [P\u200a=\u200a0.01]). No difference was observed in the length between the 2 groups. There was no difference in growth indices and neurodevelopmental outcomes at 12 to 18 months corrected age in the 2 groups.\nFortification of expressed human milk with fortifier containing higher protein results in better head growth and weight gain at 40 weeks PMA in preterm infants <32 weeks or 1500 g without any benefits on long-term growth and neurodevelopment at 12 to 18 months corrected age (CTRI/2014/06/004661).', 'title': 'Effect of Differential Enteral Protein on Growth and Neurodevelopment in Infants <1500 g: A Randomized Controlled Trial.', 'date': '2016-11-02'}, '10838460': {'article_id': '10838460', 'content': "Human milk fortification has been advocated to enhance premature infants' growth. We, therefore, undertook this study of a new human milk fortifier containing more protein than a reference one.\nOpen, randomized, controlled, multiclinic trial, with weekly growth parameters and safety evaluations in premature infants <1,500 g.\nThe 2 groups did not differ in demographic and baseline characteristics. The adjusted daily milk intake was significantly higher in the infants fed reference human milk fortifier (n = 29; 154.2 +/- 2.1 vs. 144.4 +/- 2.5 ml/kg/day, mean +/- SE; p < 0.05). Both human milk fortifiers produced increases over baseline in weight, length, and head circumference, with greater gains observed in the new human milk fortifier-fed infants for the former two parameters (weight gain 26.8 +/- 1.3 and 20.4 +/- 1.2 g/day, p < 0.05; head circumference 1.0 +/- 0.1 and 0.8 +/- 0.1 cm/week; length 0.9 +/- 0.1 and 0.8 +/- 0.1 cm/week, respectively). Serum chemistries were normal and acceptable for age. Study events were typical for premature infants and similar in both groups.\nThis new human milk fortifier had comparable safety to the reference human milk fortifier and promoted faster weight gain and head circumference growth.", 'title': 'Growth in human milk-Fed very low birth weight infants receiving a new human milk fortifier.', 'date': '2000-06-06'}, '8906139': {'article_id': '8906139', 'content': "To evaluate the added nutritional value of the two commercially available human breast milk fortifiers: Similac Natural Care (NC) and Enfamil Powder (EP).\nA randomized controlled evaluation in healthy preterm neonates.\nNeonatal Intensive Care Unit, Royal University Hospital, Saskatoon, Saskatchewan, and Neonatal Intensive Care Unit, Jewish General Hospital, Montreal, Quebec, Canada.\nHealthy preterm infants admitted to and cared for in the aforementioned neonatal intensive care units.\nHealthy preterm neonates who were receiving expressed breast milk from their own mothers were supplemented with human milk fortifiers (NC and EP) per manufacturer's recommendations.\nGestational age and birth weight, gender, and race. At entry to and exit from the study, serum concentrations of albumin, protein, calcium, phosphorus, and alkaline phosphatase. The age at which the supplements were added and the number of days the infant remained in the hospital. Daily weight gain, head circumference, length, and height were also measured.\nStudent's t test was used to test the differences between the groups and within the groups at entry to and exit from the study. Fisher's exact test was used to determine differences in race, size, and gestational age in each group. When necessary, a chi 2 test was used to analyze the preponderance of either sex in each group. A Wilcoxon rank test was applied to the true exit date to determine whether the bias was comparable in each group.\nThe mean (+/- standard error) gestational age and birth weight were similar in both groups: 30 +/- 0.3 weeks and 1,314 +/- 40 g, respectively, for NC vs 29.6 +/- 0.35 weeks and 1,262 +/- 45 g, respectively, for EP. At entry to the study, values for the NC group (N = 29) were albumin 31 +/- 1.2 g/L, serum protein 48 +/- 1.4 g/L, calcium 2.4 +/- 0.03 mmol/L, phosphorus 1.85 +/- 0.08 mmol/L, alkaline phosphatase 347 +/- 27 IU/L. The values for the EP group (N = 30) were albumin 32 +/- 0.9 g/L, serum protein 49 +/- 1.4 g/L, calcium 2.4 +/- 0.4 mmol/L, phosphorus 1.9 +/- 0.1 mmol/L, alkaline phosphatase 420 +/- 34 IU/L. At the study exit, the values for the NC group were albumin 30 +/- 0.7 g/L, serum protein 45 +/- 0.9 g/L, calcium 2.4 +/- 0.3 mmol/L, phosphorus 1.96 +/- 0.07 mmol/L, and alkaline phosphatase 371 +/- 23 IU/L. The values for the EP group were albumin 32 +/- 1.0 g/L, serum protein 46.0 +/- 1.4 g/L, calcium 2.5 +/- 0.03 mmol/L, serum phosphorus 2.2 +/- 0.1, and alkaline phosphatase 367 +/- 27 IU/L. No significant differences were observed between groups at entry to and exit from the study. However, in the EP group the alkaline phosphatase decreased significantly (P = .02) from entry to exit and calcium increased significantly during the same period compared with the NC group (P = .003). The mean daily weight gain was 33 +/- 0.7 g for the NC group and 31 +/- 1 g for the EP group. The weekly gain in head circumference and body length were also similar in both groups: approximately 1 cm/week. Both groups tolerated the fortifiers well.\nThese findings suggest that both products provide the additional nutritional support necessary for optimal overall postnatal growth in healthy preterm infants. The differences in calcium and alkaline phosphatase may be due to the differences in vitamin D content in fortifiers 88 IU/100 mL in mixed NC vs 270 IU/100 mL in mixed EP. This observation calls for careful monitoring of calcium and alkaline phosphatase values and possible adjustments of vitamin D intake when fortifiers are used for extended periods.", 'title': 'A randomized, controlled evaluation of two commercially available human breast milk fortifiers in healthy preterm neonates.', 'date': '1996-11-01'}}
| 0.333333
|
Pediatrics & Neonatology
|
15
|
Is head circumference gain higher, lower, or the same when comparing moderate protein concentration to low protein concentration?
|
higher
|
very low
|
no
|
['27801753', '10838460', '8906139']
| 33,215,474
| 2,020
|
{'27801753': {'article_id': '27801753', 'content': 'The aim of the study was to determine whether higher enteral protein intake leads to improved head growth at 40 weeks postmenstrual age (PMA) in preterm infants <32 weeks or 1500 g.\nRandomized controlled trial in which 120 infants were assigned to either group A with higher enteral protein intake achieved by fortification with higher protein containing fortifier (1 g/100 mL expressed breast milk) or to group B with lower enteral protein intake where fortification was done with standard available protein fortifier (0.4 g /100 mL expressed breast milk).\nThe mean (standard deviation) protein intake was higher in group A as compared to group B; 4.2 (0.47) compared with 3.6 (0.37) g\u200a·\u200akg\u200a·\u200aday, P\u200a<\u200a0.001. At 40 weeks PMA, the mean (standard deviation) weekly occipitofrontal circumference gain was significantly higher in group A as compared to group B; 0.66 (0.16) compared with 0.60 (0.15) cm/week (mean difference 0.064, 95% confidence interval [0.004-0.123], [P\u200a=\u200a0.04]). Weight growth velocity in group A was 11.95 (2.2) g\u200a·\u200akg\u200a·\u200aday as compared to 10.78 (2.6) g\u200a·\u200akg\u200a·\u200aday in group B (mean difference 1.10, 95% confidence interval [0.25-2.07], [P\u200a=\u200a0.01]). No difference was observed in the length between the 2 groups. There was no difference in growth indices and neurodevelopmental outcomes at 12 to 18 months corrected age in the 2 groups.\nFortification of expressed human milk with fortifier containing higher protein results in better head growth and weight gain at 40 weeks PMA in preterm infants <32 weeks or 1500 g without any benefits on long-term growth and neurodevelopment at 12 to 18 months corrected age (CTRI/2014/06/004661).', 'title': 'Effect of Differential Enteral Protein on Growth and Neurodevelopment in Infants <1500 g: A Randomized Controlled Trial.', 'date': '2016-11-02'}, '10838460': {'article_id': '10838460', 'content': "Human milk fortification has been advocated to enhance premature infants' growth. We, therefore, undertook this study of a new human milk fortifier containing more protein than a reference one.\nOpen, randomized, controlled, multiclinic trial, with weekly growth parameters and safety evaluations in premature infants <1,500 g.\nThe 2 groups did not differ in demographic and baseline characteristics. The adjusted daily milk intake was significantly higher in the infants fed reference human milk fortifier (n = 29; 154.2 +/- 2.1 vs. 144.4 +/- 2.5 ml/kg/day, mean +/- SE; p < 0.05). Both human milk fortifiers produced increases over baseline in weight, length, and head circumference, with greater gains observed in the new human milk fortifier-fed infants for the former two parameters (weight gain 26.8 +/- 1.3 and 20.4 +/- 1.2 g/day, p < 0.05; head circumference 1.0 +/- 0.1 and 0.8 +/- 0.1 cm/week; length 0.9 +/- 0.1 and 0.8 +/- 0.1 cm/week, respectively). Serum chemistries were normal and acceptable for age. Study events were typical for premature infants and similar in both groups.\nThis new human milk fortifier had comparable safety to the reference human milk fortifier and promoted faster weight gain and head circumference growth.", 'title': 'Growth in human milk-Fed very low birth weight infants receiving a new human milk fortifier.', 'date': '2000-06-06'}, '8906139': {'article_id': '8906139', 'content': "To evaluate the added nutritional value of the two commercially available human breast milk fortifiers: Similac Natural Care (NC) and Enfamil Powder (EP).\nA randomized controlled evaluation in healthy preterm neonates.\nNeonatal Intensive Care Unit, Royal University Hospital, Saskatoon, Saskatchewan, and Neonatal Intensive Care Unit, Jewish General Hospital, Montreal, Quebec, Canada.\nHealthy preterm infants admitted to and cared for in the aforementioned neonatal intensive care units.\nHealthy preterm neonates who were receiving expressed breast milk from their own mothers were supplemented with human milk fortifiers (NC and EP) per manufacturer's recommendations.\nGestational age and birth weight, gender, and race. At entry to and exit from the study, serum concentrations of albumin, protein, calcium, phosphorus, and alkaline phosphatase. The age at which the supplements were added and the number of days the infant remained in the hospital. Daily weight gain, head circumference, length, and height were also measured.\nStudent's t test was used to test the differences between the groups and within the groups at entry to and exit from the study. Fisher's exact test was used to determine differences in race, size, and gestational age in each group. When necessary, a chi 2 test was used to analyze the preponderance of either sex in each group. A Wilcoxon rank test was applied to the true exit date to determine whether the bias was comparable in each group.\nThe mean (+/- standard error) gestational age and birth weight were similar in both groups: 30 +/- 0.3 weeks and 1,314 +/- 40 g, respectively, for NC vs 29.6 +/- 0.35 weeks and 1,262 +/- 45 g, respectively, for EP. At entry to the study, values for the NC group (N = 29) were albumin 31 +/- 1.2 g/L, serum protein 48 +/- 1.4 g/L, calcium 2.4 +/- 0.03 mmol/L, phosphorus 1.85 +/- 0.08 mmol/L, alkaline phosphatase 347 +/- 27 IU/L. The values for the EP group (N = 30) were albumin 32 +/- 0.9 g/L, serum protein 49 +/- 1.4 g/L, calcium 2.4 +/- 0.4 mmol/L, phosphorus 1.9 +/- 0.1 mmol/L, alkaline phosphatase 420 +/- 34 IU/L. At the study exit, the values for the NC group were albumin 30 +/- 0.7 g/L, serum protein 45 +/- 0.9 g/L, calcium 2.4 +/- 0.3 mmol/L, phosphorus 1.96 +/- 0.07 mmol/L, and alkaline phosphatase 371 +/- 23 IU/L. The values for the EP group were albumin 32 +/- 1.0 g/L, serum protein 46.0 +/- 1.4 g/L, calcium 2.5 +/- 0.03 mmol/L, serum phosphorus 2.2 +/- 0.1, and alkaline phosphatase 367 +/- 27 IU/L. No significant differences were observed between groups at entry to and exit from the study. However, in the EP group the alkaline phosphatase decreased significantly (P = .02) from entry to exit and calcium increased significantly during the same period compared with the NC group (P = .003). The mean daily weight gain was 33 +/- 0.7 g for the NC group and 31 +/- 1 g for the EP group. The weekly gain in head circumference and body length were also similar in both groups: approximately 1 cm/week. Both groups tolerated the fortifiers well.\nThese findings suggest that both products provide the additional nutritional support necessary for optimal overall postnatal growth in healthy preterm infants. The differences in calcium and alkaline phosphatase may be due to the differences in vitamin D content in fortifiers 88 IU/100 mL in mixed NC vs 270 IU/100 mL in mixed EP. This observation calls for careful monitoring of calcium and alkaline phosphatase values and possible adjustments of vitamin D intake when fortifiers are used for extended periods.", 'title': 'A randomized, controlled evaluation of two commercially available human breast milk fortifiers in healthy preterm neonates.', 'date': '1996-11-01'}}
| 0.666667
|
Pediatrics & Neonatology
|
16
|
Is weight gain higher, lower, or the same when comparing moderate protein concentration to low protein concentration?
|
higher
|
very low
|
no
|
['27801753', '10838460']
| 33,215,474
| 2,020
|
{'27801753': {'article_id': '27801753', 'content': 'The aim of the study was to determine whether higher enteral protein intake leads to improved head growth at 40 weeks postmenstrual age (PMA) in preterm infants <32 weeks or 1500 g.\nRandomized controlled trial in which 120 infants were assigned to either group A with higher enteral protein intake achieved by fortification with higher protein containing fortifier (1 g/100 mL expressed breast milk) or to group B with lower enteral protein intake where fortification was done with standard available protein fortifier (0.4 g /100 mL expressed breast milk).\nThe mean (standard deviation) protein intake was higher in group A as compared to group B; 4.2 (0.47) compared with 3.6 (0.37) g\u200a·\u200akg\u200a·\u200aday, P\u200a<\u200a0.001. At 40 weeks PMA, the mean (standard deviation) weekly occipitofrontal circumference gain was significantly higher in group A as compared to group B; 0.66 (0.16) compared with 0.60 (0.15) cm/week (mean difference 0.064, 95% confidence interval [0.004-0.123], [P\u200a=\u200a0.04]). Weight growth velocity in group A was 11.95 (2.2) g\u200a·\u200akg\u200a·\u200aday as compared to 10.78 (2.6) g\u200a·\u200akg\u200a·\u200aday in group B (mean difference 1.10, 95% confidence interval [0.25-2.07], [P\u200a=\u200a0.01]). No difference was observed in the length between the 2 groups. There was no difference in growth indices and neurodevelopmental outcomes at 12 to 18 months corrected age in the 2 groups.\nFortification of expressed human milk with fortifier containing higher protein results in better head growth and weight gain at 40 weeks PMA in preterm infants <32 weeks or 1500 g without any benefits on long-term growth and neurodevelopment at 12 to 18 months corrected age (CTRI/2014/06/004661).', 'title': 'Effect of Differential Enteral Protein on Growth and Neurodevelopment in Infants <1500 g: A Randomized Controlled Trial.', 'date': '2016-11-02'}, '10838460': {'article_id': '10838460', 'content': "Human milk fortification has been advocated to enhance premature infants' growth. We, therefore, undertook this study of a new human milk fortifier containing more protein than a reference one.\nOpen, randomized, controlled, multiclinic trial, with weekly growth parameters and safety evaluations in premature infants <1,500 g.\nThe 2 groups did not differ in demographic and baseline characteristics. The adjusted daily milk intake was significantly higher in the infants fed reference human milk fortifier (n = 29; 154.2 +/- 2.1 vs. 144.4 +/- 2.5 ml/kg/day, mean +/- SE; p < 0.05). Both human milk fortifiers produced increases over baseline in weight, length, and head circumference, with greater gains observed in the new human milk fortifier-fed infants for the former two parameters (weight gain 26.8 +/- 1.3 and 20.4 +/- 1.2 g/day, p < 0.05; head circumference 1.0 +/- 0.1 and 0.8 +/- 0.1 cm/week; length 0.9 +/- 0.1 and 0.8 +/- 0.1 cm/week, respectively). Serum chemistries were normal and acceptable for age. Study events were typical for premature infants and similar in both groups.\nThis new human milk fortifier had comparable safety to the reference human milk fortifier and promoted faster weight gain and head circumference growth.", 'title': 'Growth in human milk-Fed very low birth weight infants receiving a new human milk fortifier.', 'date': '2000-06-06'}}
| 1
|
Pediatrics & Neonatology
|
17
|
Is head circumference gain higher, lower, or the same when comparing high protein concentration to low protein concentration?
|
uncertain effect
|
very low
|
no
|
['26488118', '22301933', '22987877', '29772833', '28727654']
| 33,215,474
| 2,020
|
{'26488118': {'article_id': '26488118', 'content': "J Pediatr Gastroenterol NutrJ. Pediatr. Gastroenterol. NutrJPGAJournal of Pediatric Gastroenterology and Nutrition0277-21161536-4801Lippincott Williams & Wilkins26488118464595610.1097/MPG.000000000000101000012Original Articles: NutritionGrowth and Tolerance of Preterm Infants Fed a New Extensively Hydrolyzed Liquid Human Milk FortifierKimJae H.∗ChanGary†SchanlerRichard‡Groh-WargoSharon§BloomBarry||DimmitReed¶WilliamsLarry#BaggsGeraldine#Barrett-ReisBridget#∗University of California, San Diego-Rady Children's Hospital of San Diego, San Diego†University of Utah, Salt Lake City‡Cohen Children's Medical Center of New York, New Hyde Park§Case Western Reserve University, MetroHealth Medical Center, Cleveland, OH||Wesley Medical Center, Wichita, KS¶University of Alabama, Birmingham#Abbott Nutrition, Columbus, OH.Address correspondence and reprint requests to Jae H. Kim, MD, PhD, University of California, San Diego, 200 W Arbor Dr, MPF 1140, San Diego, CA 92103 (e-mail: neojae@ucsd.edu).12201524112015616665671212201512102015Copyright 2015 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.2015This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License, where it is permissible to download and share the work, provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0ABSTRACTObjectives:This study was a comparison of growth and tolerance in premature infants fed either standard powdered human milk fortifier (HMF) or a newly formulated concentrated liquid that contained extensively hydrolyzed protein.Methods:This was an unblinded randomized controlled multicenter noninferiority study on preterm infants receiving human milk (HM) supplemented with 2 randomly assigned HMFs, either concentrated liquid HMF containing extensively hydrolyzed protein (LE-HMF) or a powdered intact protein HMF (PI-HMF) as the control. The study population consisted of preterm infants ≤33 weeks who were enterally fed HM. Infants were studied from the first day of HM fortification until day 29 or hospital discharge, whichever came first.Results:A total of 147 preterm infants were enrolled. Noninferiority was observed in weight gain reported in the intent-to-treat (ITT) analysis was 18.2 and 17.5 g · kg−1 · day−1 for the LE-HMF and PI-HMF groups, respectively. In an a priori defined subgroup of strict protocol followers (n\u200a=\u200a75), the infants fed LE-HMF achieved greater weight over time than those fed PI-HMF (P\u200a=\u200a0.036). The LE-HMF group achieved greater linear growth over time compared to the PI-HMF (P\u200a=\u200a0.029). The protein intake from fortified HM was significantly higher in the LE-HMF group compared with the PI-HMF group (3.9 vs 3.3 g · kg−1 · day−1, P\u200a<\u200a0.0001). Both fortifiers were well tolerated with no significant differences in overall morbidity.Conclusions:Both fortifiers showed excellent weight gain (grams per kilograms per day), tolerance, and low incidence of morbidity outcomes with the infants who were strict protocol followers fed LE-HMF having improved growth during the study. These data point to the safety and suitability of this new concentrated liquid HMF (LE-HMF) in preterm infants. Growth with this fortifier closely matches the recent recommendations for a weight gain of >18 g · kg−1 · day−1.Keywordsbreast-feedinggrowthhuman milk fortifierpreterm infantsOPEN-ACCESSTRUEWhat Is KnownPowdered infant milk products cannot be sterilized and is a source of bacterial infection.Very-low-birth-weight infants often require more protein than presently can be provided with conventional human milk fortifiers.A liquid fortifier with higher protein than conventional fortifiers is desirable to increase safety and improved growth.What Is NewA liquid human milk fortifier that is based on extensively hydrolyzed bovine casein with higher amounts of total protein than powder human milk fortifiers confers equal to improved growth to very-low-birth-weight infantsUse of this new liquid fortifier provides sterility without any increase in feeding intolerance or short-term adverse effects.Human milk (HM) is a source of essential nutrients and immunologic factors for the preterm infant, but alone it is not sufficient nutritionally to meet the high demands of the rapidly growing infant. Human milk fortifiers (HMFs) are nutritional supplements designed to increase total energy, protein, and micronutrient delivery to preterm infants. The primary benefits of HM fortification have been improved growth, bone mineralization, and protein status such as blood urea nitrogen (BUN) (1–5).Increasing survival and improving growth of the preterm infant to avoid extrauterine growth restriction have resulted in demands for protein that present powdered HMF may not achieve. Although some of these infants may compensate with higher volume intake, many are unable to consume a sufficient volume because of pulmonary or other clinical issues and therefore require further concentration of protein and energy. Higher intake of protein between 3 and 4 g · kg−1 · day−1 has been associated with improved growth without complications compared with a lower consumption of protein (<3 g · kg−1 · day−1) (6). Poor weight gain has been associated with a higher risk for retinopathy of prematurity and poor neurodevelopmental outcomes (7,8). It is common practice in the neonatal intensive care units (NICUs) to add protein modular (powder or liquid) to the feeding to better meet the protein needs of the smaller preterm infant. In fact, 42% of the respondents to a recent survey on nutritional practices in the NICU reported adding protein to HM (9).There has been a gradual transition to sterile liquid nutritionals in the neonatal environment during the last decade because of concerns about powder-based transmission of pathogens such as Cronobacteria sakasakii(10). The recent development of a liquid HM–based HMF and a partially hydrolyzed whey-acidified liquid HMF respond to these concerns (11,12). Unlike powder nutritionals, a liquid HMF may have the advantage of sterility and simpler liquid-liquid mixing with human milk (HM). One disadvantage of a liquid fortifier is volume displacement of HM.In this study, we evaluated a novel liquid HMF containing extensively hydrolyzed protein source to determine efficacy and safety in very-low-birth-weight preterm infants.METHODSStudy PopulationA total of 14 NICUs from across the United States participated in this study, including Tampa, Florida; Wichita, Kansas; Toledo, Ohio; Salt Lake City, Utah; Birmingham, Alabama; Cleveland, Ohio; Allentown, Pennsylvania; San Diego, California; Valhalla, New York; Manhasset, New York; Portland, Oregon; Cleveland, Ohio; South Bend, India; and Brooklyn, New York. The study population consisted of preterm infants born at ≤33 weeks’ gestational age with birth weights ranging from 700 to 1500 g who were enterally fed HM in the NICU. Infants identified as eligible for randomization and for whom consent was obtained were randomly assigned to one of the 2 study regimens. Sealed envelopes containing the subject treatment group assignment were prepared from randomization schedules that were computer-generated using a pseudorandom permuted blocks algorithm. A separate computer-generated randomization schedule was produced for twins to ensure that eligible twins were both assigned to the same product. The randomization was block stratified by birth weight (700–1000 g and 1000–1500\u200ag) and sex.Eligibility criteria included appropriate intrauterine growth and maternal intent to provide breast milk during the study. The use of donor HM was not permitted during the study period unless indicated by the clinical staff or PI but could have been used in the first week of life before study initiation. Infants were excluded for enteral feeds not started within 21 days of life, severe congenital anomalies, expectant transfer to another facility, 5-minute Apgar <5, severe intraventricular hemorrhage (grade 3 or 4), mechanical ventilation, major abdominal surgery, severe asphyxia, and necrotizing enterocolitis (NEC). Use of probiotics or postnatal corticosteroids was not permitted.Study DesignThis was an unblinded randomized controlled multicenter study conducted on preterm infants receiving HM supplemented with 2 randomly assigned HMFs, either a newly formulated concentrated liquid HMF containing extensively hydrolyzed protein (Abbott Nutrition, Columbus, OH; LE-HMF) or a conventional powdered intact protein HMF (Similac Human Milk Fortifier, PI-HMF, Abbott Nutrition) as control. For every 25 mL of HM, HMF was added as a 5-mL dose of LE-HMF or 1 single packet of PI-HMF. Study Day (SDAY) 1 was defined as the first day of HM fortification and occurred within 72 hours after the subject had reached an intake of at least 100 mL · kg−1 · day−1 of HM. The primary study period was from SDAY 1 until SDAY 29 or hospital discharge, whichever came first. This study was approved by institutional research ethics board as appropriate at each study sites. Table 1 shows the key study fortifier differences.Anthropometric indices (weight, length, and head circumference [HC]), tolerance, serum biochemistries, intake, and morbidity data were assessed. Anthropometric variables and tolerance outcomes were collected after SDAY 29 if the infant remained on study HMF.Weight, length, and HC of infants were measured according to standardized procedures from SDAY 1 to SDAY 29 or hospital discharge, whichever came first. Weight measures were taken daily using the hospital scales (incubator or bedside). Documentation of scale calibration was reviewed during routine visits. The other anthropometric measurements were performed weekly. Recumbent length was obtained with a fixed headboard and moveable footboard and HC using a nonstretchable tape.Feeding tolerance was assessed by variables such as stool characteristics (bloody, hard, black, and/or watery) and the incidence of feedings withheld because of abdominal distention, gastric residuals, and vomiting. Any nil per os periods were also collected.Enteral intake was collected from enrollment to SDAY 29. Intake of HM (including donor/banked HM) or other enteral feeding (including supplements such as protein modulars) were recorded. Although the LE-HMF contained the same amount of energy as the PI-HMF, it contained higher protein and a different source of protein. It also contained added lutein, docosahexaenoic acid, and arachidonic acid.Blood samples were drawn from each infant by venipuncture or, if necessary, by heelstick on SDAYs 1, 15, and 29. Serum electrolytes, bicarbonate, calcium, phosphorus, magnesium, alkaline phosphatase, BUN, and prealbumin were analyzed at the hospital site. Confirmed NEC (determined by using modified Bell staging criteria) and sepsis were recorded. The occurrence of these and other serious adverse events was documented throughout the study.Statistical AnalysisStudy data were analyzed on an intent-to-treat (ITT) basis including all enrolled infants who received study fortifier. Based on anticipated protocol deviations in this high-risk population, a subgroup analysis was prospectively planned to analyze data from infants who strictly adhered to the assigned HMF. The strict protocol followers (SPFs) were defined a priori as those infants who received <20% of total energy from sources other than the assigned study HMF; and <3 consecutive days on modular supplements (eg, protein supplements, another study HMF, nonstudy formula, or donor milk) for at least 2 weeks from SDAY 1 to SDAY 29.Sample size was calculated to test the hypothesis that LE-HMF was noninferior to PI-HMF using an equivalence limit of 1.6 g · kg−1 · day−1 in weight gain per day. With a noninferiority hypothesis and assuming that the expected difference in means is zero and the common standard deviation is 2.56 g · kg−1 · day−1, the total sample size required to have 80% power was 66 subjects who are SPF (33 per group). The power for this unbalanced sample size distribution is 83%. Assuming an attrition rate of approximately 46%, the target number for enrollment was 124 subjects (62 per group). A study designed for noninferiority does not preclude testing for superiority (13). Weight gain (grams per kilogram per day) for each subject was calculated by an exponential model that involved a regression line fit on loge (wt), where wt is weight (in grams) on each day (13). Weight gain (grams per kilogram per day) was analyzed using analysis of variance with factors for center and feeding (primary). Analyses were also made adjusting for sex, birth weight, and average fortified HM intake (milliliters per kilogram per day) diluted full strength during the study period. A 95% 1-sided confidence interval for the difference in means between groups was used for noninferiority evaluation.Length (centimeters per week) and HC gains (centimeters per week) were analyzed using the same models. Weight, length, and HC collected at 1-week intervals were analyzed with repeated measures analysis of covariance (ANCOVA) testing effects of center, feeding, sex, study day, interaction of feeding with sex, feeding with study day, and covariate birth weight. By time point analyses of weight, length, and HC using ANCOVA were made post-hoc using 1-sided tests consistent with a noninferiority design.Average daily volume enteral intake (milliliters per kilogram per day) was analyzed using analysis of variance. Complete blood cell counts with differential and serum blood biochemistries were analyzed using repeated measures ANCOVA with covariate SDAY 1 measure.Outcomes expressed as percent of infants (tolerance, morbidity, and respiratory variables) were analyzed using the Cochran-Mantel-Haenzsel test stratified by center. The frequencies of occurrence of adverse events by system organ class and preferred terms using MedDRA codes were tabulated and analyzed using Fisher exact test. Hypothesis testing for this study was done using 2-sided, 0.05 level tests. All analyses were made using SAS version 9.2 (SAS Institute, Cary, NC) on a computer.RESULTSStudy PopulationA total of 147 subjects were randomized into the study. Of the 147 subjects, 129 were included in the ITT group, that is, all randomized subjects who received study HMF. Of those subjects in the ITT group, 75% completed the study duration (45 PI-HMF, 52 LE-HMF). More than half the infants in the ITT group met the definition for the SPFs (Fig. 1). The number of days on the assigned study fortifier was 25 and 29 for the PI-HMF (n\u200a=\u200a63) and LE-HMF (n\u200a=\u200a66) groups, respectively. The median number of days on the assigned study fortifier for SPF was 29 days for both the PI-HMF and LE-HMF groups as some extended their use beyond the study period. Of note, some SPF subjects did not complete the study duration because they were discharged from the hospital.FIGURE 1Disposition of subjects.Demographic and Other Baseline CharacteristicsCharacteristics of the study patients are summarized in Table 2. There were no statistically significant differences among study subjects randomized to the PI-HMF or the LE-HMF group in gestational age, sex, race, mode of delivery and multiple birth status. There were, however, more Hispanic infants in the PI-HMF as compared to the LE-HMF group (28% vs 13%, P\u200a=\u200a0.041). In addition, there were no statistical differences between groups at birth or SDAY 1 for weight, length, and HC. Furthermore, there were no differences in clinical history and progression of enteral feeds. Infants in the 2 feeding groups who were SPF reflect comparable demographic and baseline characteristics patterns.GrowthThere were no statistical differences in the primary outcome of weight gain (grams per kilogram per day) during the study period regardless of whether the statistical analysis was performed on the ITT group or SPFs. Hence, noninferiority was achieved. Respective weight gains were 17.5 and 18.2 g · kg−1 · day−1 for PI-HMF and LE-HMF (Table 3). Likewise in the subgroup (SPF) analysis weight gains were 18.2 and 18.4 g · kg−1 · day−1 for PI-HMF and LE-HMF. There was, however, a main feeding effect that was the infants fed LE-HMF compared with infants fed PI-HMF had increased weight during the study among SPFs as depicted in Fig. 2A (P\u200a=\u200a0.036). When analyzing the data at separate time points the weight at SDAY 29 was significantly higher in LE-HMF group versus the PI-HMF group (P\u200a=\u200a0.024). Likewise, infants in the ITT group fed LE-HMF had higher weights at SDAYs 15, 22, and 29 than infants fed PI-HMF whether or not adjusted for differences in ethnicity. The SPF infants receiving LE-HMF reached 1800 g 7 days sooner than the infants fed PI-HMF (19 vs 26 days, respectively, P\u200a=\u200a0.049).FIGURE 2Evaluable analysis: A, weight (in grams); B, length (in centimeters); C, head circumference (in centimeters). A, Weight (in grams). Repeated measures analysis main effect, P\u200a=\u200a0.036; post-hoc per time point analysis: SDAY 29, P\u200a=\u200a0.024. B, Length (in centimeters). Repeated measures analysis main effect, P\u200a=\u200a0.029; post-hoc per time point analysis: SDAY 22, P\u200a=\u200a0.006, SDAY 29, P\u200a=\u200a0.037. C, Head circumference (in centimeters).The length and HC gains (centimeters per week) during the study period revealed no statistical differences between the groups and met growth targets (Table 3). The infants fed LE-HMF compared with infants fed PI-HMF had increased linear growth during the study among SPFs as depicted in Fig. 2B (P\u200a=\u200a0.029). When analyzing the data at separate time points adjusted for birth length, the length at SDAY 22 and SDAY 29 were significantly higher in LE-HMF group versus the PI-HMF group (P\u200a<\u200a0.05). HC was not different between the fortifier groups (Fig. 2C).Feeding Tolerance and Stool CharacteristicsIn both the ITT and SPF groups, both fortifiers were well tolerated with similar number and percentage of infants having feedings withheld because of abdominal distention, gastric residuals and/or vomiting. There was no difference in the percentage of infants who were nil per os between the groups (22.7 LE-HMF, 19 PI-HMF). The stool characteristics in both groups were similar with no differences in bloody stools, hard stools or black stools. Loose stools were commonly reported—56% in the PI-HMF group and 53% in the LE-HMF group—and were considered normal for infants who are receiving HM as their primary feeding.Enteral NutritionThe mean caloric and protein intakes are reported for both HMF groups. For the SPFs, the average percentage of calories from fortified HM was ∼96% in both the PI-HMF and LE-HMF groups. The mean intake of fortified HM was 116 and 114 kcal · kg−1 · day−1 in the PI-HMF and LE-HMF groups, respectively. The calculated protein intake from fortified HM was significantly higher in the LE-HMF group as compared to the PI-HMF group (3.9 vs 3.3\u200a g · kg−1 · day−1, P\u200a<\u200a0.0001). This difference was expected as LE-HMF contains more protein than PI-HMF. Energy intakes were not different between the groups.Blood ChemistriesThe blood chemistries reported in Table 4 include bicarbonate, BUN, prealbumin, calcium, phosphorus, magnesium, alkaline phosphatase, and electrolytes. In general, the blood biochemistries at SDAYs 1, 15, and 29 were within the normal reference ranges for preterm infants for both the ITT and SPF groups fed milk fortified with either fortifier (14,15). There were significant differences between groups in both the ITT and SPF analyses for BUN (P\u200a<\u200a0.001) and prealbumin (P\u200a<\u200a0.01), with both being higher in the LE-HMF group. Both groups were well within reference ranges for these parameters. Bicarbonate was significantly higher in the LE-HMF group only at SDAY1 in the ITT analysis.Safety and Morbidity DataIn the ITT group, fewer infants discontinued fortifier because of feeding intolerance in the LE-HMF group as compared to the PI-HMF group (2% vs 10%, P\u200a=\u200a0.048). There was a low incidence of confirmed NEC (1.5% in the LE-HMF group and 3.2% in the PI-HMF group) and confirmed sepsis (4.5% vs 3.2%, respectively)DISCUSSIONThe purpose of developing LE-HMF was to provide a concentrated liquid fortifier that would be superior to conventional powder HMF by virtue of sterility, higher protein concentration, and absence of intact cow's-milk protein. An extensively hydrolyzed protein source is included to promote feeding tolerance in preterm infants. The extensively hydrolyzed protein may be tolerated better for infants who are sensitive to the intact cow's-milk protein.The primary purpose of the present clinical trial was to assess whether the new HMF would promote targeted weight gain, with good tolerance and without association with specific comorbidities in a noninferiority comparison with a commercially available powder HMF that has demonstrated safety and efficacy in preterm infants (13).Weight gain and linear growth approaching intrauterine rates are important goals in the management of premature infants. The mean weight gain for both groups (PI-HMF and LE-HMF) exceeded the intrauterine growth rate of 15 g · kg−1 · day−1 and closely matched recent recommendations for a weight gain of >18 g · kg−1 · day−1(7). The mean HC gain for both groups also closely matched recent recommendations for a HC gain of >0.9 cm/wk (7). This result was not surprising given the excellent weight, length, and HC gains previously reported in infants fed PI-HMF powder (13).Ehrenkranz et al (7) have reported that as the rate of weight gain increased in hospitalized preterm infants, the incidence of cerebral palsy, neurodevelopmental impairment, and need for re-hospitalization decreased significantly. A weight gain rate of >18 g · kg−1 · day−1 and a HC growth rate of >0.9 cm/wk were associated with better neurodevelopmental and growth outcomes. Lower quartile growth was associated with the poorest neurodevelopmental outcomes.Weight and length differed between the groups. Although there were no significant differences in mean weight at birth or SDAY 1, infants receiving LE-HMF had ∼½ lb greater mean weight than the infants in the PI-HMF group at the end of the study period. Although the rate of linear growth was not statistically different, infants in the LE-HMF group had greater achieved linear growth during the study period. It is possible that the greater weight and length in the LE-HMF infants was because of the higher number of infants in this group that adhered to the assigned study feeding.New expert recommendations suggest that extremely-low-birth-weight infants (<1000 g birth weight) have higher protein requirements (3.5–4.5 g/100 kcal) (16). HMFs provide an important strategy to overcoming nutrient deficits for preterm and low-birth-weight infants. Differences in the level and ingredient sources of the macronutrients, especially the protein quantity, in PI-HMF versus LE-HMF may have contributed to the overall performance of the LE-HMF group. The higher protein intake in infants receiving LE-HMF (∼3.6 g/100 kcal) as compared to PI-HMF (∼3.0 g/100 kcal) was likely one of the reasons for the improved growth observed in these infants. Although infants in the LE-HMF group had higher protein intakes, energy intakes were not different between the groups.Preterm infants fed fortified HM have variable rates of growth at least partly because of differences in intake of calories, carbohydrates, electrolytes, calcium, phosphate, and protein. The acid-base status of the preterm infant also, however, affects growth. In preterm infants the kidney may not tolerate an acid load, leading to the development of metabolic acidosis. In a recent study, a liquid acidified HMF caused metabolic acidosis and poor growth in preterm infants in the NICU (17,18). In another study, Rochow et al (19) described a commercially available fortifier in Europe that had to be reformulated because of the development of metabolic acidosis from an imbalance of electrolytes. The authors recorded a mean weight gain of only 9.7 g · kg−1 · day−1 and decreased bone mineralization with metabolic acidosis. No infants in our study developed metabolic acidosis.The LE-HMF protein source may be beneficial for this population because it was extensively hydrolyzed casein formulation without any intact cow's-milk protein. It has been suggested that a combination of free amino acids and short chain peptides (di- and tri peptides) may allow more optimal nitrogen absorption (20,21). Intact bovine protein powder HMF has an excellent safety record; however, a recent study by Sullivan et al (11) suggested the possibility that even in the presence of a HM base diet, the addition of intact bovine protein powder HMF is associated with higher rates of total and surgical NEC. The mechanism for the higher NEC risk is not known yet. Although this study was not powdered for NEC there was no difference in the NEC or sepsis rates between the infants fed an intact bovine protein and the extensively hydrolyzed protein. Both groups had rates lower than previously reported (22–24).Intact bovine protein has higher associated long-term risk for allergy and atopy compared with HM-fed infants. Protein intolerance is seen in premature infants and in term infants (25). Because preterm infants have a similar risk for allergy and atopy compared with term infants and in the NICU have presented with symptoms suggestive of allergic colitis, avoiding intact bovine protein may be a desirable objective. For preterm infants fed HM the use of an extensively hydrolyzed protein-based HMF is an appropriate option.In general, blood chemistries were within normal reference ranges for preterm infants. The higher BUN and prealbumin seen in the LE-HMF group can be attributed to the higher protein content of LE-HMF. These higher values may be indicative of improved protein nutriture. It should be noted that although BUN is influenced by renal function and hydration state, all other influences being equal, it is proportional to protein intake and responds rapidly to changes in protein intake (4,5,26,27).Postnatal growth failure remains common in premature infants. Nearly 25 years ago Kashyap et al showed that even a small deficit in protein intake impairs both growth in lean body mass and linear growth (28). In recent years, Arslanoglu et al reported that addition of protein to preterm feedings of recovering VLBW infants resulted in significantly improved linear growth (4,5). This was accomplished by monitoring the BUN level so that when it was less than 9\u200amg/dL, increased protein was added to their feedings. It was observed in the present study that the mean BUN level fell <9 mg/dL by week 2 in infants receiving PI-HMF; however, in infants receiving LE-HMF it never fell <9 mg/dL during the entire study period. Our results, in part, agree with other investigators that an increased protein-to-calorie ratio in the feeds of preterm infants will improve linear growth (4,5,9,28). It is becoming increasingly evident that promoting catch-up growth in the NICU may have implications for long-term development and health (7,29).Our study did have several limitations. The study examined the combined effects of changing both protein content and type (hydrolyzed vs intact). Future studies may want to capture effects of changing one of these variables. A number of subjects in this study did not complete the protocol to SDAY 29. This partially diluted the effects seen in the ITT groups but still permitted demonstration of differential effects seen in the SPF subgroup. A larger study design may improve this in the future. Infants <700 g birth weight were excluded from this study and therefore the study findings cannot be readily extrapolated to this vulnerable group. It is expected however that this group would have higher protein demands than infants in this study and therefore would be as likely or more to have a favorable response to higher protein. Although no differences were seen between both groups for NEC and sepsis the study size was too small to discern true differences for these outcomes.CONCLUSIONSBoth fortifiers showed excellent tolerance and a low rate of morbidity outcomes, with the infants who were SPFs fed LE-HMF having improved growth. These data confirm the safety and suitability of this new concentrated liquid HMF for preterm infants.AcknowledgmentsThe authors thank the following individuals for their hard work and dedication: Coryn Commare, MS, RD; Christy Saulters, BS; Debra Lee-Butcher, BSN, RN; Holy Boyko, BSN, RN; Angela Worley; Carolyn Richardson; Sue Zhang, MS, MAS; Mustafa Vurma, PhD; Maggie Hroncich, BS; Aimee Diley; Kristen Fithian; Sue Nicholson, MS, RD; and Jennifer Teran, BS, RD. The authors also thank study investigators and their staff for their cooperation: Terri Ashmeade, MD; Anthony Killian, MD; Lance Parton, MD; Robert Schelonka, MD; Robert White, MD; Ivan Hand, MD, FAAP; Michelle Walsh, MD; Jeffrey Blumer, PhD, MD; Paula Delmore, RN; Carrie Rau, RN; Renee Bridge, RN; Lisa Lepis, RN; Judy Zaritt, RN; Claire Roane, RN, MSN; Julie Gualtier, RN; Diane Fierst, RN; Christina Gogal; Natalie Dweck; Debra Potak, RN; Barbara Wilkens, RN; Nakia Clay, BS; Mashelle Monhaut, NNP-BC; Rickey Taing, NPL; Susan Bergant, RN, CCRP; and Bonnie Rosolowski, RPT.www.clinicaltrials.gov registration number: NCT01373073.This study was funded by Abbott Nutrition.J.H.K., B.B., G.C., R.S. and S.G.-W. received research funds from the study sponsor, Abbott Nutrition, to conduct the study. J.H.K. is on the speakers’ bureaus for Abbott Nutrition, Mead Johnson Nutrition, Nestle Nutrition, Nutricia, and Medela. J.H.K. and R.S. are on the medical advisory board for Medela. J.H.K. owns shares in PediaSolutions and has provided medical expert testimony. B.B. received a grant from the Wichita Medical Research and Education Foundation. G.C. received a research grant from the University of Utah and has provided medical expert testimony. S.G.-W. is on the speakers’ bureau of Abbott Nutrition. B.B.-R., L.W., and G.B. are employees of Abbott Nutrition.The authors report no conflicts of interest.REFERENCES1.SchanlerRJ\nSuitability of human milk for the low-birthweight infant. Clin Perinatol\n1995; 22:207–222.77812532.SchanlerRJAbramsSA\nPostnatal attainment of intrauterine macromineral accretion rates in low birth weight infants fed fortified human milk. J Pediatr\n1995; 126:441–447.78692083.KuschelCAHardingJE\nMulticomponent fortified human milk for promoting growth in preterm infants. Cochrane Database Syst Rev\n2004; 1:CD000343.149739534.ArslanogluSBertinoECosciaA\nUpdate of adjustable fortification regimen for preterm infants: a new protocol. 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Pediatrics\n1999; 104\n(2 Pt 1):280–289.10429008TABLE 1Approximate nutrient composition of PI-HMF or LE-HMF added to HMNutrient PI-HMFLE-HMFEnergy, cal100100Fat, g5.25.1CHO, g10.410.1Protein, g33.6Source/type of proteinIntact whey protein concentrateExtensively hydrolyzed caseinDHA, mg1224Vitamin D, IU150150Calcium, mg175153Phosphorus, mg9886Osmolality, mOsm/kg water385450Lutein, μg*23Values per 100 calories mixed at a ratio of 1 pkt or 5 mL:25 mL HM (as fed). CHO\u2009=\u2009carbohydrate; DHA\u2009=\u2009docosahexaenoic acid; HM\u2009=\u2009human milk; LE-HMF \u2009=\u2009liquid HMF containing extensively hydrolyzed protein; PI-HMF\u2009=\u2009powdered intact protein HMF.*Lutein not added to product but available in varying amounts from HM.TABLE 2Neonatal and perinatal characteristics of preterm infantsTreatment group*PI-HMF (n\u2009=\u200963)LE-HMF (n\u2009=\u200966)Gestational age, wk28.7\u2009±\u20090.228.8\u2009±\u20090.2Birth weight, g1156\u2009±\u2009241193\u2009±\u200926Birth length, cm37.4\u2009±\u20090.337.7\u2009±\u20090.3Birth HC, cm26.1\u2009±\u20090.226.5\u2009±\u20090.2Male sex, n (%)35 (56)36 (55)Ethnicity: Hispanic, n (%)17 (28)8 (13)†Race, n (%)\u2003White42 (67)43 (65)\u2003Black13 (21)17 (26)\u2003Asian1 (2)1 (2)\u2003Other7 (11)3 (5)\u2003White/other0 (0)2 (3)C-section, n (%)38 (60)42 (64)Twin, n (%)16 (25)12 (18)Age at study day 1, d12.3\u2009±\u20090.712.8\u2009±\u20090.6Birth class, n (%)\u2003≤1000\u2009g16 (24)12 (19)\u2003>1000\u2009g66 (76)63 (81)LE-HMF\u2009=\u2009liquid HMF containing extensively hydrolyzed protein; PI-HMF\u2009=\u2009powdered intact protein HMF.*Mean\u2009±\u2009SEM.†P\u2009=\u20090.0407.TABLE 3Anthropometric gainsTreatment group*Targeted growth†,‡PI-HMF (n\u2009=\u200963)LE-HMF (n\u2009=\u200966)Weight gain, g kg−1 day−117.5\u2009±\u20090.618.2\u2009±\u20090.3>18Length gain, cm/wk1.2\u2009±\u20090.071.2\u2009±\u20090.06>0.9HC gain, cm/wk1.0\u2009±\u20090.041.0\u2009±\u20090.05>0.9LE-HMF\u2009=\u2009liquid HMF containing extensively hydrolyzed protein; PI-HMF\u2009=\u2009powdered intact protein HMF; HC\u2009=\u2009head circumference.*Intent-to-treat group, n\u2009=\u2009129.†Ehrenkranz et al (7).‡Ehrenkranz et al (30).TABLE 4Blood chemistry dataCharacteristicsReference rangesStudy dayTreatment group*PI-HMFLE-HMFBicarbonate, mEq/L†17–24123.27\u2009±\u20090.45 (59)25.05\u2009±\u20090.45 (62)1524.32\u2009±\u20090.50 (49)25.40\u2009±\u20090.39 (58)2925.04\u2009±\u20090.43 (40)25.54\u2009±\u20090.44 (50)BUN, mg/dL‡2.5–31.4111.47\u2009±\u20090.78 (56)11.89\u2009±\u20091.03 (61)158.30\u2009±\u20091.15 (50)11.72\u2009±\u20090.68 (58)295.81\u2009±\u20090.38 (40)9.31\u2009±\u20090.53 (49)Prealbumin, mg/dL§7.0–39.0110.05\u2009±\u20090.37 (58)9.69\u2009±\u20090.33 (54)1510.11\u2009±\u20090.37 (47)11.40\u2009±\u20090.41 (46)299.08\u2009±\u20090.35 (36)10.01\u2009±\u20090.35 (37)Calcium, mg/dL8.0–11.0110.10\u2009±\u20090.08 (56)9.93\u2009±\u20090.08 (60)159.93\u2009±\u20090.10 (50)9.95\u2009±\u20090.07 (57)299.89\u2009±\u20090.09 (40)9.82\u2009±\u20090.06 (49)Phosphorus, mg/dL4.2–8.716.41\u2009±\u20090.17 (54)6.20\u2009±\u20090.13 (58)156.71\u2009±\u20090.13 (46)6.50\u2009±\u20090.12 (56)296.66\u2009±\u20090.10 (40)6.46\u2009±\u20090.12 (47)Magnesium, mg/dL1.5–2.111.90\u2009±\u20090.03 (54)1.88\u2009±\u20090.02 (59)151.80\u2009±\u20090.03 (47)1.86\u2009±\u20090.03 (55)291.81\u2009±\u20090.02 (40)1.82\u2009±\u20090.03 (46)Alkaline phosphatase, U/L150–4001443.89\u2009±\u200924.50 (55)415.40\u2009±\u200915.78 (60)15366.13\u2009±\u200921.80 (48)332.68\u2009±\u200910.87 (57)29335.28\u2009±\u200921.84 (40)342.36\u2009±\u200913.10 (47)Sodium, mEq/L129–1431137.49\u2009±\u20090.49 (61)138.42\u2009±\u20090.34 (65)15137.46\u2009±\u20090.55 (52)137.56\u2009±\u20090.29 (59)29139.07\u2009±\u20090.41 (41)138.70\u2009±\u20090.40 (50)Potassium, mEq/L4.5–7.115.39\u2009±\u20090.11 (61)5.20\u2009±\u20090.09 (65)155.25\u2009±\u20090.09 (52)5.23\u2009±\u20090.09 (59)295.25\u2009±\u20090.10 (41)5.06\u2009±\u20090.07 (50)Chloride, mEq/L100–1171104.16\u2009±\u20090.60 (58)104.03\u2009±\u20090.55 (63)15104.10\u2009±\u20090.72 (49)103.88\u2009±\u20090.43 (57)29106.00\u2009±\u20090.57 (40)106.14\u2009±\u20090.37 (49)BUN\u2009=\u2009blood urea nitrogen; LE-HMF\u2009=\u2009liquid HMF containing extensively hydrolyzed protein; PI-HMF\u2009=\u2009powdered intact protein HMF; HC\u2009=\u2009head circumference.*Values are mean\u2009±\u2009SEM (n).†Bicarbonate (mEq/L): (SDAY 1) LE-HMF > PI-HMF, P\u2009=\u20090.0419, LSM\u2009±\u2009SE: LE-HMF\u2009=\u200924.71\u2009±\u20090.56, PI-HMF\u2009=\u200923.33\u2009±\u20090.62.‡BUN (mg/dL): Feeding main effect: LE-HMF > PI-HMF, P\u2009=\u20090.0013, LSM\u2009±\u2009SE: LE-HMF\u2009=\u200911.99\u2009±\u20090.73, PI-HMF\u2009=\u20098.99\u2009±\u20090.83.§Prealbumin (mg/dL): Feeding main effect: LE-HMF > PI-HMF, P\u2009=\u20090.0049, LSM\u2009±\u2009SE: LE-HMF\u2009=\u200910.61\u2009±\u20090.35, PI-HMF\u2009=\u20099.32\u2009±\u20090.38.", 'title': 'Growth and Tolerance of Preterm Infants Fed a New Extensively Hydrolyzed Liquid Human Milk Fortifier.', 'date': '2015-10-22'}, '22301933': {'article_id': '22301933', 'content': 'Preterm human milk-fed infants often experience suboptimal growth despite the use of human milk fortifier (HMF). The extra protein supplied in fortifiers may be inadequate to meet dietary protein requirements for preterm infants.\nWe assessed the effect of human milk fortified with a higher-protein HMF on growth in preterm infants.\nThis is a randomized controlled trial in 92 preterm infants born at <31 wk gestation who received maternal breast milk that was fortified with HMF containing 1.4 g protein/100 mL (higher-protein group) or 1.0 g protein/100 mL (current practice) until discharge or estimated due date, whichever came first. The HMFs used were isocaloric and differed only in the amount of protein or carbohydrate. Length, weight, and head-circumference gains were assessed over the study duration.\nLength gains did not differ between the higher- and standard-protein groups (mean difference: 0.06 cm/wk; 95% CI: -0.01, 0.12 cm/wk; P = 0.08). Infants in the higher-protein group achieved a greater weight at study end (mean difference: 220 g; 95% CI: 23, 419 g; P = 0.03). Secondary analyses showed a significant reduction in the proportion of infants who were less than the 10th percentile for length at the study end in the higher-protein group (risk difference: 0.186; 95% CI: 0.370, 0.003; P = 0.047).\nA higher protein intake results in less growth faltering in human milk-fed preterm infants. It is possible that a higher-protein fortifier than used in this study is needed. This trial was registered with the Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au/) as ACTRN12606000525583.', 'title': 'Effect of increasing protein content of human milk fortifier on growth in preterm infants born at <31 wk gestation: a randomized controlled trial.', 'date': '2012-02-04'}, '22987877': {'article_id': '22987877', 'content': 'To evaluate the growth, tolerance, and safety of a new ultraconcentrated liquid human milk fortifier (LHMF) designed to provide optimal nutrients for preterm infants receiving human breast milk in a safe, nonpowder formulation.\nPreterm infants with a body weight ≤ 1250 g fed expressed and/or donor breast milk were randomized to receive a control powder human milk fortifier (HMF) or a new LHMF for 28 days. When added to breast milk, the LHMF provided ∼20% more protein than the control HMF. Weight, length, head circumference, and serum prealbumin, albumin, blood urea nitrogen, electrolytes, and blood gases were measured. The occurrence of sepsis, necrotizing enterocolitis, and serious adverse events were monitored.\nThis multicenter, third party-blinded, randomized controlled, prospective study enrolled 150 infants. Achieved weight and linear growth rate were significantly higher in the LHMF versus control groups (P = .04 and 0.03, respectively). Among infants who adhered closely to the protocol, the LHMF had a significantly higher achieved weight, length, head circumference, and linear growth rate than the control HMF (P = .004, P = .003, P = .04, and P = .01, respectively). There were no differences in measures of feeding tolerance or days to achieve full feeding volumes. Prealbumin, albumin, and blood urea nitrogen were higher in the LHMF group versus the control group (all P < .05). There was no difference in the incidence of confirmed sepsis or necrotizing enterocolitis.\nUse of a new LHMF in preterm infants instead of powder HMF is safe. Benefits of LHMF include improvements in growth and avoidance of the use of powder products in the NICU.', 'title': 'A new liquid human milk fortifier and linear growth in preterm infants.', 'date': '2012-09-19'}, '29772833': {'article_id': '29772833', 'content': "NutrientsNutrientsnutrientsNutrients2072-6643MDPI29772833598651310.3390/nu10050634nutrients-10-00634ArticleThe Effect of Increasing the Protein Content of Human Milk Fortifier to 1.8 g/100 mL on Growth in Preterm Infants: A Randomised Controlled TrialReidJessica1MakridesMaria12McPheeAndrew J.13StarkMichael J.34https://orcid.org/0000-0002-6474-0505MillerJacqueline15CollinsCarmel T.12*1Healthy Mothers, Babies and Children, South Australian Health and Medical Research Institute, Adelaide, SA 5006, Australia; jessica.reid@adelaide.edu.au (J.R.); maria.makrides@sahmri.com (M.M.); andrew.mcphee@sa.gov.au (A.J.M.); jacqueline.miller@sahmri.com (J.M.)2Adelaide Medical School, Discipline of Paediatrics, The University of Adelaide, Adelaide, SA 5006, Australia3Neonatal Medicine, Women’s and Children’s Hospital, Adelaide, SA 5006, Australia; michael.stark@adelaide.edu.au4The Robinson Research Institute, The University of Adelaide, Adelaide, SA 5006, Australia5Nutrition and Dietetics, Flinders University, Adelaide, SA 5006, Australia*Correspondence: carmel.collins@sahmri.com; Tel.: +61-8-8128-440917520185201810563426420181552018© 2018 by the authors.2018Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).The aim of this study was to assess the effect of feeding high protein human milk fortifier (HMF) on growth in preterm infants. In this single-centre randomised trial, 60 infants born 28–32 weeks’ gestation were randomised to receive a higher protein HMF providing 1.8 g protein (n = 31) or standard HMF providing 1 g protein per 100 mL expressed breast milk (EBM) (n = 29). The primary outcome was rate of weight gain. Baseline characteristics were similar between groups. There was no difference between high and standard HMF groups for weight gain (mean difference (MD) −14 g/week; 95% CI −32, 4; p = 0.12), length gain (MD −0.01 cm/week; 95% CI −0.06, 0.03; p = 0.45) or head circumference gain (MD 0.007 cm/week; 95% CI −0.05, 0.06; p = 0.79), despite achieving a 0.7 g/kg/day increase in protein intake in the high protein group. Infants in the high protein group had a higher proportion of lean body mass at trial entry; however, there was no group by time effect on lean mass gains over the study. Increasing HMF protein content to 1.8 g per 100 mL EBM does not improve growth in preterm infants born 28–32 weeks’ gestation.human milkgrowthlow birth weighthuman milk fortifier1. IntroductionIt is well established that fortified human milk improves growth rates in preterm infants [1,2,3]. However, the optimal amount of protein in the fortifier is yet to be determined, partly due to the variability in the protein content of human milk, both within mothers and over time. Too little protein results in a failure to meet protein requirements, estimated to be 4.0–4.5 g/kg/day for infants born <1000 g and 3.5–4.0 g/kg/day for those born 1000–1800 g [4]. Consequently, growth failure in the neonatal period is common in infants fed fortified human milk compared with infants fed preterm formula [5,6,7]. Conversely, too much protein may result in metabolic acidosis [8]. Individualized fortification, based on either the metabolic response of the infant [9,10,11], or the macronutrient content of mother’s milk [12] has been investigated and provides evidence in support of inadequate protein concentration of human milk fortifiers (HMFs) when used in a standardised approach. However, individualised approaches are time consuming and not easily translated to the clinical environment [13]. We previously investigated a fortifier providing 1.4 g compared with 1 g protein per 100 mL human milk in preterm infants <31 weeks’ gestation [14]. While we found no difference in the rate of weight and length gain between groups, there were fewer infants with length <10th percentile at discharge in the high protein group, suggesting a higher protein concentration fortifier may be needed to improve growth. We therefore aimed to determine the effect of further increasing the protein content of HMF to 1.8 g/100 mL compared with 1 g/100 mL, on growth in preterm infants born 28–32 weeks’ gestation.2. Materials and Methods2.1. Study DesignThe study was a single centre (Women’s and Children’s Hospital, North Adelaide, South Australia), parallel group randomised controlled trial conducted between February 2012 and May 2013.2.2. ParticipantsInfants born 28–32 completed weeks’ gestation whose mothers intended to provide breast milk were eligible to participate. Multiple births were eligible and were randomised individually. Infants with a major congenital or chromosomal abnormality likely to affect growth, or where protein therapy was contraindicated (e.g., major heart defects, cystic fibrosis, phenylketonuria, disorders of the urea cycle) were ineligible. Infants likely to transfer to remote locations and infants who had received standard practice HMF for more than four days were also excluded.2.3. Randomisation and BlindingInfants were randomised to one of two groups: the higher protein intervention group or the standard protein control group. An independent researcher created the randomisation schedule using a computer generated variable block design of 4 and 6. Stratification occurred for sex and gestational age 28–29 weeks and 30–32 weeks. Parents of eligible infants were approached by a neonatologist and followed-up for consent by a research nurse who was not involved in clinical care. Upon consent, infants were randomised by telephoning an independent researcher who held the randomisation schedule and assigned a unique study identification number. Participants, clinicians, outcome assessors and data analysts were blinded to randomisation group.2.4. InterventionsThe base HMF used for both trial groups was FM85 Human Milk Supplement (Nestlé Nutrition, Gland, Switzerland) which provides 1.0 g protein and 17.5 kcal when 5 g HMF is added to 100 mL expressed breast milk (EBM). The high protein fortifier was prepared by adding 0.9 g Protifar (Nutricia, Zoetermeer, The Netherlands), a bovine casein-based powder, to the FM 85. This resulted in an additional 0.8 g protein and 3.5 kcal per 100 mL EBM providing 1.8 g protein and 21 kcal when added to 100 mL of EBM. To ensure both fortifiers were isocaloric, thereby eliminating the effect of different energy intakes on growth, 0.9 g Polyjoule (Nutricia, Zoetermeer, The Netherlands), a glucose polymer, was added to the standard fortifier providing an additional 3.5 kcal but no extra protein, giving a total of 1.0 g protein and 21 kcal when added to 100 mL of EBM. The Polyjoule and Protifar supplements were packaged into identical 400-g containers each with a tamper proof seal (Pharmaceutical Packaging Professionals Pty Ltd., Thebarton, Australia). The containers were differentiated by four colour-coded labels to facilitate blinding, with each trial group separately color-coded into two groups. Infant nutrition attendants, under the direction of the Nutrition and Food Services Department, were trained in the preparation of the HMF. Trial fortifier was mixed at the rate of 5 g FM 85 plus either 0.9 g Protifar, or 0.9 g Polyjoule, for the high and standard protein groups respectively, with 4 mL of sterile water, to give a total volume of 8 mL for use with each 100 mL of EBM.2.5. Intervention AdministrationThe fortifier intervention and control fortifiers were delivered via the enteral tube, immediately prior to a feed (tube, bottle or breast). Trial HMFs were delivered at 8 mL HMF/100 mL EBM with the volume of HMF for each feed ordered daily by the medical or neonatal nurse practitioners. In cases where a mix of EBM and preterm formula was to be given, the trial HMF was only given if EBM was >50% of the total feed. When the infant received a direct breast feed, the timing of administration of the trial product (before, during or after the feed) was at the discretion of the primary care nurse in consultation with the mother. For each day, the trial HMFs were decanted into syringes and labelled with infant identification, volume of HMF and trial details. Syringes were stored refrigerated in the neonatal unit in each infant’s individually labelled container. Any syringes not administered in the 24-h period were recorded and discarded. Fluid balance records were audited daily for compliance with the trial protocol. Administration of trial HMF began as soon as practical after randomisation (within one to two days) and continued until study end, defined as the removal of the naso-gastric tube or estimated date of delivery, whichever came first.2.6. Nutritional IntakeMeasured protein and fat content of a weekly sample of unfortified EBM (MilkoScan Minor, Foss, Denmark) were used to represent the weekly composition of EBM [14]. The lactose concentration was assumed to be 6.8 g/100 mL. EBM was only sampled when the supply was surplus to the infant’s requirements. Missing values were substituted with the average macronutrient composition of all available samples (32 of the 45 mothers involved in the study were able to provide breast milk samples). Macronutrient intakes for the study fortifiers, EBM and formula were calculated from the volume ingested, the protein and fat concentration of EBM, and the manufacturer’s information on the study fortifiers and formula. The protein content of the preterm formula in use at the time of the study was 2.2 g/100 mL. Energy content was calculated by using the Atwater factors of 4, 4, and 9 kcal/g for protein, carbohydrate, and fat respectively.2.7. Outcome Assessments2.7.1. Primary outcomeThe primary outcome was rate of weight gain (g/week) from trial start (day of randomisation) to trial end. In addition to routine clinical measurements, a research nurse and J.R. weighed infants on randomisation, weekly and at study end; duplicate weight measurements were taken using electronic balance scales accurate to 5 g. Measurements were repeated if there was a discrepancy ≥10 g, with the average of the two closest measurements used.2.7.2. Secondary Efficacy and Safety OutcomesSecondary efficacy outcomes included length and head circumference gain (cm/week), infant weight at study end, small for gestational age (SGA) at study end and body composition (fat-free mass). Length measurements were taken weekly with the infant in the supine position and measured to the nearest 0.1 cm using a recumbent length board. Head circumference was measured weekly using a non-stretching tape placed around the largest occipito-frontal circumference. Duplicate measurements were done and repeated if there was a discrepancy ≥0.5 cm, with the average of the 2 closest measures taken. SGA was defined as below the 10th percentile for infants of the same sex and gestational age, as determined from Australian birth reference data [15]. Fat free (lean) mass was measured weekly by bioelectrical impedance spectroscopy (BIS) using the Imp™ SFB7 (ImpediMed Limited, Queensland, Australia) with the first measurement taken during the first week of the study.Secondary safety outcomes included feeding tolerance (days feeds interrupted and days to reach enteral intake ≥150 mL/kg/day). A protocol was developed for discontinuation of the trial fortifier based on uraemia (blood urea nitrogen (BUN) concentration >8.0 mmol/L) and/or a metabolic acidosis (base excess <−6 mmol/L) persisting for more than 48 hours. However, no infant met these criteria. Similarly, criteria were defined for the addition of protein to feeds if an infant had poor weight gain defined as <15 g/kg/day over the preceding 7-day period associated with a BUN of <2 mmol/L when feed volumes reached 170 to 180 mL/kg/day. In this case, Protifar could be added at the discretion of the attending neonatologist, in addition to the allocated intervention fortifier. Additional protein was ceased when weight gain of 15 g/kg/day and a BUN >2 mmol/L were achieved.2.7.3. Biochemical AnalysesWeekly blood samples were taken and BUN, plasma albumin, plasma creatinine, pH and base deficit measured. Blood spots were collected weekly on filter paper and amino acids measured using tandem mass spectrometry (SA Pathology, Neonatal Screening Centre, Adelaide, Australia).2.7.4. Sample Size and Statistical AnalysisA sample size of 60 (30 per group) would detect a difference in weight gain of 3.31 g per day between the high protein and standard protein groups (80% power, p = 0.05). Consultation with the neonatal medical team agreed that this was a clinically important difference on which clinical practice could be changed. Mean weight, length, head circumference and lean mass gains over the trial period, were calculated for each infant using a linear effects model with a random intercept and slope. Using the slope, a linear regression model was fitted for each infant. Clustering (multiple births) was accounted for by using a generalised estimating equation with an independent working correlation matrix. All analyses were intention-to-treat. All models were adjusted for sex and gestational age category (28–29 and 30–32 weeks’ gestation). A per protocol analysis was specified a priori for infants who consumed ≥70% of their prescribed trial fortifier.2.7.5. EthicsEthical approval was granted by the Women’s and Children’s Health Network Human Research Ethics Committee (REC2401/10/14). This trial was registered with the Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au/) as ACTRN12611001275954.3. Results3.1. Study PopulationSixty infants were enrolled in the trial with 31 infants randomised to the high protein group and 29 infants to the standard protein group (Figure 1). There were 31 infants born from multiple births (14 sets of twins, 1 set of triplets). In all multiple births, apart from two sets of twins, the infants were randomly allocated to different interventions. For the triplets, two were randomised to the high protein group and one to the standard protein group. Four infants, two from each group, were withdrawn from the study after randomisation but before the first dose of trial fortifier was administered after parents changed their minds about involvement. A further two infants (twins) in the high protein group did not have any available breast milk and withdrew before the commencement of fortifier. One set of twins and one singleton were withdrawn by the parents midway through the trial due to perceived feeding intolerance and another infant was withdrawn by the clinical team after developing necrotising enterocolitis. In all cases of withdrawal, parents consented to the ongoing collection of data and all were included in intention-to-treat analyses. Baseline infant and maternal demographic, clinical and nutritional characteristics at randomisation were comparable between groups except that there were more male infants in the high protein group, n = 16 (52%) than the standard protein group, n = 12 (41%), the mean ± SD birth weight was lower in the higher protein group (1483 ± 423 g versus 1551 ± 407 g in the high and standard groups, respectively) and there were more infants classified as SGA for weight in the high protein group, n = 5 (16%) than the standard protein group, n = 1 (3%) (Table 1).3.2. Nutritional ManagementForty infants received standard ward HMF, S-26 SMA HMF (Wyeth Nutrition) while waiting for consent, 18 in the high and 22 in the standard protein group (Table 1). The remaining twenty trial infants started immediately on their allocated trial intervention.Nutritional intake of the infants for the first 28 days of the study did not differ between the groups except that the high protein group received more protein (mean ± SD 4.2 ± 1.3 vs. 3.5 ± 0.93 g/kg/day in the high and standard protein groups respectively). The protein concentration of the EBM was not different between groups (mean ± SD 1.43 ± 0.27 and 1.45 ± 0.28 g protein/100 mL in the high and standard groups, respectively) and the difference in protein intake was due to more protein derived from the HMF (mean ± SD 1.9 ± 1.2 and 1.2 ± 0.6 g/kg/day, in the high and standard groups, respectively. Energy intakes and fluid volume were similar between the groups (energy: mean ± SD 124 ± 34 and 126 ± 27 kcal/kg/day and fluid: mean ± SD 154 ± 39 and 157 ± 32 mL/kg/day in the high and standard groups, respectively). The high protein group received 83% (±32) of their total enteral intake as EBM compared with the control group who received 90% (±23).3.3. Primary OutcomeThere was no difference in the rate of weight gain between groups (Table 2) (mean (95% CI) high protein 245 (230, 260) g/week and standard protein 258 (244, 272) g/week, adjusted mean difference −14 (−32, 4) p = 0.12). Results were similar when analysed per protocol (Table 2).3.4. Secondary Outcomes3.4.1. GrowthThere were no differences in rate of length or head circumference gain (Table 2). High protein HMF infants weighed less at study end but this was not statistically significant (Table 2) and is consistent with the difference in birth weight between the groups (Table 1). There were no differences in length or head circumference at study end between the groups (Table 2). There was no difference in SGA status for weight between high and standard protein HMF groups at the end of the study (n = 8, 25%, and n = 3, 10% SGA infants in the high and standard protein groups, respectively, adjusted Relative Risk (95% CI); 2.5 (0.8, 7.9), p = 0.11).Over the first four weeks of the trial, when >75% of participants were still in hospital, fat free (lean) mass was measured with the week one measurement taken a mean of 8 ± SD 2 days after randomisation. Fat free mass as a proportion of body weight (Figure 2) from weeks one to four was greater in high protein group infants than standard protein group infants (p = 0.03). However, there was no significant group by time interaction (p = 0.84). At week three alone, there was a significant increase for fat free mass as a proportion of body weight in the high protein group (p = 0.04).3.4.2. BiochemistryDue to the variable nature of blood chemistry data and length of hospital stay (to discharge), only the first three trial weeks could be accurately analysed using a linear mixed effects model.There was a significant group by time interaction for BUN levels (p < 0.001) with BUN levels significantly increased in the high protein group (Figure 3). This difference continued for the duration of the trial (p < 0.001). There were 12 occurrences in nine separate infants where BUN levels were measured over the pre-specified safety threshold of 8 mmol/L. Seven of these occurred during baseline blood tests taken at randomisation and were therefore not a result of the intervention. Six of these infants had BUN measurements in the normal range at their next weekly blood test. One infant had a BUN measurement >8 mmol/L at week one; the infant did not have another BUN measurement over 8 mmol/L for the rest of the trial. Two other infants, both in the high protein group, recorded BUN concentrations >8.0 mmol/L, peaking at 8.8 mmol/L, on five occasions, however the base excess remained above −6 mmol/L with no other abnormal biochemistry. There was one occurrence of an infant in the standard protein group requiring additional protein due to poor weight gain and BUN <2 mmol/L.There were no group by time interactions or group differences for albumin, creatinine, glucose, pH (results not shown). Phenylalanine (Phe) and tyrosine (Tyr), amino acids associated with increased protein intake, were both increased in the high protein group compared to the standard group at study week 3 (Phe median (IQR) μmol/L: 33 (28–42) vs. 25 (23–30), p <0.001 and Tyr median (IQR) μmol/L: 196 (151–267) vs. 128 (99–172) μmol/L, p <0.003 in the high and standard groups respectively.3.4.3. Clinical OutcomesHigh protein HMF infants were significantly more likely to have feeds interrupted (11 (35%) vs. 6 (21%), p = 0.01, in the high and standard protein groups, respectively) Table 3. There was no significant difference in the number of days spent on parenteral nutrition, days of intravenous lipid or the days taken to reach full enteral feeds. Likewise, there was no significant difference between the groups for any other clinical outcome (Table 3).4. DiscussionThe aim of this study was to assess the effect of a higher protein HMF on preterm infant growth. Our trial interventions resulted in the high protein group infants receiving 0.7 g/kg/day more protein than infants in the standard protein group, with mean protein intakes within recommended ranges for both groups. Despite this, there were no differences in growth between the two groups. The accumulation of fat free mass and fat mass, also did not differ between groups. While the higher protein group had a greater proportion of fat free mass from week one, the absence of a baseline measurement makes the interpretation of this difficult. It is unlikely that the intervention would have had an effect in the first week of the study, particularly as the change in fat free mass over time did not differ between groups. A significant difference between groups was noted at week three only and the implication of this is unclear. It is possible that this is a chance finding of no clinical significance.These results are confirmed by a recent study by Maas et al. [16] who compared 1 and 1.8 g protein concentration in powdered HMFs in a similar population to ours and found no difference in growth. Their trial interventions achieved a 0.6 g/kg/day median greater intake of protein, similar to our study, and protein intakes were within recommendations. Growth rates in both studies approximated foetal growth rates. A further two studies compared two different, newly formulated liquid HMFs with higher protein concentrations, with standard powdered HMFs. Moya et al. [17] compared Mead Johnson Nutrition products: a liquid fortifier with an Enfamil powdered fortifier, which when mixed with EBM provided 3.2 and 2.6 g protein/100 mL, respectively, equating to an additional 1.8 and 1.1 g protein. Kim et al. [18], in a non-inferiority trial, compared the Abbott Nutrition products of Similac HMF liquid, providing 3.6 g protein/100 kcal when mixed with EBM, with Similac HMF powder providing 3 g protein/100 kcal when mixed. These comparisons equate to an additional 1.6 and 1 g protein added to 100 mL EBM in the liquid and powder, respectively. The populations were similar between studies [17,18] except that Moya et al. [17] inclusion criteria (≤30 weeks’ gestation, birth weight ≤1250 g) resulted in a slightly less mature and smaller population than in both Kim et al. [18] study and this current study. Neither study [17,18] showed a difference in weight gain between groups, however, Moya et al. [17] found improved length gain with the higher protein. Both studies found infants in the high protein group were heavier at study end. Almost half the participants in Moya’s study were <1000 g at birth; hence their protein requirements of 4 to 4.5 g/kg would have been met by the high, but not the control, protein fortifier at volumes of 150 mL/kg. This may explain the effect seen on length gain. Two other studies have compared fortifiers containing 1 and 1.4 g protein added to 100 mL EBM with mixed results. Our previous trial [14] showed no effect of increased protein on growth, although did show a reduction in the number of infants SGA for length at discharge. However, Rigo et al. [19], in a non-inferiority trial, found improved weight gain of 2.3 g/day with the higher protein fortifier. The trial products in both these studies were similar, as were the population. It is possible that the smallest infants, with the highest protein needs, are the ones to benefit most from increased protein and that the larger sample size in Rigo (n = 153) compared to that in Miller (n = 92) elucidated the differences. Taken collectively, these results and ours suggest that protein concentrations in HMFs of 1.8 g provide no additional benefit in the population studied, but smaller infants are worthy of further investigation.The significantly elevated BUN levels seen at weeks 1, 2 and 3 were expected and have occurred in other high protein nutritional intervention studies [9,14,17]. Assuming adequate renal function, BUN is proportional to protein intake [20] and is often used as a crude marker of protein sufficiency. Low BUN levels suggest inadequate protein intake and high levels indicate possible excessive intake [9]. Blood phenylalanine and tyrosine concentrations were also significantly increased in the higher protein group, in week 3 only, and this is unlikely to be clinically significant. There were no differences in creatinine, albumin or other biochemical markers suggesting the intervention did not harm the infants.A strength of this study is the rigour with which dietary intake and growth were assessed. The protein and fat concentrations of EBM were measured, rather than assumed, resulting in accurate reporting of dietary intake and confirmation that, despite the variability of protein in EBM, we achieved a mean intake difference of 0.7 g/kg/day of protein between groups. Similarly, we measured both growth and body composition in an attempt to discern differences in weight gain arising from extra protein. This trial also has some limitations. Although all infants were included in the analyses, there were 10 who either did not receive, or ceased the intervention, which may have impacted results. In addition, the pragmatic nature of this trial may have influenced results as clinicians may have adjusted feed regimes if poor weight gain was identified. There was one instance of extra Protifar prescribed to an infant in the standard protein group and subtle increases in feed volume may also have occurred although volume of intake was not different between groups. This may have made it more difficult to detect differences between intervention groups. We used BIS to determine fat and fat free mass. BIS is the only cot-side technique available where infants requiring respiratory support can be assessed. While accuracy of BIS at the individual level is poor, BIS provides a useful means of determining differences in body composition between population means [21].Many of the recent trials discussed have already achieved mean growth rates approaching intra-uterine growth, with similar growth rates between groups. Findings from this current study are only generalisable to a similar population (infants born 28–32 week’s gestation). Therefore, to explicate the subtle effects of increasing protein on growth, future trials may need to focus on birth weight categories as they relate to protein requirements (i.e., <1000 g and 1000–1800 g). Due to the small proportion of infants born <1000 g, large multi-centre trials will be needed to tease out the effect.5. ConclusionsIncreasing the protein concentration of HMF from 1.0 to 1.8 g protein added per 100 mL EBM does not improve growth in preterm infants born 28–32 weeks’ gestation.AcknowledgmentsWe thank the families who participated in this study.Author ContributionsConceptualization, J.R., M.M., A.J.M. and C.T.C.; Formal analysis, J.R., M.M., A.J.M., M.J.S., J.M. and C.T.C.; Funding acquisition, J.R., M.M., A.J.M., M.J.S. and C.T.C.; Investigation, J.R., M.M., A.J.M., M.J.S. and C.T.C.; Supervision, M.M., A.J.M., M.J.S. and C.T.C.; Writing: original draft, J.R., J.M. and C.T.C.; Writing: review and editing, J.R., M.M., A.J.M., M.J.S., J.M. and C.T.C.FundingThis research was funded by a Women’s and Children’s Hospital Foundation Grant. Research Fellowships were provided by the National Health and Medical Research Council of Australia (M.M. Principal Research Fellow APP1061704) and the MS McLeod Research Fellowship, MS McLeod Research Fund, Women's and Children’s Hospital Research Foundation (C.T.C). The contents of the published material are solely the responsibility of the authors and do not reflect the views of the National Health and Medical Research Council of Australia.Conflicts of InterestOutside the submitted work, Maria Makrides serves on scientific advisory boards for Fonterra and Nestle. Honoraria are paid to her institution for continuing education of early career researchers. Maria Makrides also holds a Principal Research Fellowship from the NHMRC (APP1061704). Other authors declare no conflict of interest. Nestlé Nutrition donated half of the human milk fortifier used in the trial and Nutricia donated the Polyjoule and Protifar supplements. 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Nutr.201765e83e9310.1097/MPG.00000000000016862872765420.PolbergerS.K.AxelssonI.E.RaihaN.C.Urinary and serum urea as indicators of protein metabolism in very low birthweight infants fed varying human milk protein intakesActa Paediatr. Scand.19907973774210.1111/j.1651-2227.1990.tb11548.x223926621.CollinsC.T.ReidJ.MakridesM.LingwoodB.E.McPheeA.J.MorrisS.A.GibsonR.A.WardL.C.Prediction of body water compartments in preterm infants by bioelectrical impedance spectroscopyEur. J. Clin. Nutr.201367Suppl. 1S47S5310.1038/ejcn.2012.16423299871Figure 1Participant flow through the trial. 1 from rural locations (n = 52), insufficient milk supply (n = 36), required interpreter (n = 6); congenital abnormality (n = 3); 2 did not want to take part (n = 25), did not want twins to be randomized individually (n = 8), parent not visiting (n = 1), immediately transferred to another centre (n = 1).Figure 2Fat free mass as a proportion of body weight for the first four weeks of the trial. Values are means, error bars are 95% CI. High protein n = 30, 30, 27, 26 and standard protein 29, 27, 26, 23 in weeks 1, 2, 3, 4 respectively. Adjusted for sex and gestational age, group interaction, p = 0.03, time interaction, p = 0.01. group × time interaction p = 0.84; * p = 0.04.Figure 3BUN from randomisation to week 3. Values are mean, error bars are 95% CI. High protein: n = 31, 28, 26, 25; Standard protein: n = 29, 26, 24, 24 for weeks baseline, 1, 2, 3. Adjusted for sex and GA, overall group effect <0.001, group * week interaction, p <0.001, * p = 0.04; ** p <0.001.nutrients-10-00634-t001_Table 1Table 1Baseline infant and maternal characteristics.CharacteristicHigh Protein (n = 31)Standard Protein (n = 29)\nInfant characteristics\n\n\nSingleton15 (48)16 (55)Twin15 (48)12 (41)Triplet2 (7)1 (3)Gestational age (week)30.5 ± 1.530.1 ± 1.428–29 weeks’ gestation10 (32)9 (31)30–32 weeks’ gestation21 (68)20 (69)Male infants16 (52)12 (41)Birth weight (g)1483 ± 4231551 ± 407SGA for weight at birth5 (16)1 (3)Birth length (cm)40.0 ± 3.340.2 ± 2.8Head circumference (cm)28.5 ± 328.5 ± 1.8Infants received standard ward HMF before randomisation18 (58)22 (76)Length of standard ward fortification before trial HMF start (day)1.3 ± 1.72.0 ± 1.5Time between birth and trial HMF start (day)8.9 ± 3.29.0 ± 2.5\nMaternal characteristics\n\n\nMaternal age (years)29.9 ± 6.331.7 ± 5.3Mother smoked during pregnancy5 (16.1)3 (10.3)Caucasian27 (96)23 (82)Primiparous19 (61.3)12 (41.4)Previous preterm birth4 (33.3)6 (35.3)Data are presented as n (%) or mean ± SD.nutrients-10-00634-t002_Table 2Table 2Anthropometric changes over the study.\nIntention to Treat AnalysesPer Protocol Analyses 1High Protein (n = 31)Standard Protein (n = 29)Adjusted Mean Difference 2\np\n2\nHigh Protein (n = 21)Standard Protein (n = 23)Adjusted Mean Difference 2\np\n2\nWeight gain (g/week)245 (230, 260)258 (244, 272)−14 (−32, 4)0.12245 (228, 262)262 (247, 277)−15 (−36, 5)0.14Length gain (cm/week)1.1 (1.1, 1.2)1.1 (1.1, 1.2)−0.01 (−0.06, 0.03)0.451.1 (1.1, 1.2)1.2 (1.1, 1.2)−0.01 (−0.06, 0.04)0.62Head circumference gain (cm/week)1.1 (1.0, 1.1)1.1 (1.0,1.1)0.007 (−0.05, 0.06)0.791.1 (1.1, 1.1)1.1 (1.1, 1.1)−0.004 (−0.06, 0.05)0.88Weight at study end (g) 32658 (2544, 2771)2757 (2632, 2883)−100 (−251, 50)0.192646 (2489, 2805)2815 (2675, 2955)−157 (−341, 28) 0.1Length at study end (cm)45.2 (44.5, 45.9)45.8 (45.0, 46.6)−0.5 (−1.3, 0.3)0.1945.2 (44.4, 46.0)46.3 (45.6, 47)−0.86 (−1.85, 0.12)0.09Head circumference at study end (cm)33.1 (32.5, 33.6)33.0 (32.4, 33.7)0.03 (−0.6, 0.7)0.9233.3 (32.7, 33.9)33.6 (33.0, 34.1)−0.16 (−0.90, 0.57)0.66Data are presented as mean, (95% CI); 1 For inclusion in ‘per protocol’ analysis, infants must have consumed 70% or more of their trial group HMF; 2 adjusted for sex and gestational age; 3 study end defined as removal of naso-gastric tube or term equivalent, whichever came first.nutrients-10-00634-t003_Table 3Table 3Feeding and clinical management.VariableHigh Protein (n = 31)Standard Protein (n = 29)\np\nInfant required enteral protein supplementation 101 (3.4)0.48Feeding interrupted 211 (35)6 (21)0.01Days receiving parenteral nutrition10 (7, 13)9 (7, 11)0.34Days of intravenous lipid4 (3, 7)4 (3, 6)0.72Days to full enteral feeds 38 (6, 10)8 (7, 10)0.72Confirmed necrotizing enterocolitis1 (3.2)0>0.99Oxygen at discharge2 (6.5)1 (3.4)0.15Late onset sepsis1 (3.2)0>0.99Data are reported as n (%) or mean (95% CI).1 One infant in the standard protein group was prescribed a protein supplement (Protifar) 2 Feeding interrupted was defined as one of more feeds not given in a day; 3 Full enteral feeds was defined as 150 mL/kg/day).", 'title': 'The Effect of Increasing the Protein Content of Human Milk Fortifier to 1.8 g/100 mL on Growth in Preterm Infants: A Randomised Controlled Trial.', 'date': '2018-05-19'}, '28727654': {'article_id': '28727654', 'content': "J Pediatr Gastroenterol NutrJ. Pediatr. Gastroenterol. NutrJPGAJournal of Pediatric Gastroenterology and Nutrition0277-21161536-4801Lippincott Williams & Wilkins287276545625962JPGN-16-82510.1097/MPG.000000000000168600025Original Articles: NutritionGrowth and Nutritional Biomarkers of Preterm Infants Fed a New Powdered Human Milk Fortifier: A Randomized TrialRigoJacques∗HascoëtJean-Michel†BilleaudClaude‡PicaudJean-Charles§MoscaFabio||RubioAmandine¶SalibaElie#RadkëMichaël∗∗SimeoniUmberto††GuilloisBernard‡‡de HalleuxVirginie∗JaegerJonathan§§AmeyeLaurent||||HaysNicholas P.¶¶SpalingerJohannes##∗Department of Neonatology, University of Liège, CHR Citadelle, Liège, Belgium†Maternité Régionale Universitaire A. Pinard, Nancy‡CIC Pédiatrique 1401 INSERM-CHU, Bordeaux§Service de Neonatologie, Hôpital de la Croix Rousse, Lyon, France||Neonatal Intensive Care Unit, Department of Clinical Science and Community Health, Fondazione IRCCS “Ca’ Granda” Ospedale Maggiore Policlinico, University of Milan, Milan, Italy¶Hôpital Couple Enfant, CHU de Grenoble, Grenoble#Hôpital Clocheville, CHU de Tours, Tours, France∗∗Klinikum Westbrandenburg GmbH, Potsdam, Germany††Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland‡‡Hôpital Clemenceau, CHU de Caen, Caen, France§§Nestlé Clinical Development Unit, Lausanne, Switzerland||||Nestlé Nutrition R&D, Vevey, Switzerland¶¶Nestlé Nutrition R&D, King of Prussia, PA##Children's Hospital of Lucerne, Lucerne, Switzerland.Address correspondence to Jacques Rigo, MD, PhD, Service Universitaire de Néonatologie, CHR de la Citadelle, Boulevard du Douzième de Ligne, 1 4000 Liège, Belgium (e-mail: J.Rigo@ulg.ac.be); Address reprint or protocol requests to: Nicholas P. Hays, PhD, 3000 Horizon Dr., Suite 100, King of Prussia, PA 19406 (e-mail: Nicholas.Hays@rd.nestle.com).1020172292017654e83e93231120162952017Copyright © The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition2017This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0ABSTRACTObjectives:The aim of this study was to assess growth and nutritional biomarkers of preterm infants fed human milk (HM) supplemented with a new powdered HM fortifier (nHMF) or a control HM fortifier (cHMF). The nHMF provides similar energy content, 16% more protein (partially hydrolyzed whey), and higher micronutrient levels than the cHMF, along with medium-chain triglycerides and docosahexaenoic acid.Methods:In this controlled, multicenter, double-blind study, a sample of preterm infants ≤32 weeks or ≤1500\u200ag were randomized to receive nHMF (n\u200a=\u200a77) or cHMF (n\u200a=\u200a76) for a minimum of 21 days. Weight gain was evaluated for noninferiority (margin\u200a=\u200a–1\u200ag/day) and superiority (margin\u200a=\u200a0\u200ag/day). Nutritional status and gut inflammation were assessed by blood, urine, and fecal biochemistries. Adverse events were monitored.Results:Adjusted mean weight gain (analysis of covariance) was 2.3\u200ag/day greater in nHMF versus cHMF; the lower limit of the 95% CI (0.4\u200ag/day) exceeded both noninferiority (P\u200a<\u200a0.001) and superiority margins (P\u200a=\u200a0.01). Weight gain rate (unadjusted) was 18.3 (nHMF) and 16.8\u200ag\u200a·\u200akg−1\u200a·\u200aday−1 (cHMF) between study days 1 and 21 (D1–D21). Length and head circumference (HC) gains between D1 and D21 were not different. Adjusted weight-for-age z score at D21 and HC-for-age z score at week 40 corrected age were greater in nHMF versus cHMF (P\u200a=\u200a0.013, P\u200a=\u200a0.003 respectively). nHMF had higher serum blood urea nitrogen, pre-albumin, alkaline phosphatase, and calcium (all within normal ranges; all P\u200a≤\u200a0.019) at D21 versus cHMF. Both HMFs were well tolerated with similar incidence of gastrointestinal adverse events.Conclusions:nHMF providing more protein and fat compared to a control fortifier is safe, well-tolerated, and improves the weight gain of preterm infants.Keywordsgrowthhuman milklow birth weightSTATUSONLINE-ONLYOPEN-ACCESSTRUEWhat Is KnownDue in part to variability in human milk composition, incidence of postnatal growth restriction is more frequently reported in very-low-birth-weight infants fed fortified human milk compared to those fed preterm formulas.The optimal composition of human milk fortifier and nutritional recommendations for preterm infants fed fortified human milk are still debated.What Is NewA new human milk fortifier containing partially hydrolyzed protein, fat, and carbohydrate provides a higher protein:energy ratio while achieving lower osmolality versus a current fortifier.In preterm infants, the new fortifier improves weight gain and reduces postnatal growth restriction compared to the current fortifier.Feeding of human milk (HM) rather than preterm formulas provides many benefits to preterm infants (eg, accelerated gut maturation (1); protection against infections (2), sepsis (3), necrotizing enterocolitis (2), and retinopathy of prematurity (4); possible protective effect on neurodevelopment (5)) that are mediated by protective biomolecules and trophic factors in HM. HM, however, provides inadequate protein and micronutrients to support the rapid growth and bone mineralization of preterm infants. These deficits are particularly acute in the smallest infants (birthweight <1500\u200ag) who have the highest protein and mineral needs (6). Fortification of mother's own milk or banked HM is therefore recommended for all preterm infants with birthweight <1800\u200ag to improve nutrient accretion and in-hospital growth (7,8).Feeding fortified HM helps support adequate growth and bone mineralization (9), and is associated with favorable neurodevelopmental outcomes (10), although evidence for improved outcomes other than in-hospital growth is limited (11). The nutritional content, however, of some currently available fortifiers may be inadequate for many preterm infants. Incidence of postnatal growth restriction is more frequently reported in very-low-birth-weight infants fed fortified HM compared to those fed preterm formulas (12,13). In addition, the nutritional profile of HM from mothers of premature infants varies greatly (14) and may differ from published reference compositional data, which may lead to less-than-recommended intakes of protein and energy (15,16). These nutritional inadequacies may worsen with use of donor HM, which is often from mothers of term infants >1-month postpartum (17).A new powdered HM fortifier has been developed with a higher protein:energy ratio (protein provided as partially hydrolyzed whey), non-protein energy from lipids and carbohydrate, and higher electrolyte and vitamin levels (enriching HM in line with ESPGHAN (18) and expert group (19) recommendations) versus a control fortifier. When mixed with HM containing 1.5\u200ag protein/100\u200amL (2–4 week milk) (20–22), it provides 3.6\u200ag protein/100 kcal (within the ESPGHAN-recommended ranges (18) for protein and energy intakes for a minimal intake volume of 140\u200amL/kg/day in very-low-birth-weight infants up to 1.8\u200akg body weight), with osmolality below the recommended threshold of 450\u200amOsm/kg (23,24).This study evaluated growth and nutritional biomarkers during a 21-day interval in clinically stable preterm infants receiving the new HM fortifier (nHMF) compared to infants fed a control fortifier (cHMF). The primary objective was to assess weight gain velocity (grams per day); evaluations of other growth parameters (including weight gain velocity in gram per kilograms per day) and intervals (eg, to 40 weeks corrected age [W40CA]), feeding tolerance, adverse events, time to full fortification/full enteral feeding, and markers of protein-energy, electrolytes, bone metabolic status, gut inflammation, and maturity of gastrointestinal (GI) function were also conducted as secondary outcomes. We hypothesized that weight gain of infants fed nHMF would be both noninferior (lower limit of 95% confidence interval [CI] of mean difference >–1\u200ag/day) and superior (lower limit of 95% CI of mean difference >0\u200ag/day) to that of infants fed cHMF.METHODSStudy design and participantsThis was a controlled, double-blind, randomized, parallel-group study conducted in neonatal intensive care units (NICUs) at 11 metropolitan hospitals in France, Belgium, Germany, Switzerland, and Italy. NICU size ranged from 25 to 45 beds. Clinically stable male and female preterm infants with gestational age ≤32 weeks or birthweight ≤1500\u200ag and born to mothers who had agreed to provide expressed or donor breastmilk for the entire 21-day study duration were enrolled in the study from April 2011 to March 2014. Infants were excluded if they had a history of or current systemic, metabolic, or chromosomic disease, any congenital anomalies of the GI tract, were small for gestational age (defined in this study as bodyweight ≤5th percentile (25)), or were receiving steroids or preterm formula during the study period. For multiple births, the first sibling was randomized and other siblings were allocated to the same group. The study was reviewed and approved by an institutional review board/independent Ethics Committee at each study site. Each subject's parent/legal representative provided written informed consent before participating in the study.Infants tolerating ≥100\u200amL\u200a·\u200akg−1\u200a·\u200aday−1 of HM for >24\u200ahours were randomized to receive either nHMF or cHMF for a minimum of 21 days; infants continued to receive their allocated study fortifier (or were transitioned to a routine/standard fortifier) until NICU discharge or medical decision to stop fortification, and fortification was stopped after discharge. The fortifiers were both cow's milk-based and provided similar energy supplementation (17\u200akcal/100\u200amL of HM). For every 100\u200amL of HM, nHMF provided 1.4\u200ag partially hydrolyzed whey protein, 0.7\u200ag lipids (primarily medium chain triglycerides and docosahexaenoic acid), 1.3\u200ag carbohydrate (maltodextrin), with a blend of micronutrients. cHMF (FM85 Human Milk Fortifier, Nestlé, Switzerland) provided 1.0\u200ag extensively hydrolyzed whey protein, no lipids, 3.3\u200ag carbohydrate (lactose and maltodextrin), with a blend of micronutrients. nHMF contained higher concentrations of some vitamins and electrolytes compared to cHMF, but both contained similar levels of minerals, including calcium (as calcium glycerophosphate and calcium phosphate) and phosphorus. Table 1 presents the estimated composition and osmolality of preterm HM (22) fortified with each fortifier. Fortifiers were fed beginning at half-strength (Fortification Strength Increase day 1; FSI1), then advanced per hospital practice, with full-strength fortification occurring once infants could maintain intakes of 150 to 180\u200amL\u200a·\u200akg−1\u200a·\u200aday−1 (ie, full enteral feeds; study day 1 [D1]). A study plan schematic is presented in Figure 1.FIGURE 1Study design. cHMF\u200a=\u200acontrol human milk fortifier; D1\u200a=\u200astudy day 1; D7\u200a=\u200astudy day 7; D10/11\u200a=\u200astudy day 10/11; D14\u200a=\u200astudy day 14; D21\u200a=\u200astudy day 21; DC\u200a=\u200adischarge (note that infants continued to receive their allocated study fortifier [or were transitioned to a routine/standard fortifier] until neonatal unit discharge or medical decision to stop fortification if length of stay was >21 days, and fortification was stopped after discharge) ; FSI1\u200a=\u200afortification strength increase day 1; HC\u200a=\u200ahead circumference; HM\u200a=\u200ahuman milk; nHMF\u200a=\u200anew human milk fortifier; W40CA\u200a=\u200aweek 40 corrected age.Study ProceduresGrowthInfant nude weight (to the nearest 1\u200ag) was measured daily by trained nursery personnel using a calibrated electronic scale (Baby Scale 717, Seca, Semur-en-Auxois, France). Recumbent length and head circumference (HC; both to the nearest 0.1\u200acm) were measured at FSI1, D1, and weekly thereafter. At least 2 trained examiners measured recumbent length using a length board (Mobile Measuring Board 417, Seca, Semur-en-Auxois, France) while maintaining proper body alignment and full body extension with feet flexed. HC was measured using a nonelastic measuring tape (Measuring Tape 212 or 218, Seca, Semur-en-Auxois, France) placed over the largest circumference of the skull (above the supraorbital ridges while covering the most prominent part of the frontal bulge anteriorly). The same calibrated equipment was used for anthropometric measures for each infant at all sites. Weight-for-age, length-for-age, and HC-for-age z scores were calculated using Fenton (25). Weight gain velocity (grams per kilograms per day) was calculated using the average of the start and end weights as the denominator.Markers of Protein-energy, Electrolyte, and Bone Metabolic StatusBlood and urine samples were collected at D1, D10/11, and D21 and analyzed for serum creatinine and prealbumin, blood urea nitrogen (BUN), urinary urea, hemoglobin, hematocrit, electrolyte status, and bone metabolic status. All blood and urine parameters were analyzed as part of routine clinical assessments at each NICU. Since 24-hour urine collections were not performed in this study owing to logistical infeasibility, urinary markers were corrected for 24-hour creatinine excretion (26) assuming a standard urinary excretion in preterm infants of 10\u200amg\u200a·\u200akg−1\u200a·\u200aday−1(27).Feeding Tolerance and Adverse EventsFeeding tolerance was evaluated by trained nursery staff who recorded daily milk intake (milliliters), stool pattern (defecation frequency and stool consistency [5\u200a=\u200ahard, 4\u200a=\u200aformed, 3\u200a=\u200asoft, 2\u200a=\u200aliquid, or 1\u200a=\u200awatery]), presence of abdominal distention, and incidence of spitting-up (defined as return of a small amount of swallowed food, usually a mouthful, and usually occurring during or shortly after feeding) and vomiting (defined as return of a larger amount of food with more complete emptying of the stomach, and usually occurring sometime after feeding). In addition, frequency, type, and attribution to fortifier intake of adverse events (AEs; including clinical and laboratory) were evaluated using physician-reported information recorded using standardized forms from enrollment to W40CA. AEs were categorized by the reporting investigator as “serious” in accordance with International Conference on Harmonization criteria (28) and as “related to the intervention” based on detailed, standardized criteria provided in the protocol.Statistical AnalysisSample size was based on a previous study (29), which investigated growth and zinc status in preterm infants fed fortified HM. In the present trial, a group-sequential design was chosen (Wang and Tsiatis) (30) with 1 interim analysis. To detect a noninferior weight gain in infants fed with nHMF versus cHMF from D1 to D21 (noninferiority margin –1\u200ag/day, expected weight gain difference 2\u200ag/day, standard deviation 4.73\u200ag/day, type I error 5%, power 80%) (29), 192 subjects (males and females combined) were needed. A computer-generated list of random numbers was used to allocate group assignments. Minimization algorithm with allocation ratio 1:1 and second best probability of 15% was used. Stratification factors were center, sex, and birthweight (100g intervals). Group coding was used with 2 nonspeaking codes per group; fortifier packaging was coded accordingly but otherwise identical in appearance. Infants were enrolled and assigned to their intervention by the study investigators or trained delegates. All study personnel (both site- and sponsor-based) and participants (infants’ families) were blind to group assignment. Noninferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference in weight gain from D1 to D21 was larger than the noninferiority margin. Superiority was evaluated if noninferiority was demonstrated. Weight gain was analyzed in the intent-to-treat (ITT) and per-protocol populations by analysis of covariance (ANCOVA) adjusting for D1 postmenstrual age and weight, sex, and center (random effect). Sensitivity analyses were conducted using ANCOVA models that adjusted for covariates that were determined post hoc to be significantly different between groups and which may have confounded the primary results (eg, mother smoking status). Secondary endpoints were analyzed in the ITT population only. For noninferiority and superiority tests, 1-sided P values are provided and should be compared to a reference value of 0.025. For other tests, 2-sided P values are provided and should be compared to a reference value of 0.05. 95% CIs provide estimates for feeding effects on all endpoints. Based on prespecified guidelines in the independent Data Monitoring Committee's (DMC) charter, a single interim analysis was conducted when 134 subjects had completed their D21 visit. The interim analysis was planned to occur when the first 100 infants completed at least 21 days of full fortification; however, the analysis was conducted using data from 134 infants owing to unforeseen delays in conducting the analysis (eg, performing statistical programming, data cleaning, and query resolution) while recruitment continued. The type 1 error rate was adjusted to account for the analysis being conducted at ∼70% enrollment rather than the planned 52%. The DMC consisted of independent experts (2 clinicians, 1 biostatistician) who reviewed growth, formula intake, and key biochemical data as well as AEs. The purpose of the interim analysis was to examine unblinded growth velocity results and determine whether the trial could be stopped early for success or futility, or whether the targeted sample size required adjustment (the interim statistical analysis plan was finalized before unblinding, and the analysis was unblinded only to the DMC to facilitate ethical decision-making) (31). On April 2, 2014, the DMC recommended to stop the trial, as noninferiority and superiority in regard to the primary outcome had been demonstrated. The sponsor was notified of this decision on April 3, 2014, and the final study population included infants enrolled through March 31, 2014.RESULTSA total of 274 infants were screened, with 153 enrolled and randomized to either nHMF (n\u200a=\u200a77) or cHMF (n\u200a=\u200a76) (Fig. 2). Demographic and baseline anthropometry data are summarized in Table 2. There was no evidence of imbalance between the 2 groups with respect to infant characteristics. A significantly lower percentage of mothers and fathers of infants in the nHMF group, however, smoked during pregnancy. Number of twins was similar in each group.FIGURE 2Flow of study participants. AE\u200a=\u200aadverse event; cHMF\u200a=\u200acontrol human milk fortifier; D21\u200a=\u200astudy day 21; ITT\u200a=\u200aintent-to-treat; NEC\u200a=\u200anecrotizing enterocolitis; nHMF\u200a=\u200anew human milk fortifier; NICU\u200a=\u200aneonatal intensive care unit; PP\u200a=\u200aper-protocol; SAE\u200a=\u200aserious adverse event. ∗Although screening procedures were standardized across sites, some variability in prescreening procedures did occur. Based on the typical clinical characteristics of infants who were admitted to each NICU during the study interval, the total number of infants who would have been theoretically considered eligible for the study was higher than the number shown here.The majority (84% and 87% by volume in nHMF and cHMF, respectively) of milk provided to infants was pasteurized. Donor milk was always pasteurized and accounted for 49% and 51% of the fortified HM volume provided in the nHMF and cHMF groups, respectively. There was no significant difference in mean volume of fortified milk intake between groups (152.7\u200a±\u200a13.0 and 152.6\u200a±\u200a17.2\u200amL\u200a·\u200akg−1\u200a·\u200aday−1 in nHMF and cHMF, respectively). Protein intake estimated using standard values for preterm HM composition per 100\u200amL (22) was significantly greater in nHMF compared to cHMF (4.48\u200a±\u200a0.38 vs 3.81\u200a±\u200a0.43\u200ag\u200a·\u200akg−1\u200a·\u200aday−1, respectively; P\u200a<\u200a0.001) because of higher protein content of the nHMF. Estimated energy intake was not significantly different between groups (125\u200akcal\u200a·\u200akg−1\u200a·\u200aday−1 in both groups). There was no significant difference in number of days between FSI1 and D1, but adjusted time between birth and D1 was significantly shorter in nHMF (16.8\u200a±\u200a5.4 vs 18.7\u200a±\u200a8.8 days; −8.5% [95% CI: −15.0%, −1.0%]).GrowthIn the ITT population, adjusted weight gain from D1 to D21 was 2.3\u200ag/day higher in nHMF, with the 95% CI ranging from 0.4 to 4.2\u200ag/day, demonstrating noninferiority (P\u200a<\u200a0.001) and superiority (P\u200a=\u200a0.01) of nHMF. Per-protocol results were similar. Weight gain from D1 to D21 remained significantly higher in nHMF when expressed in grams per kilogram per day (Table 3). Weight-for-age z scores (Fig. 3) remained stable from FSI1 to D21 in nHMF, but continued to decrease in cHMF (P\u200a=\u200a0.007 vs D1). At D21, weight-for-age z score was significantly higher in nHMF compared to cHMF (0.12 [95% CI: 0.03, 0.22]). Length and HC gains during the D1 to D21 period were not significantly different between groups (Table 3), with comparable results observed from analyses of unadjusted means (Table 4). Length-for-age z scores at D21 (Fig. 3) were significantly lower than D1 values in cHMF (P\u200a=\u200a0.041). Additionally, at W40CA, adjusted HC-for-age z scores were significantly higher in nHMF compared to cHMF (0.41 [95% CI: 0.14, 0.68]). Mean weight, length, and HC at D1, D21, and W40CA are summarized in Table 5.FIGURE 3Mean\u200a±\u200aSD weight-for-age (panel A), length-for-age (panel B), and head circumference-for-age (panel C) z scores for the overall ITT population. Circle symbols/solid line represents nHMF. Triangle symbols/dashed line represents cHMF. FSI1\u200a=\u200afortification strength increase day 1; ITT\u200a=\u200aintent-to-treat; SD\u200a=\u200astandard deviation; W40CA\u200a=\u200aweek 40 corrected age; z scores calculated using Fenton preterm growth chart (25). ∗P\u200a=\u200a0.013 vs cHMF (by analysis of covariance, adjusting for value at D1, sex, and center); †P\u200a=\u200a0.007 vs day 1 (by t test); ‡P\u200a=\u200a0.041 vs day 1 (by t test); ∗∗P\u200a=\u200a0.003 vs cHMF (by analysis of covariance, adjusting for value at D1, sex, and center).Protein-Energy StatusBUN decreased progressively in cHMF (P\u200a=\u200a0.004 for D21 vs D1), whereas it increased in nHMF (P\u200a<\u200a0.001 for D10/11 vs D1 [data not shown]) and remained stable up to D21 (Table 6). Prealbumin levels were similar at D1 and increased in both groups during the study (Table 6). The increase from D1 to D21, however, was only significant in nHMF (P\u200a=\u200a0.004). At D21, adjusted mean prealbumin in nHMF was significantly higher (+11.8% [95%CI: +2.3%, +22.2%]) than in cHMF. Urinary urea excretion (corrected for creatinine excretion) at D1 was similar in the 2 groups (Table 6). Urea excretion remained steady in cHMF but increased sharply in nHMF (P\u200a<\u200a0.001 for D10/11 vs D1 [data not shown]), after which it remained stable (to D21). At D21, urea excretion was significantly higher in nHMF versus cHMF (+108.7% [95% CI: +66.0%, +162.5%]).Bone Metabolic StatusSerum calcium concentrations were generally stable during the study (Table 6), with mean values for both groups within the normal range (32). Nevertheless, adjusted mean serum calcium concentration in nHMF was minimally but significantly higher than in cHMF at D21 (+1.9% [95% CI: +0.3%, +3.5%]). Serum phosphorus increased slightly in the 2 groups (Table 6). At D1, relative hypophosphatemia (<1.55\u200ammol/L) was observed in 13 infants in both groups; this was corrected in 11 infants by D10/11 and 12 infants by D21. At D1, serum alkaline phosphatase was not significantly different in nHMF versus cHMF (P\u200a=\u200a0.208). Thereafter, serum alkaline phosphatase decreased significantly in both groups (D21 vs D1: P\u200a=\u200a0.005 for nHMF, P\u200a<\u200a0.001 for cHMF), with mean values significantly higher in nHMF versus cHMF at D10/11 (+8.6% [95% CI: +1.0%, +16.8%]; data not shown) and D21 (+12.1% [95% CI: +2.8%, +22.3%]) (Table 6). Declines from baseline were significantly greater in cHMF versus nHMF at D10/11 (P\u200a<\u200a0.001; data not shown) and D21 (P\u200a=\u200a0.035). At D1, spot urinary excretions of calcium and phosphorus corrected for urinary creatinine excretion were similar in the 2 groups (Table 6). Calcium excretion tended to increase slowly during the study in both groups, with mean concentration significantly lower in nHMF compared to cHMF at D21 (P\u200a=\u200a0.011). Phosphorus excretion increased in both groups, resulting in a decreased median urinary calcium:phosphorus molar ratio in both groups (Table 6).ElectrolytesSerum electrolyte concentrations were stable during the study and similar in both groups (Table 6). Urinary sodium and potassium concentrations were significantly higher (sodium: +31.1% [95% CI: +1.7%, +68.9%], potassium: +22.5% [95% CI: +1.0%, +48.6%]) in nHMF compared to cHMF at D21 (Table 7).Stool Characteristics and Feeding ToleranceStool frequency from D1 to D21 was not significantly different in nHMF and cHMF (3.9\u200a±\u200a1.05 vs 3.6\u200a±\u200a0.93\u200astools/day; 0.29 [95% CI: −0.05, 0.63]). Stool consistency was slightly more “formed” in nHMF compared to cHMF during this interval (3.1\u200a±\u200a0.26 vs 3.0\u200a±\u200a0.27; 0.12 [95% CI: 0.02, 0.21]). Most infants (>90%) had stool consistency scores of “soft.” There were no significant differences between groups in frequencies of spitting-up, vomiting, or abdominal distention. There also were no group differences in incidence of AEs indicative of feeding intolerance (all P\u200a≥\u200a0.25).Adverse EventsThe overall incidence of AEs was significantly larger in nHMF (103 events in 56 infants, including 26 events categorized as GI disorders, 18 as infections or infestations, and 5 as metabolism and nutrition disorders) compared to cHMF (78 events in 41 infants, including 21 events categorized as GI disorders, 18 as infections or infestations, and 1 as metabolism and nutrition disorder; odds ratio: 2.26 [95% CI: 1.10, 4.47]). Other AEs that occurred more frequently in nHMF included several that were classified by study investigators as unlikely to be related to consumption of milk fortifiers (eg, cardiac disorders [16 events in nHMF vs 5 in cHMF], eye disorders [10 events in nHMF vs 3 in cHMF]). The number of AEs considered related to study product intake as determined by physician report was low (3 events in nHMF [2 events of hyponatremia, 1 of vomiting] and 0 events in cHMF). No significant difference was demonstrated in overall incidence of serious AEs between the 2 groups (7 events in 7 infants [including 2 events of necrotizing enterocolitis, 0 events of bronchopulmonary dysplasia, 0 events of sepsis, 0 events of retinopathy] in nHMF and 12 events in 11 subjects [including 4 events of necrotizing enterocolitis, 1 event of bronchopulmonary dysplasia, 0 events of sepsis, 0 events of retinopathy] in cHMF; odds ratio: 0.54 [95% CI: 0.17, 1.58]).DISCUSSIONThis study demonstrated that weight gain from D1 of full fortification until D21 in preterm infants fed HM fortified with a new fortifier designed to add 1.4\u200ag partially hydrolyzed protein and 0.7\u200ag fat to 100\u200amL of HM was significantly greater than weight gain in infants fed HM fortified with an isocaloric control fortifier designed to add 1.0\u200ag extensively hydrolyzed protein and no fat. The mean difference was 2.3\u200ag/day or 1.2\u200ag\u200a·\u200akg−1\u200a·\u200aday−1, consistent with our hypothesized difference of 2\u200ag/day, and which indicates the superiority of the new fortifier compared to the control with regard to weight gain. In addition, the weight gain benefit tended to persist until discharge, with a significantly higher adjusted weight gain difference in the nHMF group compared to cHMF from FSI1 to W40CA (2.01\u200ag/day; P\u200a=\u200a0.009). In the nHMF group, weight-for-age z scores were stable from FSI1 to D21 and average weight gain exceeded 18\u200ag\u200a·\u200akg−1\u200a·\u200aday−1, matching recommended rates of postnatal weight gain to mimic intrauterine growth (33,34). Consistent with the increased protein content of the new fortifier, the nHMF group had significantly higher serum prealbumin concentrations, suggesting an increase in nitrogen retention compared to cHMF. The lack of difference, however, in length gain during the study may be in part the result of the relatively limited period of protein supplementation (only 21 days) or because mean length gains in both groups were already quite high (ie, ≥1.1\u200acm/week), whereas the significantly higher HC-for-age z score at W40CA in the nHMF group may be because of the increased protein and lipid content of the new fortifier. In contrast, the absence of a significant difference at earlier timepoints could be attributable to the relatively high variability of HC gain (31% and 27% for nHMF and cHMF, respectively, from D1 to D21) induced by the natural dolichocephalic evolution of the skull that occurs in preterm infants (35). Feeding tolerance and stool patterns were similar in each group, and AEs related to feeding were low and not significantly different between groups, consistent with fortified HM osmolality values slightly lower in nHMF versus cHMF and below the recommended cutoff (23,24) in both groups.Although there was no evidence of imbalance between the 2 fortifier groups with respect to infant baseline characteristics, significant differences in maternal weight gain, smoking, and alcohol usage during pregnancy were observed. As these may be confounding factors in the analysis of weight gain, post hoc ANCOVAs including these parameters were performed. The post hoc results were essentially the same as the main results, indicating that differences in maternal baseline characteristics did not confound the results. Additionally, to determine the possible impact of including clustered data from twins in the analyses, a sensitivity analysis on weight gain (grams per day) from D1 to D21 accounting for the correlated multiple-birth data was performed. Again, these results were similar to those of the main analysis (weight gain 3.2\u200ag/day higher in nHMF [95% CI: 0.5, 5.9\u200ag/day]).Our results are consistent with those of previous studies (36–42). A recent meta-analysis of 5 studies (comprising 352 infants with birthweight ≤1750\u200ag and gestational age ≤34 weeks) compared growth of infants fed HM fortified with either lower-protein or higher-protein fortifier (43). Infants receiving higher-protein fortifier had significantly greater weight (mean difference 1.77\u200ag/kg/day), length (0.21\u200acm/week), and HC gains (0.19\u200acm/week) compared to those receiving lower-protein fortifier (43). Miller et al (39) used a higher-protein fortifier similar in protein content to the one used in the present study, and reported a higher bodyweight at study end among infants in the higher-protein HMF group (mean difference 220\u200ag), but no significant differences in length or HC. In contrast, Moya et al (40) observed a significantly higher achieved weight, length, and HC in the experimental group compared to controls, but their fortifier had a slightly higher protein content (3.2\u200ag/100\u200amL) versus the one used in the present study (3.04\u200ag/100\u200amL), plus the intervention lasted 28 rather than 21 days.Energy and protein content of HM samples were not analyzed in this study but estimated according to Tsang et al (22). Variability of protein, fat, and energy content of HM fed to preterm infants in the NICU is high (15,21). In addition, fat content may be reduced during processing of HM from expression to administration (44), which could be exacerbated with the use of continuous tube feeding (45). In our study, percentage of intake from mother's own milk, donor milk, and pasteurized HM was assessed. Pasteurized donor milk accounted for 51% of the fortified HM provided during the study, whereas 56% of mother's own milk was also pasteurized. Considering that protein content of donor HM is lower than that of mother's own milk (46) and that all the required processing steps (eg, collection, transfer, refrigeration, pasteurization, tube feeding) may significantly decrease fat and energy content (47), the characteristics of the HM used in the present study suggests that protein and energy content could be overestimated when based on a theoretical composition of preterm HM.In the present study, the mean increase in protein supplementation provided by nHMF compared to cHMF was 0.65\u200ag\u200a·\u200akg−1\u200a·\u200aday−1 or 7.4\u200ammol\u200a·\u200akg−1\u200a·\u200aday−1 of nitrogen, from which approximately 6.14\u200ammol\u200a·\u200akg−1\u200a·\u200aday−1 of nitrogen (83%) is absorbed (based on data from balance studies) (48). During the study, urea production increased significantly in the nHMF group leading to an increase in BUN of 1.7\u200ammol/L at D21 and in urea excretion of 2.3\u200ammol\u200a·\u200akg−1\u200a·\u200aday−1 (2.3\u200ammol/10\u200amg creatinine). These data suggest that the nitrogen balance was improved to ∼3.8\u200ammol nitrogen (52% of nitrogen intake) in preterm infants fed nHMF compared to control. This relatively limited protein utilization could result from reduced energy bioavailability of HM, and an increase in energy supply could improve protein utilization in preterm infants fed fortified HM. These data also suggest that specific nutritional recommendations should be formulated for infants fed fortified HM. Nevertheless, the increase in nitrogen retention (∼3.8\u200ammol\u200a·\u200akg−1\u200a·\u200aday−1) appears to be higher than the nitrogen content of the higher weight gain observed with the nHMF (12% of the 1.5\u200ag\u200a·\u200akg−1\u200a·\u200aday−1 corresponding to 2\u200ammol\u200a·\u200akg−1\u200a·\u200aday−1 of nitrogen), suggesting an increase in lean body mass accretion and a moderate reduction in fat mass gain as previously demonstrated in preterm infants fed protein-fortified HM (49).Indices of bone metabolism were satisfactory in both groups, with a significant decrease in serum alkaline phosphatase observed in both groups and 98% of the infants having normal serum phosphorus concentrations at D21. Adequate postnatal bone mineralization is difficult to obtain in preterm infants owing to the interruption of mineral transplacental transfer (50). Although elevated alkaline phosphatase activity may be associated with reduced bone mineralization when mineral intake is deficient (51), the decrease in enzyme levels observed in the presence of normal serum phosphorus values, as well as the low urinary calcium and moderate urinary phosphorus excretion observed in both groups in this study, suggest that intakes were adequate to promote bone mineralization and limit postnatal osteopenia. Mean serum creatinine concentration decreased significantly in both groups suggesting a similar maturation of renal function during this period. Urinary electrolyte concentrations were higher in nHMF versus cHMF at D21, likely in parallel with the higher electrolyte content of nHMF.A lack of HM composition data (allowing estimation of nutritional balance) is a limitation of our study, although standardized accurate techniques are still not available in the NICU. Additionally, the composition of the faster weight gain can only be estimated as lean body mass and/or bone mineralization were not determined. As a result, nutrient absorption and metabolism can only be estimated from serum and urinary metabolite concentrations. Lastly, the results need to be confirmed in a broader population of preterm infants commonly admitted to the NICU including SGA infants and partially breast-fed infants, as these infants were excluded by design. Strengths of this study include the size and multiple sites (11 pediatric hospitals in 4 European countries), which enhances external validity.In conclusion, these results indicate that the new HM fortifier, made with partially hydrolyzed whey protein and a higher protein:energy ratio is safe, well-tolerated, and improves weight gain of preterm infants compared to control fortifier. Providing some energy as fat and replacing extensively hydrolyzed with partially hydrolyzed protein in the new HM fortifier allows a reduction in osmolality <400\u200amOsm/kg immediately after fortification. Protein intakes from HM supplemented with the new fortifier are within the range of the most recent nutritional recommendations for preterm infants.AcknowledgmentsThe authors thank the families of the infants who participated in the study, as well as the research staff at each participating institution. The authors also thank Christelle Perdrieu and Samir Dahbane from the Clinical Development Unit at the Nestlé Research Center for assistance with trial management and Philippe Steenhout, Medical Director at Nestlé Nutrition, for input on study design and assistance with trial supervision.This study was sponsored by Nestlé Nutrition. J.J., L.A., and N.P.H. are employees of Nestlé SA. J.R., J.M.H., C.B., J.C.P., F.M., A.R., E.S., M.R., U.S., B.G., and J.S. received research funding from Nestlé Nutrition. J.R., J.C.P., and C.B. are consultants for Nestlé Nutrition. U.S. has been a speaker, consultant, and expert panel participant for Nestlé, Danone, and Bledina over the past 3 years. V.d.H. has no conflicts of interest to declare.www.clinicaltrials.gov NCT01771588This study was sponsored by Nestlé Nutrition.Portions of these data were presented in abstract form at the 1st Congress of joint European Neonatal Societies, Budapest, Hungary, 15–20 September 2015.REFERENCES1.GarciaCDuanRDBrevaut-MalatyV\nBioactive compounds in human milk and intestinal health and maturity in preterm newborn: an overview. Cell Mol Biol (Noisy-le-grand)\n2013; 59:108–131.253266482.CorpeleijnWEKouwenhovenSMPaapMC\nIntake of own mother's milk during the first days of life is associated with decreased morbidity and mortality in very low birth weight infants during the first 60 days of life. 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Neonatal Netw\n1998; 17:55–57.TABLE 1Calculated∗ nutrient composition of fortified preterm human milkPreterm HM\u2009+\u2009nHMFPreterm HM\u2009+\u2009cHMF4\u2009g fortifier alone4\u2009g fortifier per 100\u2009kcal milk4\u2009g fortifier per 100\u2009mL milk5\u2009g fortifier alone5\u2009g fortifier per 100\u2009kcal milk5\u2009g fortifier per 100\u2009mL milkRecommended intake range (per 100\u2009kcal)†NutrientEnergy, kcal17.410084.617.410084.5Protein, g1.423.63.041.03.102.623.2–4.1Protein sourcePartially hydrolyzed wheyExtensively hydrolyzed wheyFat, g0.725.004.230.024.163.524.4–6MCT, g0.500.590.50000DHA, mg6.319.316.3011.810.0(16.4–) 50–55Carbohydrate, g1.3010.178.603.3012.5310.6010.5–12Carbohydrate sourceMaltodextrinLactose and maltodextrinCalcium, mg7611910175118100109–182Phosphorus, mg44695845705955–127Magnesium, mg4.08.67.32.46.75.77.3–13.6Sodium, mg36.776.564.720.056.848.063–105Potassium, mg48.4116.498.442.0108.892.071–177Chloride, mg32.1106.690.117.088.775.095–161Iron, mg1.802.231.891.301.641.391.8–2.7Zinc, mg0.941.551.310.801.381.171.3–2.3Manganese, μg8.089.988.445.006.345.360.9–13.6Copper, mg0.050.110.090.040.090.080.09–0.21Iodine, μg16.936.630.915.034.329.09–50Selenium, μg3.77.26.11.54.63.94.5–9Vitamin A, IU1183175414835009468001217–3333Vitamin D, IU150187158100128108100–350Vitamin E, IU4.45.64.72.23.02.52.2–11.1Vitamin K, μg8.09.88.34.05.14.34–25Thiamin, mg0.150.190.160.050.070.060.13–0.27Riboflavin, mg0.200.270.230.100.150.130.18–0.36Vitamin B6, mg0.130.160.140.050.070.060.05–0.27Vitamin B12, μg0.200.260.220.100.140.120.09–0.73Niacin, mg1.502.021.710.801.191.010.9–5Folic acid, μg40.051.043.140.051.043.132–91Pantothenic acid, mg0.701.100.930.400.740.630.45–1.9Biotin, μg3.504.784.043.004.193.541.5–15Vitamin C, mg20.028.924.410.017.014.418–50Osmolality‡, mOsm/kg390441cHMF\u2009=\u2009control human milk fortifier; DHA\u2009=\u2009docosahexaenoic acid; HM\u2009=\u2009human milk; nHMF\u2009=\u2009new human milk fortifier; MCT\u2009=\u2009medium chain triglycerides.*Calculated based on preterm human milk composition from Tsang et al, 2005 (22).†Recommended nutrient intakes for fully enterally fed preterm very low birth weight infants (19).‡Measured immediately after fortification at room temperature (25°C).TABLE 2Demographic and baseline characteristics of infants and parentsnHMF (n\u2009=\u200976)cHMF (n\u2009=\u200974)Infant characteristicsSex\u2003Boys38 (50)35 (47)Delivery type\u2003Vaginal24 (32)20 (27)Twin18 (24)16 (22)Birth weight, g1147\u2009±\u20092581156\u2009±\u2009289Birth weight by birth weight category\u2003<1000\u2009g\u2003\u2003n (%)24 (32)26 (35)\u2003\u2003Birth weight, g850.5\u2009±\u2009118.9847.3\u2009±\u2009105.1\u2003≥1000\u2009g\u2003\u2003Birth weight, g1283.6\u2009±\u2009175.41323.9\u2009±\u2009206.2Birth length, cm37.1\u2009±\u20092.737.1\u2009±\u20093.1Birth head circumference, cm26.5\u2009±\u20092.726.7\u2009±\u20092.5Gestational age at birth, weeks28.8\u2009±\u20092.128.7\u2009±\u20091.8Postnatal age at study time points, days*\u2003FSI113 (11, 18)14 (10, 20)\u2003Day 116 (13, 20)17 (13, 23)\u2003Day 2136 (33, 40)37 (33, 43)\u2003Week 40 corrected age76 (66, 91)76 (67, 83)Apgar score\u20031 min5.8\u2009±\u20092.55.8\u2009±\u20092.3\u20035 min8.0\u2009±\u20091.87.7\u2009±\u20091.9Parent characteristicsSmoking status\u2003Mother smoker during pregnancy6 (9)18 (29)\u2003Father smoker3 (5)12 (21)\u2003Mother drank alcohol during pregnancy0 (0)4 (6)Mother's age, y31.1\u2009±\u20095.130.8\u2009±\u20095.5Mother's BMI before pregnancy, kg/m2*23.2 (20.6, 27.2)21.3 (19.7, 26.1)Mother's weight gain during pregnancy, kg11.2\u2009±\u20096.89.2\u2009±\u20095.2BMI\u2009=\u2009body mass index; cHMF\u2009=\u2009control human milk fortifier; FSI1\u2009=\u2009fortification strength increase day 1; nHMF\u2009=\u2009new human milk fortifier . Data are presented as n (%) for categorical variables and mean\u2009±\u2009SD for continuous variables except where noted.*Data are presented as median (Q1, Q3).TABLE 3Anthropometric gains from D1 to D21Treatment groupnnHMFncHMFP*Weight gain, g\u2009·\u2009kg−1\u2009·\u2009day−16418.3\u2009±\u20093.76716.8\u2009±\u20093.70.013†Length gain, cm/wk551.23\u2009±\u20090.62651.18\u2009±\u20090.490.842HC gain, cm/wk571.04\u2009±\u20090.32650.96\u2009±\u20090.260.125cHMF\u2009=\u2009control human milk fortifier; D1\u2009=\u2009study day 1 (first day of full-strength fortification); D21\u2009=\u2009study day 21; HC\u2009=\u2009head circumference; nHMF\u2009=\u2009new human milk fortifier. Data are presented as unadjusted mean\u2009±\u2009SD.*One-sided superiority P value based on analysis of covariance model adjusted for postmenstrual age and relevant anthropometric measure at D1, sex, and center.†Adjusted difference in weight gain (nHMF–cHMF): mean difference\u2009=\u20091.18\u2009g\u2009·\u2009kg−1\u2009·\u2009day−1; 95% CI\u2009=\u20090.14, 2.21.TABLE 4Body length and head circumference gains between study days 1 and 21, by infant sex and by birth weight categoryUnadjusted length gain, cm/wk*Unadjusted head circumference gain, cm/wk*nHMFcHMFnHMFcHMFnMean\u2009±\u2009SDnMean\u2009±\u2009SDP†nMean\u2009±\u2009SDnMean\u2009±\u2009SDP†Overall551.23\u2009±\u20090.62651.18\u2009±\u20090.490.842571.04\u2009±\u20090.32650.96\u2009±\u20090.260.126Boys271.40\u2009±\u20090.65281.18\u2009±\u20090.490.364281.12\u2009±\u20090.28280.99\u2009±\u20090.220.062Girls281.08\u2009±\u20090.56371.17\u2009±\u20090.500.510290.97\u2009±\u20090.35370.93\u2009±\u20090.290.598<1000\u2009g191.07\u2009±\u20090.52211.27\u2009±\u20090.520.563191.04\u2009±\u20090.34210.94\u2009±\u20090.280.223≥1000\u2009g361.32\u2009±\u20090.66441.13\u2009±\u20090.480.499381.05\u2009±\u20090.32440.96\u2009±\u20090.260.270cHMF\u2009=\u2009control human milk fortifier; nHMF\u2009=\u2009new human milk fortifier.*Data are presented as unadjusted mean\u2009±\u2009SD.†Superiority P value for gain differences adjusted for postmenstrual age and the relevant anthropometric measure at D1, sex, and center by analysis of covariance.TABLE 5Weight, length, and head circumference at selected study time pointsnHMFcHMFVariablenMeanSDnMeanSDWeight, g\u2003D1721346271741347270\u2003D21641884336671863328\u2003W40CA603076519632897416Length, cm\u2003D16738.72.57438.72.8\u2003D215841.82.46542.02.7\u2003W40CA6047.62.66247.32.5Head circumference, cm\u2003D16827.72.57327.61.9\u2003D215930.22.26630.32.0\u2003W40CA5935.31.46434.61.5cHMF\u2009=\u2009control human milk fortifier; D1\u2009=\u2009study day 1; D21\u2009=\u2009study day 21; nHMF\u2009=\u2009new human milk fortifier; SD\u2009=\u2009standard deviation; W40CA\u2009=\u2009week 40 corrected age.TABLE 6Markers of protein-energy status, electrolytes, and bone metabolic status at study days 1 and 21nHMFcHMFVariablenMedianIQRGeometric meannMedianIQRGeometric meanP*Serum creatinine, μmol/L\u2003D16944.036.2–48.041.57044.138.0–51.843.50.303\u2003D216328.023.5–32.026.76530.025.0–35.029.50.001BUN, mmol/L\u2003D1703.101.70–4.562.89712.501.65–4.672.730.585\u2003D21633.903.05–4.653.89642.151.50–2.632.15<0.001Serum prealbumin, mg/L\u2003D15110080–12096.8469080–10087.80.073\u2003D214611691.3–140113.84110090–12098.10.015Urinary urea†, mmol/10\u2009mg creatinine\u2003D1472.72.0–4.72.8532.51.9–3.32.50.302\u2003D21425.84.6–6.85.1402.82.0–3.32.7<0.001Serum calcium, mmol/L\u2003D1502.442.31–2.532.41542.472.38–2.562.440.445\u2003D21502.472.40–2.542.46482.432.34–2.532.430.019Serum phosphorus, mmol/L\u2003D1681.991.85–2.221.96711.941.76–2.251.940.816\u2003D21622.101.93–2.232.05642.121.93–2.262.080.681Alkaline phosphatase, U/L\u2003D167353.0298.5–459.5377.963333.0250.0–438.5343.80.208\u2003D2162320.5273.3–405.5337.562270.5233.0–354.3297.50.010Urinary calcium †, mmol/10\u2009mg creatinine\u2003D1600.110.07–0.190.12690.140.09–0.200.120.985\u2003D21550.140.09–0.230.15540.210.13–0.320.190.011Urinary phosphorus†, mmol/10\u2009mg creatinine\u2003D1590.410.12–0.660.22650.340.14–0.650.230.867\u2003D21520.680.44–1.100.53520.710.40–0.920.580.896Urinary calcium:phosphorus molar ratio\u2003D1590.390.15–0.900.50640.410.16–1.340.470.824\u2003D21530.220.12–0.480.28530.310.19–0.600.340.054Serum sodium, mmol/L\u2003D171138.0137.0–140.0138.672138.6136.6–140.0138.50.891\u2003D2165138.0136.4–140.0138.064138.0137.0–139.9138.30.449Serum potassium, mmol/L\u2003D1714.734.30–5.324.83724.774.40–5.104.780.685\u2003D21644.744.29–5.104.72644.514.14–4.884.540.091Serum chloride, mmol/L\u2003D171106.0104.0–109.0106.172105.0102.8–108.0105.20.148\u2003D2163105.0103.0–107.0104.662105.0104.0–107.0105.30.111BUN\u2009=\u2009blood urea nitrogen; cHMF\u2009=\u2009control human milk fortifier; D1\u2009=\u2009study day 1; D21\u2009=\u2009study day 21; IQR\u2009=\u2009interquartile range; nHMF\u2009=\u2009new human milk fortifier.*D1 geometric mean values were log-transformed and analyzed using t test; D21 geometric mean values were log-transformed and analyzed using analysis of covariance (adjusting for the relevant biochemical parameter at D1, sex, and center).†Corrected for urinary creatinine excretion of 10\u2009mg/kg body weight/day.TABLE 7Markers of kidney function, blood count, and urinary electrolyte status at study days 1 and 21nHMFcHMFVariablenMedianIQRGeometric meannMedianIQRGeometric meanP*Urinary creatinine, μmol/L\u2003D1631300.0785.5–1685.51224.7691105.0900.0–1500.01182.3\u2003D21571030.0660.0–1609.01000.355854.0618.0–1273.0900.80.447Serum hemoglobin, mmol/L\u2003D1682.081.84–2.292.14722.021.84–2.262.18\u2003D21631.711.56–1.911.83661.691.50–1.981.760.936Serum hematocrit, %\u2003D1680.400.35–0.430.39720.390.35–0.430.38\u2003D21630.320.29–0.380.33660.330.28–0.380.330.805Urinary sodium, mmol/L\u2003D16637.023.3–57.337.56932.019.4–54.031.2\u2003D215934.021.1–48.033.35623.014.3–36.424.00.037Urinary potassium, mmol/L\u2003D16625.913.6–37.023.66921.815.0–32.220.0\u2003D215930.016.9–45.027.65722.916.9–30.422.80.040Urinary chloride, mmol/L\u2003D16037.026.3–60.040.26733.020.5–55.034.2\u2003D215431.017.8–43.830.75526.018.0–39.527.80.558cHMF\u2009=\u2009control human milk fortifier; D1\u2009=\u2009study day 1; D21\u2009=\u2009study day 21; IQR\u2009=\u2009interquartile range; nHMF\u2009=\u2009new human milk fortifier .*D21 geometric mean values were log-transformed and analyzed using analysis of covariance (adjusting for the relevant biochemical measure at D1, sex, and center).", 'title': 'Growth and Nutritional Biomarkers of Preterm Infants Fed a New Powdered Human Milk Fortifier: A Randomized Trial.', 'date': '2017-07-21'}}
| 0
|
Pediatrics & Neonatology
|
18
|
Is length gain higher, lower, or the same when comparing high protein concentration to low protein concentration?
|
uncertain effect
|
very low
|
no
|
['26488118', '22301933', '22987877', '29772833', '28727654']
| 33,215,474
| 2,020
|
{'26488118': {'article_id': '26488118', 'content': "J Pediatr Gastroenterol NutrJ. Pediatr. Gastroenterol. NutrJPGAJournal of Pediatric Gastroenterology and Nutrition0277-21161536-4801Lippincott Williams & Wilkins26488118464595610.1097/MPG.000000000000101000012Original Articles: NutritionGrowth and Tolerance of Preterm Infants Fed a New Extensively Hydrolyzed Liquid Human Milk FortifierKimJae H.∗ChanGary†SchanlerRichard‡Groh-WargoSharon§BloomBarry||DimmitReed¶WilliamsLarry#BaggsGeraldine#Barrett-ReisBridget#∗University of California, San Diego-Rady Children's Hospital of San Diego, San Diego†University of Utah, Salt Lake City‡Cohen Children's Medical Center of New York, New Hyde Park§Case Western Reserve University, MetroHealth Medical Center, Cleveland, OH||Wesley Medical Center, Wichita, KS¶University of Alabama, Birmingham#Abbott Nutrition, Columbus, OH.Address correspondence and reprint requests to Jae H. Kim, MD, PhD, University of California, San Diego, 200 W Arbor Dr, MPF 1140, San Diego, CA 92103 (e-mail: neojae@ucsd.edu).12201524112015616665671212201512102015Copyright 2015 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.2015This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License, where it is permissible to download and share the work, provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0ABSTRACTObjectives:This study was a comparison of growth and tolerance in premature infants fed either standard powdered human milk fortifier (HMF) or a newly formulated concentrated liquid that contained extensively hydrolyzed protein.Methods:This was an unblinded randomized controlled multicenter noninferiority study on preterm infants receiving human milk (HM) supplemented with 2 randomly assigned HMFs, either concentrated liquid HMF containing extensively hydrolyzed protein (LE-HMF) or a powdered intact protein HMF (PI-HMF) as the control. The study population consisted of preterm infants ≤33 weeks who were enterally fed HM. Infants were studied from the first day of HM fortification until day 29 or hospital discharge, whichever came first.Results:A total of 147 preterm infants were enrolled. Noninferiority was observed in weight gain reported in the intent-to-treat (ITT) analysis was 18.2 and 17.5 g · kg−1 · day−1 for the LE-HMF and PI-HMF groups, respectively. In an a priori defined subgroup of strict protocol followers (n\u200a=\u200a75), the infants fed LE-HMF achieved greater weight over time than those fed PI-HMF (P\u200a=\u200a0.036). The LE-HMF group achieved greater linear growth over time compared to the PI-HMF (P\u200a=\u200a0.029). The protein intake from fortified HM was significantly higher in the LE-HMF group compared with the PI-HMF group (3.9 vs 3.3 g · kg−1 · day−1, P\u200a<\u200a0.0001). Both fortifiers were well tolerated with no significant differences in overall morbidity.Conclusions:Both fortifiers showed excellent weight gain (grams per kilograms per day), tolerance, and low incidence of morbidity outcomes with the infants who were strict protocol followers fed LE-HMF having improved growth during the study. These data point to the safety and suitability of this new concentrated liquid HMF (LE-HMF) in preterm infants. Growth with this fortifier closely matches the recent recommendations for a weight gain of >18 g · kg−1 · day−1.Keywordsbreast-feedinggrowthhuman milk fortifierpreterm infantsOPEN-ACCESSTRUEWhat Is KnownPowdered infant milk products cannot be sterilized and is a source of bacterial infection.Very-low-birth-weight infants often require more protein than presently can be provided with conventional human milk fortifiers.A liquid fortifier with higher protein than conventional fortifiers is desirable to increase safety and improved growth.What Is NewA liquid human milk fortifier that is based on extensively hydrolyzed bovine casein with higher amounts of total protein than powder human milk fortifiers confers equal to improved growth to very-low-birth-weight infantsUse of this new liquid fortifier provides sterility without any increase in feeding intolerance or short-term adverse effects.Human milk (HM) is a source of essential nutrients and immunologic factors for the preterm infant, but alone it is not sufficient nutritionally to meet the high demands of the rapidly growing infant. Human milk fortifiers (HMFs) are nutritional supplements designed to increase total energy, protein, and micronutrient delivery to preterm infants. The primary benefits of HM fortification have been improved growth, bone mineralization, and protein status such as blood urea nitrogen (BUN) (1–5).Increasing survival and improving growth of the preterm infant to avoid extrauterine growth restriction have resulted in demands for protein that present powdered HMF may not achieve. Although some of these infants may compensate with higher volume intake, many are unable to consume a sufficient volume because of pulmonary or other clinical issues and therefore require further concentration of protein and energy. Higher intake of protein between 3 and 4 g · kg−1 · day−1 has been associated with improved growth without complications compared with a lower consumption of protein (<3 g · kg−1 · day−1) (6). Poor weight gain has been associated with a higher risk for retinopathy of prematurity and poor neurodevelopmental outcomes (7,8). It is common practice in the neonatal intensive care units (NICUs) to add protein modular (powder or liquid) to the feeding to better meet the protein needs of the smaller preterm infant. In fact, 42% of the respondents to a recent survey on nutritional practices in the NICU reported adding protein to HM (9).There has been a gradual transition to sterile liquid nutritionals in the neonatal environment during the last decade because of concerns about powder-based transmission of pathogens such as Cronobacteria sakasakii(10). The recent development of a liquid HM–based HMF and a partially hydrolyzed whey-acidified liquid HMF respond to these concerns (11,12). Unlike powder nutritionals, a liquid HMF may have the advantage of sterility and simpler liquid-liquid mixing with human milk (HM). One disadvantage of a liquid fortifier is volume displacement of HM.In this study, we evaluated a novel liquid HMF containing extensively hydrolyzed protein source to determine efficacy and safety in very-low-birth-weight preterm infants.METHODSStudy PopulationA total of 14 NICUs from across the United States participated in this study, including Tampa, Florida; Wichita, Kansas; Toledo, Ohio; Salt Lake City, Utah; Birmingham, Alabama; Cleveland, Ohio; Allentown, Pennsylvania; San Diego, California; Valhalla, New York; Manhasset, New York; Portland, Oregon; Cleveland, Ohio; South Bend, India; and Brooklyn, New York. The study population consisted of preterm infants born at ≤33 weeks’ gestational age with birth weights ranging from 700 to 1500 g who were enterally fed HM in the NICU. Infants identified as eligible for randomization and for whom consent was obtained were randomly assigned to one of the 2 study regimens. Sealed envelopes containing the subject treatment group assignment were prepared from randomization schedules that were computer-generated using a pseudorandom permuted blocks algorithm. A separate computer-generated randomization schedule was produced for twins to ensure that eligible twins were both assigned to the same product. The randomization was block stratified by birth weight (700–1000 g and 1000–1500\u200ag) and sex.Eligibility criteria included appropriate intrauterine growth and maternal intent to provide breast milk during the study. The use of donor HM was not permitted during the study period unless indicated by the clinical staff or PI but could have been used in the first week of life before study initiation. Infants were excluded for enteral feeds not started within 21 days of life, severe congenital anomalies, expectant transfer to another facility, 5-minute Apgar <5, severe intraventricular hemorrhage (grade 3 or 4), mechanical ventilation, major abdominal surgery, severe asphyxia, and necrotizing enterocolitis (NEC). Use of probiotics or postnatal corticosteroids was not permitted.Study DesignThis was an unblinded randomized controlled multicenter study conducted on preterm infants receiving HM supplemented with 2 randomly assigned HMFs, either a newly formulated concentrated liquid HMF containing extensively hydrolyzed protein (Abbott Nutrition, Columbus, OH; LE-HMF) or a conventional powdered intact protein HMF (Similac Human Milk Fortifier, PI-HMF, Abbott Nutrition) as control. For every 25 mL of HM, HMF was added as a 5-mL dose of LE-HMF or 1 single packet of PI-HMF. Study Day (SDAY) 1 was defined as the first day of HM fortification and occurred within 72 hours after the subject had reached an intake of at least 100 mL · kg−1 · day−1 of HM. The primary study period was from SDAY 1 until SDAY 29 or hospital discharge, whichever came first. This study was approved by institutional research ethics board as appropriate at each study sites. Table 1 shows the key study fortifier differences.Anthropometric indices (weight, length, and head circumference [HC]), tolerance, serum biochemistries, intake, and morbidity data were assessed. Anthropometric variables and tolerance outcomes were collected after SDAY 29 if the infant remained on study HMF.Weight, length, and HC of infants were measured according to standardized procedures from SDAY 1 to SDAY 29 or hospital discharge, whichever came first. Weight measures were taken daily using the hospital scales (incubator or bedside). Documentation of scale calibration was reviewed during routine visits. The other anthropometric measurements were performed weekly. Recumbent length was obtained with a fixed headboard and moveable footboard and HC using a nonstretchable tape.Feeding tolerance was assessed by variables such as stool characteristics (bloody, hard, black, and/or watery) and the incidence of feedings withheld because of abdominal distention, gastric residuals, and vomiting. Any nil per os periods were also collected.Enteral intake was collected from enrollment to SDAY 29. Intake of HM (including donor/banked HM) or other enteral feeding (including supplements such as protein modulars) were recorded. Although the LE-HMF contained the same amount of energy as the PI-HMF, it contained higher protein and a different source of protein. It also contained added lutein, docosahexaenoic acid, and arachidonic acid.Blood samples were drawn from each infant by venipuncture or, if necessary, by heelstick on SDAYs 1, 15, and 29. Serum electrolytes, bicarbonate, calcium, phosphorus, magnesium, alkaline phosphatase, BUN, and prealbumin were analyzed at the hospital site. Confirmed NEC (determined by using modified Bell staging criteria) and sepsis were recorded. The occurrence of these and other serious adverse events was documented throughout the study.Statistical AnalysisStudy data were analyzed on an intent-to-treat (ITT) basis including all enrolled infants who received study fortifier. Based on anticipated protocol deviations in this high-risk population, a subgroup analysis was prospectively planned to analyze data from infants who strictly adhered to the assigned HMF. The strict protocol followers (SPFs) were defined a priori as those infants who received <20% of total energy from sources other than the assigned study HMF; and <3 consecutive days on modular supplements (eg, protein supplements, another study HMF, nonstudy formula, or donor milk) for at least 2 weeks from SDAY 1 to SDAY 29.Sample size was calculated to test the hypothesis that LE-HMF was noninferior to PI-HMF using an equivalence limit of 1.6 g · kg−1 · day−1 in weight gain per day. With a noninferiority hypothesis and assuming that the expected difference in means is zero and the common standard deviation is 2.56 g · kg−1 · day−1, the total sample size required to have 80% power was 66 subjects who are SPF (33 per group). The power for this unbalanced sample size distribution is 83%. Assuming an attrition rate of approximately 46%, the target number for enrollment was 124 subjects (62 per group). A study designed for noninferiority does not preclude testing for superiority (13). Weight gain (grams per kilogram per day) for each subject was calculated by an exponential model that involved a regression line fit on loge (wt), where wt is weight (in grams) on each day (13). Weight gain (grams per kilogram per day) was analyzed using analysis of variance with factors for center and feeding (primary). Analyses were also made adjusting for sex, birth weight, and average fortified HM intake (milliliters per kilogram per day) diluted full strength during the study period. A 95% 1-sided confidence interval for the difference in means between groups was used for noninferiority evaluation.Length (centimeters per week) and HC gains (centimeters per week) were analyzed using the same models. Weight, length, and HC collected at 1-week intervals were analyzed with repeated measures analysis of covariance (ANCOVA) testing effects of center, feeding, sex, study day, interaction of feeding with sex, feeding with study day, and covariate birth weight. By time point analyses of weight, length, and HC using ANCOVA were made post-hoc using 1-sided tests consistent with a noninferiority design.Average daily volume enteral intake (milliliters per kilogram per day) was analyzed using analysis of variance. Complete blood cell counts with differential and serum blood biochemistries were analyzed using repeated measures ANCOVA with covariate SDAY 1 measure.Outcomes expressed as percent of infants (tolerance, morbidity, and respiratory variables) were analyzed using the Cochran-Mantel-Haenzsel test stratified by center. The frequencies of occurrence of adverse events by system organ class and preferred terms using MedDRA codes were tabulated and analyzed using Fisher exact test. Hypothesis testing for this study was done using 2-sided, 0.05 level tests. All analyses were made using SAS version 9.2 (SAS Institute, Cary, NC) on a computer.RESULTSStudy PopulationA total of 147 subjects were randomized into the study. Of the 147 subjects, 129 were included in the ITT group, that is, all randomized subjects who received study HMF. Of those subjects in the ITT group, 75% completed the study duration (45 PI-HMF, 52 LE-HMF). More than half the infants in the ITT group met the definition for the SPFs (Fig. 1). The number of days on the assigned study fortifier was 25 and 29 for the PI-HMF (n\u200a=\u200a63) and LE-HMF (n\u200a=\u200a66) groups, respectively. The median number of days on the assigned study fortifier for SPF was 29 days for both the PI-HMF and LE-HMF groups as some extended their use beyond the study period. Of note, some SPF subjects did not complete the study duration because they were discharged from the hospital.FIGURE 1Disposition of subjects.Demographic and Other Baseline CharacteristicsCharacteristics of the study patients are summarized in Table 2. There were no statistically significant differences among study subjects randomized to the PI-HMF or the LE-HMF group in gestational age, sex, race, mode of delivery and multiple birth status. There were, however, more Hispanic infants in the PI-HMF as compared to the LE-HMF group (28% vs 13%, P\u200a=\u200a0.041). In addition, there were no statistical differences between groups at birth or SDAY 1 for weight, length, and HC. Furthermore, there were no differences in clinical history and progression of enteral feeds. Infants in the 2 feeding groups who were SPF reflect comparable demographic and baseline characteristics patterns.GrowthThere were no statistical differences in the primary outcome of weight gain (grams per kilogram per day) during the study period regardless of whether the statistical analysis was performed on the ITT group or SPFs. Hence, noninferiority was achieved. Respective weight gains were 17.5 and 18.2 g · kg−1 · day−1 for PI-HMF and LE-HMF (Table 3). Likewise in the subgroup (SPF) analysis weight gains were 18.2 and 18.4 g · kg−1 · day−1 for PI-HMF and LE-HMF. There was, however, a main feeding effect that was the infants fed LE-HMF compared with infants fed PI-HMF had increased weight during the study among SPFs as depicted in Fig. 2A (P\u200a=\u200a0.036). When analyzing the data at separate time points the weight at SDAY 29 was significantly higher in LE-HMF group versus the PI-HMF group (P\u200a=\u200a0.024). Likewise, infants in the ITT group fed LE-HMF had higher weights at SDAYs 15, 22, and 29 than infants fed PI-HMF whether or not adjusted for differences in ethnicity. The SPF infants receiving LE-HMF reached 1800 g 7 days sooner than the infants fed PI-HMF (19 vs 26 days, respectively, P\u200a=\u200a0.049).FIGURE 2Evaluable analysis: A, weight (in grams); B, length (in centimeters); C, head circumference (in centimeters). A, Weight (in grams). Repeated measures analysis main effect, P\u200a=\u200a0.036; post-hoc per time point analysis: SDAY 29, P\u200a=\u200a0.024. B, Length (in centimeters). Repeated measures analysis main effect, P\u200a=\u200a0.029; post-hoc per time point analysis: SDAY 22, P\u200a=\u200a0.006, SDAY 29, P\u200a=\u200a0.037. C, Head circumference (in centimeters).The length and HC gains (centimeters per week) during the study period revealed no statistical differences between the groups and met growth targets (Table 3). The infants fed LE-HMF compared with infants fed PI-HMF had increased linear growth during the study among SPFs as depicted in Fig. 2B (P\u200a=\u200a0.029). When analyzing the data at separate time points adjusted for birth length, the length at SDAY 22 and SDAY 29 were significantly higher in LE-HMF group versus the PI-HMF group (P\u200a<\u200a0.05). HC was not different between the fortifier groups (Fig. 2C).Feeding Tolerance and Stool CharacteristicsIn both the ITT and SPF groups, both fortifiers were well tolerated with similar number and percentage of infants having feedings withheld because of abdominal distention, gastric residuals and/or vomiting. There was no difference in the percentage of infants who were nil per os between the groups (22.7 LE-HMF, 19 PI-HMF). The stool characteristics in both groups were similar with no differences in bloody stools, hard stools or black stools. Loose stools were commonly reported—56% in the PI-HMF group and 53% in the LE-HMF group—and were considered normal for infants who are receiving HM as their primary feeding.Enteral NutritionThe mean caloric and protein intakes are reported for both HMF groups. For the SPFs, the average percentage of calories from fortified HM was ∼96% in both the PI-HMF and LE-HMF groups. The mean intake of fortified HM was 116 and 114 kcal · kg−1 · day−1 in the PI-HMF and LE-HMF groups, respectively. The calculated protein intake from fortified HM was significantly higher in the LE-HMF group as compared to the PI-HMF group (3.9 vs 3.3\u200a g · kg−1 · day−1, P\u200a<\u200a0.0001). This difference was expected as LE-HMF contains more protein than PI-HMF. Energy intakes were not different between the groups.Blood ChemistriesThe blood chemistries reported in Table 4 include bicarbonate, BUN, prealbumin, calcium, phosphorus, magnesium, alkaline phosphatase, and electrolytes. In general, the blood biochemistries at SDAYs 1, 15, and 29 were within the normal reference ranges for preterm infants for both the ITT and SPF groups fed milk fortified with either fortifier (14,15). There were significant differences between groups in both the ITT and SPF analyses for BUN (P\u200a<\u200a0.001) and prealbumin (P\u200a<\u200a0.01), with both being higher in the LE-HMF group. Both groups were well within reference ranges for these parameters. Bicarbonate was significantly higher in the LE-HMF group only at SDAY1 in the ITT analysis.Safety and Morbidity DataIn the ITT group, fewer infants discontinued fortifier because of feeding intolerance in the LE-HMF group as compared to the PI-HMF group (2% vs 10%, P\u200a=\u200a0.048). There was a low incidence of confirmed NEC (1.5% in the LE-HMF group and 3.2% in the PI-HMF group) and confirmed sepsis (4.5% vs 3.2%, respectively)DISCUSSIONThe purpose of developing LE-HMF was to provide a concentrated liquid fortifier that would be superior to conventional powder HMF by virtue of sterility, higher protein concentration, and absence of intact cow's-milk protein. An extensively hydrolyzed protein source is included to promote feeding tolerance in preterm infants. The extensively hydrolyzed protein may be tolerated better for infants who are sensitive to the intact cow's-milk protein.The primary purpose of the present clinical trial was to assess whether the new HMF would promote targeted weight gain, with good tolerance and without association with specific comorbidities in a noninferiority comparison with a commercially available powder HMF that has demonstrated safety and efficacy in preterm infants (13).Weight gain and linear growth approaching intrauterine rates are important goals in the management of premature infants. The mean weight gain for both groups (PI-HMF and LE-HMF) exceeded the intrauterine growth rate of 15 g · kg−1 · day−1 and closely matched recent recommendations for a weight gain of >18 g · kg−1 · day−1(7). The mean HC gain for both groups also closely matched recent recommendations for a HC gain of >0.9 cm/wk (7). This result was not surprising given the excellent weight, length, and HC gains previously reported in infants fed PI-HMF powder (13).Ehrenkranz et al (7) have reported that as the rate of weight gain increased in hospitalized preterm infants, the incidence of cerebral palsy, neurodevelopmental impairment, and need for re-hospitalization decreased significantly. A weight gain rate of >18 g · kg−1 · day−1 and a HC growth rate of >0.9 cm/wk were associated with better neurodevelopmental and growth outcomes. Lower quartile growth was associated with the poorest neurodevelopmental outcomes.Weight and length differed between the groups. Although there were no significant differences in mean weight at birth or SDAY 1, infants receiving LE-HMF had ∼½ lb greater mean weight than the infants in the PI-HMF group at the end of the study period. Although the rate of linear growth was not statistically different, infants in the LE-HMF group had greater achieved linear growth during the study period. It is possible that the greater weight and length in the LE-HMF infants was because of the higher number of infants in this group that adhered to the assigned study feeding.New expert recommendations suggest that extremely-low-birth-weight infants (<1000 g birth weight) have higher protein requirements (3.5–4.5 g/100 kcal) (16). HMFs provide an important strategy to overcoming nutrient deficits for preterm and low-birth-weight infants. Differences in the level and ingredient sources of the macronutrients, especially the protein quantity, in PI-HMF versus LE-HMF may have contributed to the overall performance of the LE-HMF group. The higher protein intake in infants receiving LE-HMF (∼3.6 g/100 kcal) as compared to PI-HMF (∼3.0 g/100 kcal) was likely one of the reasons for the improved growth observed in these infants. Although infants in the LE-HMF group had higher protein intakes, energy intakes were not different between the groups.Preterm infants fed fortified HM have variable rates of growth at least partly because of differences in intake of calories, carbohydrates, electrolytes, calcium, phosphate, and protein. The acid-base status of the preterm infant also, however, affects growth. In preterm infants the kidney may not tolerate an acid load, leading to the development of metabolic acidosis. In a recent study, a liquid acidified HMF caused metabolic acidosis and poor growth in preterm infants in the NICU (17,18). In another study, Rochow et al (19) described a commercially available fortifier in Europe that had to be reformulated because of the development of metabolic acidosis from an imbalance of electrolytes. The authors recorded a mean weight gain of only 9.7 g · kg−1 · day−1 and decreased bone mineralization with metabolic acidosis. No infants in our study developed metabolic acidosis.The LE-HMF protein source may be beneficial for this population because it was extensively hydrolyzed casein formulation without any intact cow's-milk protein. It has been suggested that a combination of free amino acids and short chain peptides (di- and tri peptides) may allow more optimal nitrogen absorption (20,21). Intact bovine protein powder HMF has an excellent safety record; however, a recent study by Sullivan et al (11) suggested the possibility that even in the presence of a HM base diet, the addition of intact bovine protein powder HMF is associated with higher rates of total and surgical NEC. The mechanism for the higher NEC risk is not known yet. Although this study was not powdered for NEC there was no difference in the NEC or sepsis rates between the infants fed an intact bovine protein and the extensively hydrolyzed protein. Both groups had rates lower than previously reported (22–24).Intact bovine protein has higher associated long-term risk for allergy and atopy compared with HM-fed infants. Protein intolerance is seen in premature infants and in term infants (25). Because preterm infants have a similar risk for allergy and atopy compared with term infants and in the NICU have presented with symptoms suggestive of allergic colitis, avoiding intact bovine protein may be a desirable objective. For preterm infants fed HM the use of an extensively hydrolyzed protein-based HMF is an appropriate option.In general, blood chemistries were within normal reference ranges for preterm infants. The higher BUN and prealbumin seen in the LE-HMF group can be attributed to the higher protein content of LE-HMF. These higher values may be indicative of improved protein nutriture. It should be noted that although BUN is influenced by renal function and hydration state, all other influences being equal, it is proportional to protein intake and responds rapidly to changes in protein intake (4,5,26,27).Postnatal growth failure remains common in premature infants. Nearly 25 years ago Kashyap et al showed that even a small deficit in protein intake impairs both growth in lean body mass and linear growth (28). In recent years, Arslanoglu et al reported that addition of protein to preterm feedings of recovering VLBW infants resulted in significantly improved linear growth (4,5). This was accomplished by monitoring the BUN level so that when it was less than 9\u200amg/dL, increased protein was added to their feedings. It was observed in the present study that the mean BUN level fell <9 mg/dL by week 2 in infants receiving PI-HMF; however, in infants receiving LE-HMF it never fell <9 mg/dL during the entire study period. Our results, in part, agree with other investigators that an increased protein-to-calorie ratio in the feeds of preterm infants will improve linear growth (4,5,9,28). It is becoming increasingly evident that promoting catch-up growth in the NICU may have implications for long-term development and health (7,29).Our study did have several limitations. The study examined the combined effects of changing both protein content and type (hydrolyzed vs intact). Future studies may want to capture effects of changing one of these variables. A number of subjects in this study did not complete the protocol to SDAY 29. This partially diluted the effects seen in the ITT groups but still permitted demonstration of differential effects seen in the SPF subgroup. A larger study design may improve this in the future. Infants <700 g birth weight were excluded from this study and therefore the study findings cannot be readily extrapolated to this vulnerable group. It is expected however that this group would have higher protein demands than infants in this study and therefore would be as likely or more to have a favorable response to higher protein. Although no differences were seen between both groups for NEC and sepsis the study size was too small to discern true differences for these outcomes.CONCLUSIONSBoth fortifiers showed excellent tolerance and a low rate of morbidity outcomes, with the infants who were SPFs fed LE-HMF having improved growth. These data confirm the safety and suitability of this new concentrated liquid HMF for preterm infants.AcknowledgmentsThe authors thank the following individuals for their hard work and dedication: Coryn Commare, MS, RD; Christy Saulters, BS; Debra Lee-Butcher, BSN, RN; Holy Boyko, BSN, RN; Angela Worley; Carolyn Richardson; Sue Zhang, MS, MAS; Mustafa Vurma, PhD; Maggie Hroncich, BS; Aimee Diley; Kristen Fithian; Sue Nicholson, MS, RD; and Jennifer Teran, BS, RD. The authors also thank study investigators and their staff for their cooperation: Terri Ashmeade, MD; Anthony Killian, MD; Lance Parton, MD; Robert Schelonka, MD; Robert White, MD; Ivan Hand, MD, FAAP; Michelle Walsh, MD; Jeffrey Blumer, PhD, MD; Paula Delmore, RN; Carrie Rau, RN; Renee Bridge, RN; Lisa Lepis, RN; Judy Zaritt, RN; Claire Roane, RN, MSN; Julie Gualtier, RN; Diane Fierst, RN; Christina Gogal; Natalie Dweck; Debra Potak, RN; Barbara Wilkens, RN; Nakia Clay, BS; Mashelle Monhaut, NNP-BC; Rickey Taing, NPL; Susan Bergant, RN, CCRP; and Bonnie Rosolowski, RPT.www.clinicaltrials.gov registration number: NCT01373073.This study was funded by Abbott Nutrition.J.H.K., B.B., G.C., R.S. and S.G.-W. received research funds from the study sponsor, Abbott Nutrition, to conduct the study. J.H.K. is on the speakers’ bureaus for Abbott Nutrition, Mead Johnson Nutrition, Nestle Nutrition, Nutricia, and Medela. J.H.K. and R.S. are on the medical advisory board for Medela. 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Acta Paediatr\n2001; 90:720–723.1151997227.PolbergerSKAxelssonIERaihaNC\nUrinary and serum urea as indicators of protein metabolism in very low birthweight infants fed varying human milk protein intakes. Acta Paediatr Scand\n1990; 79:737–742.223926628.KashyapSSchulzeKFForsythM\nGrowth, nutrient retention, and metabolic response in low birth weight infants fed varying intakes of protein and energy. J Pediatr\n1988; 113:713–721.313985629.HansonCSundermeierJDugickL\nImplementation, process, and outcomes of nutrition best practices for infants <1500\u200ag. Nutr Clin Pract\n2011; 26:614–624.2194764530.EhrenkranzRAYounesNLemonsJA\nLongitudinal growth of hospitalized very low birth weight infants. Pediatrics\n1999; 104\n(2 Pt 1):280–289.10429008TABLE 1Approximate nutrient composition of PI-HMF or LE-HMF added to HMNutrient PI-HMFLE-HMFEnergy, cal100100Fat, g5.25.1CHO, g10.410.1Protein, g33.6Source/type of proteinIntact whey protein concentrateExtensively hydrolyzed caseinDHA, mg1224Vitamin D, IU150150Calcium, mg175153Phosphorus, mg9886Osmolality, mOsm/kg water385450Lutein, μg*23Values per 100 calories mixed at a ratio of 1 pkt or 5 mL:25 mL HM (as fed). CHO\u2009=\u2009carbohydrate; DHA\u2009=\u2009docosahexaenoic acid; HM\u2009=\u2009human milk; LE-HMF \u2009=\u2009liquid HMF containing extensively hydrolyzed protein; PI-HMF\u2009=\u2009powdered intact protein HMF.*Lutein not added to product but available in varying amounts from HM.TABLE 2Neonatal and perinatal characteristics of preterm infantsTreatment group*PI-HMF (n\u2009=\u200963)LE-HMF (n\u2009=\u200966)Gestational age, wk28.7\u2009±\u20090.228.8\u2009±\u20090.2Birth weight, g1156\u2009±\u2009241193\u2009±\u200926Birth length, cm37.4\u2009±\u20090.337.7\u2009±\u20090.3Birth HC, cm26.1\u2009±\u20090.226.5\u2009±\u20090.2Male sex, n (%)35 (56)36 (55)Ethnicity: Hispanic, n (%)17 (28)8 (13)†Race, n (%)\u2003White42 (67)43 (65)\u2003Black13 (21)17 (26)\u2003Asian1 (2)1 (2)\u2003Other7 (11)3 (5)\u2003White/other0 (0)2 (3)C-section, n (%)38 (60)42 (64)Twin, n (%)16 (25)12 (18)Age at study day 1, d12.3\u2009±\u20090.712.8\u2009±\u20090.6Birth class, n (%)\u2003≤1000\u2009g16 (24)12 (19)\u2003>1000\u2009g66 (76)63 (81)LE-HMF\u2009=\u2009liquid HMF containing extensively hydrolyzed protein; PI-HMF\u2009=\u2009powdered intact protein HMF.*Mean\u2009±\u2009SEM.†P\u2009=\u20090.0407.TABLE 3Anthropometric gainsTreatment group*Targeted growth†,‡PI-HMF (n\u2009=\u200963)LE-HMF (n\u2009=\u200966)Weight gain, g kg−1 day−117.5\u2009±\u20090.618.2\u2009±\u20090.3>18Length gain, cm/wk1.2\u2009±\u20090.071.2\u2009±\u20090.06>0.9HC gain, cm/wk1.0\u2009±\u20090.041.0\u2009±\u20090.05>0.9LE-HMF\u2009=\u2009liquid HMF containing extensively hydrolyzed protein; PI-HMF\u2009=\u2009powdered intact protein HMF; HC\u2009=\u2009head circumference.*Intent-to-treat group, n\u2009=\u2009129.†Ehrenkranz et al (7).‡Ehrenkranz et al (30).TABLE 4Blood chemistry dataCharacteristicsReference rangesStudy dayTreatment group*PI-HMFLE-HMFBicarbonate, mEq/L†17–24123.27\u2009±\u20090.45 (59)25.05\u2009±\u20090.45 (62)1524.32\u2009±\u20090.50 (49)25.40\u2009±\u20090.39 (58)2925.04\u2009±\u20090.43 (40)25.54\u2009±\u20090.44 (50)BUN, mg/dL‡2.5–31.4111.47\u2009±\u20090.78 (56)11.89\u2009±\u20091.03 (61)158.30\u2009±\u20091.15 (50)11.72\u2009±\u20090.68 (58)295.81\u2009±\u20090.38 (40)9.31\u2009±\u20090.53 (49)Prealbumin, mg/dL§7.0–39.0110.05\u2009±\u20090.37 (58)9.69\u2009±\u20090.33 (54)1510.11\u2009±\u20090.37 (47)11.40\u2009±\u20090.41 (46)299.08\u2009±\u20090.35 (36)10.01\u2009±\u20090.35 (37)Calcium, mg/dL8.0–11.0110.10\u2009±\u20090.08 (56)9.93\u2009±\u20090.08 (60)159.93\u2009±\u20090.10 (50)9.95\u2009±\u20090.07 (57)299.89\u2009±\u20090.09 (40)9.82\u2009±\u20090.06 (49)Phosphorus, mg/dL4.2–8.716.41\u2009±\u20090.17 (54)6.20\u2009±\u20090.13 (58)156.71\u2009±\u20090.13 (46)6.50\u2009±\u20090.12 (56)296.66\u2009±\u20090.10 (40)6.46\u2009±\u20090.12 (47)Magnesium, mg/dL1.5–2.111.90\u2009±\u20090.03 (54)1.88\u2009±\u20090.02 (59)151.80\u2009±\u20090.03 (47)1.86\u2009±\u20090.03 (55)291.81\u2009±\u20090.02 (40)1.82\u2009±\u20090.03 (46)Alkaline phosphatase, U/L150–4001443.89\u2009±\u200924.50 (55)415.40\u2009±\u200915.78 (60)15366.13\u2009±\u200921.80 (48)332.68\u2009±\u200910.87 (57)29335.28\u2009±\u200921.84 (40)342.36\u2009±\u200913.10 (47)Sodium, mEq/L129–1431137.49\u2009±\u20090.49 (61)138.42\u2009±\u20090.34 (65)15137.46\u2009±\u20090.55 (52)137.56\u2009±\u20090.29 (59)29139.07\u2009±\u20090.41 (41)138.70\u2009±\u20090.40 (50)Potassium, mEq/L4.5–7.115.39\u2009±\u20090.11 (61)5.20\u2009±\u20090.09 (65)155.25\u2009±\u20090.09 (52)5.23\u2009±\u20090.09 (59)295.25\u2009±\u20090.10 (41)5.06\u2009±\u20090.07 (50)Chloride, mEq/L100–1171104.16\u2009±\u20090.60 (58)104.03\u2009±\u20090.55 (63)15104.10\u2009±\u20090.72 (49)103.88\u2009±\u20090.43 (57)29106.00\u2009±\u20090.57 (40)106.14\u2009±\u20090.37 (49)BUN\u2009=\u2009blood urea nitrogen; LE-HMF\u2009=\u2009liquid HMF containing extensively hydrolyzed protein; PI-HMF\u2009=\u2009powdered intact protein HMF; HC\u2009=\u2009head circumference.*Values are mean\u2009±\u2009SEM (n).†Bicarbonate (mEq/L): (SDAY 1) LE-HMF > PI-HMF, P\u2009=\u20090.0419, LSM\u2009±\u2009SE: LE-HMF\u2009=\u200924.71\u2009±\u20090.56, PI-HMF\u2009=\u200923.33\u2009±\u20090.62.‡BUN (mg/dL): Feeding main effect: LE-HMF > PI-HMF, P\u2009=\u20090.0013, LSM\u2009±\u2009SE: LE-HMF\u2009=\u200911.99\u2009±\u20090.73, PI-HMF\u2009=\u20098.99\u2009±\u20090.83.§Prealbumin (mg/dL): Feeding main effect: LE-HMF > PI-HMF, P\u2009=\u20090.0049, LSM\u2009±\u2009SE: LE-HMF\u2009=\u200910.61\u2009±\u20090.35, PI-HMF\u2009=\u20099.32\u2009±\u20090.38.", 'title': 'Growth and Tolerance of Preterm Infants Fed a New Extensively Hydrolyzed Liquid Human Milk Fortifier.', 'date': '2015-10-22'}, '22301933': {'article_id': '22301933', 'content': 'Preterm human milk-fed infants often experience suboptimal growth despite the use of human milk fortifier (HMF). The extra protein supplied in fortifiers may be inadequate to meet dietary protein requirements for preterm infants.\nWe assessed the effect of human milk fortified with a higher-protein HMF on growth in preterm infants.\nThis is a randomized controlled trial in 92 preterm infants born at <31 wk gestation who received maternal breast milk that was fortified with HMF containing 1.4 g protein/100 mL (higher-protein group) or 1.0 g protein/100 mL (current practice) until discharge or estimated due date, whichever came first. The HMFs used were isocaloric and differed only in the amount of protein or carbohydrate. Length, weight, and head-circumference gains were assessed over the study duration.\nLength gains did not differ between the higher- and standard-protein groups (mean difference: 0.06 cm/wk; 95% CI: -0.01, 0.12 cm/wk; P = 0.08). Infants in the higher-protein group achieved a greater weight at study end (mean difference: 220 g; 95% CI: 23, 419 g; P = 0.03). Secondary analyses showed a significant reduction in the proportion of infants who were less than the 10th percentile for length at the study end in the higher-protein group (risk difference: 0.186; 95% CI: 0.370, 0.003; P = 0.047).\nA higher protein intake results in less growth faltering in human milk-fed preterm infants. It is possible that a higher-protein fortifier than used in this study is needed. This trial was registered with the Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au/) as ACTRN12606000525583.', 'title': 'Effect of increasing protein content of human milk fortifier on growth in preterm infants born at <31 wk gestation: a randomized controlled trial.', 'date': '2012-02-04'}, '22987877': {'article_id': '22987877', 'content': 'To evaluate the growth, tolerance, and safety of a new ultraconcentrated liquid human milk fortifier (LHMF) designed to provide optimal nutrients for preterm infants receiving human breast milk in a safe, nonpowder formulation.\nPreterm infants with a body weight ≤ 1250 g fed expressed and/or donor breast milk were randomized to receive a control powder human milk fortifier (HMF) or a new LHMF for 28 days. When added to breast milk, the LHMF provided ∼20% more protein than the control HMF. Weight, length, head circumference, and serum prealbumin, albumin, blood urea nitrogen, electrolytes, and blood gases were measured. The occurrence of sepsis, necrotizing enterocolitis, and serious adverse events were monitored.\nThis multicenter, third party-blinded, randomized controlled, prospective study enrolled 150 infants. Achieved weight and linear growth rate were significantly higher in the LHMF versus control groups (P = .04 and 0.03, respectively). Among infants who adhered closely to the protocol, the LHMF had a significantly higher achieved weight, length, head circumference, and linear growth rate than the control HMF (P = .004, P = .003, P = .04, and P = .01, respectively). There were no differences in measures of feeding tolerance or days to achieve full feeding volumes. Prealbumin, albumin, and blood urea nitrogen were higher in the LHMF group versus the control group (all P < .05). There was no difference in the incidence of confirmed sepsis or necrotizing enterocolitis.\nUse of a new LHMF in preterm infants instead of powder HMF is safe. Benefits of LHMF include improvements in growth and avoidance of the use of powder products in the NICU.', 'title': 'A new liquid human milk fortifier and linear growth in preterm infants.', 'date': '2012-09-19'}, '29772833': {'article_id': '29772833', 'content': "NutrientsNutrientsnutrientsNutrients2072-6643MDPI29772833598651310.3390/nu10050634nutrients-10-00634ArticleThe Effect of Increasing the Protein Content of Human Milk Fortifier to 1.8 g/100 mL on Growth in Preterm Infants: A Randomised Controlled TrialReidJessica1MakridesMaria12McPheeAndrew J.13StarkMichael J.34https://orcid.org/0000-0002-6474-0505MillerJacqueline15CollinsCarmel T.12*1Healthy Mothers, Babies and Children, South Australian Health and Medical Research Institute, Adelaide, SA 5006, Australia; jessica.reid@adelaide.edu.au (J.R.); maria.makrides@sahmri.com (M.M.); andrew.mcphee@sa.gov.au (A.J.M.); jacqueline.miller@sahmri.com (J.M.)2Adelaide Medical School, Discipline of Paediatrics, The University of Adelaide, Adelaide, SA 5006, Australia3Neonatal Medicine, Women’s and Children’s Hospital, Adelaide, SA 5006, Australia; michael.stark@adelaide.edu.au4The Robinson Research Institute, The University of Adelaide, Adelaide, SA 5006, Australia5Nutrition and Dietetics, Flinders University, Adelaide, SA 5006, Australia*Correspondence: carmel.collins@sahmri.com; Tel.: +61-8-8128-440917520185201810563426420181552018© 2018 by the authors.2018Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).The aim of this study was to assess the effect of feeding high protein human milk fortifier (HMF) on growth in preterm infants. In this single-centre randomised trial, 60 infants born 28–32 weeks’ gestation were randomised to receive a higher protein HMF providing 1.8 g protein (n = 31) or standard HMF providing 1 g protein per 100 mL expressed breast milk (EBM) (n = 29). The primary outcome was rate of weight gain. Baseline characteristics were similar between groups. There was no difference between high and standard HMF groups for weight gain (mean difference (MD) −14 g/week; 95% CI −32, 4; p = 0.12), length gain (MD −0.01 cm/week; 95% CI −0.06, 0.03; p = 0.45) or head circumference gain (MD 0.007 cm/week; 95% CI −0.05, 0.06; p = 0.79), despite achieving a 0.7 g/kg/day increase in protein intake in the high protein group. Infants in the high protein group had a higher proportion of lean body mass at trial entry; however, there was no group by time effect on lean mass gains over the study. Increasing HMF protein content to 1.8 g per 100 mL EBM does not improve growth in preterm infants born 28–32 weeks’ gestation.human milkgrowthlow birth weighthuman milk fortifier1. IntroductionIt is well established that fortified human milk improves growth rates in preterm infants [1,2,3]. However, the optimal amount of protein in the fortifier is yet to be determined, partly due to the variability in the protein content of human milk, both within mothers and over time. Too little protein results in a failure to meet protein requirements, estimated to be 4.0–4.5 g/kg/day for infants born <1000 g and 3.5–4.0 g/kg/day for those born 1000–1800 g [4]. Consequently, growth failure in the neonatal period is common in infants fed fortified human milk compared with infants fed preterm formula [5,6,7]. Conversely, too much protein may result in metabolic acidosis [8]. Individualized fortification, based on either the metabolic response of the infant [9,10,11], or the macronutrient content of mother’s milk [12] has been investigated and provides evidence in support of inadequate protein concentration of human milk fortifiers (HMFs) when used in a standardised approach. However, individualised approaches are time consuming and not easily translated to the clinical environment [13]. We previously investigated a fortifier providing 1.4 g compared with 1 g protein per 100 mL human milk in preterm infants <31 weeks’ gestation [14]. While we found no difference in the rate of weight and length gain between groups, there were fewer infants with length <10th percentile at discharge in the high protein group, suggesting a higher protein concentration fortifier may be needed to improve growth. We therefore aimed to determine the effect of further increasing the protein content of HMF to 1.8 g/100 mL compared with 1 g/100 mL, on growth in preterm infants born 28–32 weeks’ gestation.2. Materials and Methods2.1. Study DesignThe study was a single centre (Women’s and Children’s Hospital, North Adelaide, South Australia), parallel group randomised controlled trial conducted between February 2012 and May 2013.2.2. ParticipantsInfants born 28–32 completed weeks’ gestation whose mothers intended to provide breast milk were eligible to participate. Multiple births were eligible and were randomised individually. Infants with a major congenital or chromosomal abnormality likely to affect growth, or where protein therapy was contraindicated (e.g., major heart defects, cystic fibrosis, phenylketonuria, disorders of the urea cycle) were ineligible. Infants likely to transfer to remote locations and infants who had received standard practice HMF for more than four days were also excluded.2.3. Randomisation and BlindingInfants were randomised to one of two groups: the higher protein intervention group or the standard protein control group. An independent researcher created the randomisation schedule using a computer generated variable block design of 4 and 6. Stratification occurred for sex and gestational age 28–29 weeks and 30–32 weeks. Parents of eligible infants were approached by a neonatologist and followed-up for consent by a research nurse who was not involved in clinical care. Upon consent, infants were randomised by telephoning an independent researcher who held the randomisation schedule and assigned a unique study identification number. Participants, clinicians, outcome assessors and data analysts were blinded to randomisation group.2.4. InterventionsThe base HMF used for both trial groups was FM85 Human Milk Supplement (Nestlé Nutrition, Gland, Switzerland) which provides 1.0 g protein and 17.5 kcal when 5 g HMF is added to 100 mL expressed breast milk (EBM). The high protein fortifier was prepared by adding 0.9 g Protifar (Nutricia, Zoetermeer, The Netherlands), a bovine casein-based powder, to the FM 85. This resulted in an additional 0.8 g protein and 3.5 kcal per 100 mL EBM providing 1.8 g protein and 21 kcal when added to 100 mL of EBM. To ensure both fortifiers were isocaloric, thereby eliminating the effect of different energy intakes on growth, 0.9 g Polyjoule (Nutricia, Zoetermeer, The Netherlands), a glucose polymer, was added to the standard fortifier providing an additional 3.5 kcal but no extra protein, giving a total of 1.0 g protein and 21 kcal when added to 100 mL of EBM. The Polyjoule and Protifar supplements were packaged into identical 400-g containers each with a tamper proof seal (Pharmaceutical Packaging Professionals Pty Ltd., Thebarton, Australia). The containers were differentiated by four colour-coded labels to facilitate blinding, with each trial group separately color-coded into two groups. Infant nutrition attendants, under the direction of the Nutrition and Food Services Department, were trained in the preparation of the HMF. Trial fortifier was mixed at the rate of 5 g FM 85 plus either 0.9 g Protifar, or 0.9 g Polyjoule, for the high and standard protein groups respectively, with 4 mL of sterile water, to give a total volume of 8 mL for use with each 100 mL of EBM.2.5. Intervention AdministrationThe fortifier intervention and control fortifiers were delivered via the enteral tube, immediately prior to a feed (tube, bottle or breast). Trial HMFs were delivered at 8 mL HMF/100 mL EBM with the volume of HMF for each feed ordered daily by the medical or neonatal nurse practitioners. In cases where a mix of EBM and preterm formula was to be given, the trial HMF was only given if EBM was >50% of the total feed. When the infant received a direct breast feed, the timing of administration of the trial product (before, during or after the feed) was at the discretion of the primary care nurse in consultation with the mother. For each day, the trial HMFs were decanted into syringes and labelled with infant identification, volume of HMF and trial details. Syringes were stored refrigerated in the neonatal unit in each infant’s individually labelled container. Any syringes not administered in the 24-h period were recorded and discarded. Fluid balance records were audited daily for compliance with the trial protocol. Administration of trial HMF began as soon as practical after randomisation (within one to two days) and continued until study end, defined as the removal of the naso-gastric tube or estimated date of delivery, whichever came first.2.6. Nutritional IntakeMeasured protein and fat content of a weekly sample of unfortified EBM (MilkoScan Minor, Foss, Denmark) were used to represent the weekly composition of EBM [14]. The lactose concentration was assumed to be 6.8 g/100 mL. EBM was only sampled when the supply was surplus to the infant’s requirements. Missing values were substituted with the average macronutrient composition of all available samples (32 of the 45 mothers involved in the study were able to provide breast milk samples). Macronutrient intakes for the study fortifiers, EBM and formula were calculated from the volume ingested, the protein and fat concentration of EBM, and the manufacturer’s information on the study fortifiers and formula. The protein content of the preterm formula in use at the time of the study was 2.2 g/100 mL. Energy content was calculated by using the Atwater factors of 4, 4, and 9 kcal/g for protein, carbohydrate, and fat respectively.2.7. Outcome Assessments2.7.1. Primary outcomeThe primary outcome was rate of weight gain (g/week) from trial start (day of randomisation) to trial end. In addition to routine clinical measurements, a research nurse and J.R. weighed infants on randomisation, weekly and at study end; duplicate weight measurements were taken using electronic balance scales accurate to 5 g. Measurements were repeated if there was a discrepancy ≥10 g, with the average of the two closest measurements used.2.7.2. Secondary Efficacy and Safety OutcomesSecondary efficacy outcomes included length and head circumference gain (cm/week), infant weight at study end, small for gestational age (SGA) at study end and body composition (fat-free mass). Length measurements were taken weekly with the infant in the supine position and measured to the nearest 0.1 cm using a recumbent length board. Head circumference was measured weekly using a non-stretching tape placed around the largest occipito-frontal circumference. Duplicate measurements were done and repeated if there was a discrepancy ≥0.5 cm, with the average of the 2 closest measures taken. SGA was defined as below the 10th percentile for infants of the same sex and gestational age, as determined from Australian birth reference data [15]. Fat free (lean) mass was measured weekly by bioelectrical impedance spectroscopy (BIS) using the Imp™ SFB7 (ImpediMed Limited, Queensland, Australia) with the first measurement taken during the first week of the study.Secondary safety outcomes included feeding tolerance (days feeds interrupted and days to reach enteral intake ≥150 mL/kg/day). A protocol was developed for discontinuation of the trial fortifier based on uraemia (blood urea nitrogen (BUN) concentration >8.0 mmol/L) and/or a metabolic acidosis (base excess <−6 mmol/L) persisting for more than 48 hours. However, no infant met these criteria. Similarly, criteria were defined for the addition of protein to feeds if an infant had poor weight gain defined as <15 g/kg/day over the preceding 7-day period associated with a BUN of <2 mmol/L when feed volumes reached 170 to 180 mL/kg/day. In this case, Protifar could be added at the discretion of the attending neonatologist, in addition to the allocated intervention fortifier. Additional protein was ceased when weight gain of 15 g/kg/day and a BUN >2 mmol/L were achieved.2.7.3. Biochemical AnalysesWeekly blood samples were taken and BUN, plasma albumin, plasma creatinine, pH and base deficit measured. Blood spots were collected weekly on filter paper and amino acids measured using tandem mass spectrometry (SA Pathology, Neonatal Screening Centre, Adelaide, Australia).2.7.4. Sample Size and Statistical AnalysisA sample size of 60 (30 per group) would detect a difference in weight gain of 3.31 g per day between the high protein and standard protein groups (80% power, p = 0.05). Consultation with the neonatal medical team agreed that this was a clinically important difference on which clinical practice could be changed. Mean weight, length, head circumference and lean mass gains over the trial period, were calculated for each infant using a linear effects model with a random intercept and slope. Using the slope, a linear regression model was fitted for each infant. Clustering (multiple births) was accounted for by using a generalised estimating equation with an independent working correlation matrix. All analyses were intention-to-treat. All models were adjusted for sex and gestational age category (28–29 and 30–32 weeks’ gestation). A per protocol analysis was specified a priori for infants who consumed ≥70% of their prescribed trial fortifier.2.7.5. EthicsEthical approval was granted by the Women’s and Children’s Health Network Human Research Ethics Committee (REC2401/10/14). This trial was registered with the Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au/) as ACTRN12611001275954.3. Results3.1. Study PopulationSixty infants were enrolled in the trial with 31 infants randomised to the high protein group and 29 infants to the standard protein group (Figure 1). There were 31 infants born from multiple births (14 sets of twins, 1 set of triplets). In all multiple births, apart from two sets of twins, the infants were randomly allocated to different interventions. For the triplets, two were randomised to the high protein group and one to the standard protein group. Four infants, two from each group, were withdrawn from the study after randomisation but before the first dose of trial fortifier was administered after parents changed their minds about involvement. A further two infants (twins) in the high protein group did not have any available breast milk and withdrew before the commencement of fortifier. One set of twins and one singleton were withdrawn by the parents midway through the trial due to perceived feeding intolerance and another infant was withdrawn by the clinical team after developing necrotising enterocolitis. In all cases of withdrawal, parents consented to the ongoing collection of data and all were included in intention-to-treat analyses. Baseline infant and maternal demographic, clinical and nutritional characteristics at randomisation were comparable between groups except that there were more male infants in the high protein group, n = 16 (52%) than the standard protein group, n = 12 (41%), the mean ± SD birth weight was lower in the higher protein group (1483 ± 423 g versus 1551 ± 407 g in the high and standard groups, respectively) and there were more infants classified as SGA for weight in the high protein group, n = 5 (16%) than the standard protein group, n = 1 (3%) (Table 1).3.2. Nutritional ManagementForty infants received standard ward HMF, S-26 SMA HMF (Wyeth Nutrition) while waiting for consent, 18 in the high and 22 in the standard protein group (Table 1). The remaining twenty trial infants started immediately on their allocated trial intervention.Nutritional intake of the infants for the first 28 days of the study did not differ between the groups except that the high protein group received more protein (mean ± SD 4.2 ± 1.3 vs. 3.5 ± 0.93 g/kg/day in the high and standard protein groups respectively). The protein concentration of the EBM was not different between groups (mean ± SD 1.43 ± 0.27 and 1.45 ± 0.28 g protein/100 mL in the high and standard groups, respectively) and the difference in protein intake was due to more protein derived from the HMF (mean ± SD 1.9 ± 1.2 and 1.2 ± 0.6 g/kg/day, in the high and standard groups, respectively. Energy intakes and fluid volume were similar between the groups (energy: mean ± SD 124 ± 34 and 126 ± 27 kcal/kg/day and fluid: mean ± SD 154 ± 39 and 157 ± 32 mL/kg/day in the high and standard groups, respectively). The high protein group received 83% (±32) of their total enteral intake as EBM compared with the control group who received 90% (±23).3.3. Primary OutcomeThere was no difference in the rate of weight gain between groups (Table 2) (mean (95% CI) high protein 245 (230, 260) g/week and standard protein 258 (244, 272) g/week, adjusted mean difference −14 (−32, 4) p = 0.12). Results were similar when analysed per protocol (Table 2).3.4. Secondary Outcomes3.4.1. GrowthThere were no differences in rate of length or head circumference gain (Table 2). High protein HMF infants weighed less at study end but this was not statistically significant (Table 2) and is consistent with the difference in birth weight between the groups (Table 1). There were no differences in length or head circumference at study end between the groups (Table 2). There was no difference in SGA status for weight between high and standard protein HMF groups at the end of the study (n = 8, 25%, and n = 3, 10% SGA infants in the high and standard protein groups, respectively, adjusted Relative Risk (95% CI); 2.5 (0.8, 7.9), p = 0.11).Over the first four weeks of the trial, when >75% of participants were still in hospital, fat free (lean) mass was measured with the week one measurement taken a mean of 8 ± SD 2 days after randomisation. Fat free mass as a proportion of body weight (Figure 2) from weeks one to four was greater in high protein group infants than standard protein group infants (p = 0.03). However, there was no significant group by time interaction (p = 0.84). At week three alone, there was a significant increase for fat free mass as a proportion of body weight in the high protein group (p = 0.04).3.4.2. BiochemistryDue to the variable nature of blood chemistry data and length of hospital stay (to discharge), only the first three trial weeks could be accurately analysed using a linear mixed effects model.There was a significant group by time interaction for BUN levels (p < 0.001) with BUN levels significantly increased in the high protein group (Figure 3). This difference continued for the duration of the trial (p < 0.001). There were 12 occurrences in nine separate infants where BUN levels were measured over the pre-specified safety threshold of 8 mmol/L. Seven of these occurred during baseline blood tests taken at randomisation and were therefore not a result of the intervention. Six of these infants had BUN measurements in the normal range at their next weekly blood test. One infant had a BUN measurement >8 mmol/L at week one; the infant did not have another BUN measurement over 8 mmol/L for the rest of the trial. Two other infants, both in the high protein group, recorded BUN concentrations >8.0 mmol/L, peaking at 8.8 mmol/L, on five occasions, however the base excess remained above −6 mmol/L with no other abnormal biochemistry. There was one occurrence of an infant in the standard protein group requiring additional protein due to poor weight gain and BUN <2 mmol/L.There were no group by time interactions or group differences for albumin, creatinine, glucose, pH (results not shown). Phenylalanine (Phe) and tyrosine (Tyr), amino acids associated with increased protein intake, were both increased in the high protein group compared to the standard group at study week 3 (Phe median (IQR) μmol/L: 33 (28–42) vs. 25 (23–30), p <0.001 and Tyr median (IQR) μmol/L: 196 (151–267) vs. 128 (99–172) μmol/L, p <0.003 in the high and standard groups respectively.3.4.3. Clinical OutcomesHigh protein HMF infants were significantly more likely to have feeds interrupted (11 (35%) vs. 6 (21%), p = 0.01, in the high and standard protein groups, respectively) Table 3. There was no significant difference in the number of days spent on parenteral nutrition, days of intravenous lipid or the days taken to reach full enteral feeds. Likewise, there was no significant difference between the groups for any other clinical outcome (Table 3).4. DiscussionThe aim of this study was to assess the effect of a higher protein HMF on preterm infant growth. Our trial interventions resulted in the high protein group infants receiving 0.7 g/kg/day more protein than infants in the standard protein group, with mean protein intakes within recommended ranges for both groups. Despite this, there were no differences in growth between the two groups. The accumulation of fat free mass and fat mass, also did not differ between groups. While the higher protein group had a greater proportion of fat free mass from week one, the absence of a baseline measurement makes the interpretation of this difficult. It is unlikely that the intervention would have had an effect in the first week of the study, particularly as the change in fat free mass over time did not differ between groups. A significant difference between groups was noted at week three only and the implication of this is unclear. It is possible that this is a chance finding of no clinical significance.These results are confirmed by a recent study by Maas et al. [16] who compared 1 and 1.8 g protein concentration in powdered HMFs in a similar population to ours and found no difference in growth. Their trial interventions achieved a 0.6 g/kg/day median greater intake of protein, similar to our study, and protein intakes were within recommendations. Growth rates in both studies approximated foetal growth rates. A further two studies compared two different, newly formulated liquid HMFs with higher protein concentrations, with standard powdered HMFs. Moya et al. [17] compared Mead Johnson Nutrition products: a liquid fortifier with an Enfamil powdered fortifier, which when mixed with EBM provided 3.2 and 2.6 g protein/100 mL, respectively, equating to an additional 1.8 and 1.1 g protein. Kim et al. [18], in a non-inferiority trial, compared the Abbott Nutrition products of Similac HMF liquid, providing 3.6 g protein/100 kcal when mixed with EBM, with Similac HMF powder providing 3 g protein/100 kcal when mixed. These comparisons equate to an additional 1.6 and 1 g protein added to 100 mL EBM in the liquid and powder, respectively. The populations were similar between studies [17,18] except that Moya et al. [17] inclusion criteria (≤30 weeks’ gestation, birth weight ≤1250 g) resulted in a slightly less mature and smaller population than in both Kim et al. [18] study and this current study. Neither study [17,18] showed a difference in weight gain between groups, however, Moya et al. [17] found improved length gain with the higher protein. Both studies found infants in the high protein group were heavier at study end. Almost half the participants in Moya’s study were <1000 g at birth; hence their protein requirements of 4 to 4.5 g/kg would have been met by the high, but not the control, protein fortifier at volumes of 150 mL/kg. This may explain the effect seen on length gain. Two other studies have compared fortifiers containing 1 and 1.4 g protein added to 100 mL EBM with mixed results. Our previous trial [14] showed no effect of increased protein on growth, although did show a reduction in the number of infants SGA for length at discharge. However, Rigo et al. [19], in a non-inferiority trial, found improved weight gain of 2.3 g/day with the higher protein fortifier. The trial products in both these studies were similar, as were the population. It is possible that the smallest infants, with the highest protein needs, are the ones to benefit most from increased protein and that the larger sample size in Rigo (n = 153) compared to that in Miller (n = 92) elucidated the differences. Taken collectively, these results and ours suggest that protein concentrations in HMFs of 1.8 g provide no additional benefit in the population studied, but smaller infants are worthy of further investigation.The significantly elevated BUN levels seen at weeks 1, 2 and 3 were expected and have occurred in other high protein nutritional intervention studies [9,14,17]. Assuming adequate renal function, BUN is proportional to protein intake [20] and is often used as a crude marker of protein sufficiency. Low BUN levels suggest inadequate protein intake and high levels indicate possible excessive intake [9]. Blood phenylalanine and tyrosine concentrations were also significantly increased in the higher protein group, in week 3 only, and this is unlikely to be clinically significant. There were no differences in creatinine, albumin or other biochemical markers suggesting the intervention did not harm the infants.A strength of this study is the rigour with which dietary intake and growth were assessed. The protein and fat concentrations of EBM were measured, rather than assumed, resulting in accurate reporting of dietary intake and confirmation that, despite the variability of protein in EBM, we achieved a mean intake difference of 0.7 g/kg/day of protein between groups. Similarly, we measured both growth and body composition in an attempt to discern differences in weight gain arising from extra protein. This trial also has some limitations. Although all infants were included in the analyses, there were 10 who either did not receive, or ceased the intervention, which may have impacted results. In addition, the pragmatic nature of this trial may have influenced results as clinicians may have adjusted feed regimes if poor weight gain was identified. There was one instance of extra Protifar prescribed to an infant in the standard protein group and subtle increases in feed volume may also have occurred although volume of intake was not different between groups. This may have made it more difficult to detect differences between intervention groups. We used BIS to determine fat and fat free mass. BIS is the only cot-side technique available where infants requiring respiratory support can be assessed. While accuracy of BIS at the individual level is poor, BIS provides a useful means of determining differences in body composition between population means [21].Many of the recent trials discussed have already achieved mean growth rates approaching intra-uterine growth, with similar growth rates between groups. Findings from this current study are only generalisable to a similar population (infants born 28–32 week’s gestation). Therefore, to explicate the subtle effects of increasing protein on growth, future trials may need to focus on birth weight categories as they relate to protein requirements (i.e., <1000 g and 1000–1800 g). Due to the small proportion of infants born <1000 g, large multi-centre trials will be needed to tease out the effect.5. ConclusionsIncreasing the protein concentration of HMF from 1.0 to 1.8 g protein added per 100 mL EBM does not improve growth in preterm infants born 28–32 weeks’ gestation.AcknowledgmentsWe thank the families who participated in this study.Author ContributionsConceptualization, J.R., M.M., A.J.M. and C.T.C.; Formal analysis, J.R., M.M., A.J.M., M.J.S., J.M. and C.T.C.; Funding acquisition, J.R., M.M., A.J.M., M.J.S. and C.T.C.; Investigation, J.R., M.M., A.J.M., M.J.S. and C.T.C.; Supervision, M.M., A.J.M., M.J.S. and C.T.C.; Writing: original draft, J.R., J.M. and C.T.C.; Writing: review and editing, J.R., M.M., A.J.M., M.J.S., J.M. and C.T.C.FundingThis research was funded by a Women’s and Children’s Hospital Foundation Grant. Research Fellowships were provided by the National Health and Medical Research Council of Australia (M.M. Principal Research Fellow APP1061704) and the MS McLeod Research Fellowship, MS McLeod Research Fund, Women's and Children’s Hospital Research Foundation (C.T.C). The contents of the published material are solely the responsibility of the authors and do not reflect the views of the National Health and Medical Research Council of Australia.Conflicts of InterestOutside the submitted work, Maria Makrides serves on scientific advisory boards for Fonterra and Nestle. Honoraria are paid to her institution for continuing education of early career researchers. Maria Makrides also holds a Principal Research Fellowship from the NHMRC (APP1061704). Other authors declare no conflict of interest. Nestlé Nutrition donated half of the human milk fortifier used in the trial and Nutricia donated the Polyjoule and Protifar supplements. However, these sponsors had no role in the design of the study, in the collection, analyses or interpretation of data; in writing of the manuscript, and the decision to publish the results.References1.AdamkinD.H.RadmacherP.G.Fortification of human milk in very low birth weight infants (VLBW <1500 g birth weight)Clin. Perinatol.20144140542110.1016/j.clp.2014.02.010248738402.MoroG.E.ArslanogluS.BertinoE.CorvagliaL.MontirossoR.PicaudJ.C.PolbergerS.SchanlerR.J.SteelC.van GoudoeverJ.Human milk in feeding premature infants: Consensus statementJ. Pediatr. Gastroenterol. Nutr.201561Suppl. 1S16S1910.1097/01.mpg.0000471460.08792.4d262959993.BrownJ.V.E.EmbletonN.D.HardingJ.E.McGuireW.Multi-nutrient fortification of human milk for preterm infantsCochrane Database Syst. 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Nutr.201765e83e9310.1097/MPG.00000000000016862872765420.PolbergerS.K.AxelssonI.E.RaihaN.C.Urinary and serum urea as indicators of protein metabolism in very low birthweight infants fed varying human milk protein intakesActa Paediatr. Scand.19907973774210.1111/j.1651-2227.1990.tb11548.x223926621.CollinsC.T.ReidJ.MakridesM.LingwoodB.E.McPheeA.J.MorrisS.A.GibsonR.A.WardL.C.Prediction of body water compartments in preterm infants by bioelectrical impedance spectroscopyEur. J. Clin. Nutr.201367Suppl. 1S47S5310.1038/ejcn.2012.16423299871Figure 1Participant flow through the trial. 1 from rural locations (n = 52), insufficient milk supply (n = 36), required interpreter (n = 6); congenital abnormality (n = 3); 2 did not want to take part (n = 25), did not want twins to be randomized individually (n = 8), parent not visiting (n = 1), immediately transferred to another centre (n = 1).Figure 2Fat free mass as a proportion of body weight for the first four weeks of the trial. Values are means, error bars are 95% CI. High protein n = 30, 30, 27, 26 and standard protein 29, 27, 26, 23 in weeks 1, 2, 3, 4 respectively. Adjusted for sex and gestational age, group interaction, p = 0.03, time interaction, p = 0.01. group × time interaction p = 0.84; * p = 0.04.Figure 3BUN from randomisation to week 3. Values are mean, error bars are 95% CI. High protein: n = 31, 28, 26, 25; Standard protein: n = 29, 26, 24, 24 for weeks baseline, 1, 2, 3. Adjusted for sex and GA, overall group effect <0.001, group * week interaction, p <0.001, * p = 0.04; ** p <0.001.nutrients-10-00634-t001_Table 1Table 1Baseline infant and maternal characteristics.CharacteristicHigh Protein (n = 31)Standard Protein (n = 29)\nInfant characteristics\n\n\nSingleton15 (48)16 (55)Twin15 (48)12 (41)Triplet2 (7)1 (3)Gestational age (week)30.5 ± 1.530.1 ± 1.428–29 weeks’ gestation10 (32)9 (31)30–32 weeks’ gestation21 (68)20 (69)Male infants16 (52)12 (41)Birth weight (g)1483 ± 4231551 ± 407SGA for weight at birth5 (16)1 (3)Birth length (cm)40.0 ± 3.340.2 ± 2.8Head circumference (cm)28.5 ± 328.5 ± 1.8Infants received standard ward HMF before randomisation18 (58)22 (76)Length of standard ward fortification before trial HMF start (day)1.3 ± 1.72.0 ± 1.5Time between birth and trial HMF start (day)8.9 ± 3.29.0 ± 2.5\nMaternal characteristics\n\n\nMaternal age (years)29.9 ± 6.331.7 ± 5.3Mother smoked during pregnancy5 (16.1)3 (10.3)Caucasian27 (96)23 (82)Primiparous19 (61.3)12 (41.4)Previous preterm birth4 (33.3)6 (35.3)Data are presented as n (%) or mean ± SD.nutrients-10-00634-t002_Table 2Table 2Anthropometric changes over the study.\nIntention to Treat AnalysesPer Protocol Analyses 1High Protein (n = 31)Standard Protein (n = 29)Adjusted Mean Difference 2\np\n2\nHigh Protein (n = 21)Standard Protein (n = 23)Adjusted Mean Difference 2\np\n2\nWeight gain (g/week)245 (230, 260)258 (244, 272)−14 (−32, 4)0.12245 (228, 262)262 (247, 277)−15 (−36, 5)0.14Length gain (cm/week)1.1 (1.1, 1.2)1.1 (1.1, 1.2)−0.01 (−0.06, 0.03)0.451.1 (1.1, 1.2)1.2 (1.1, 1.2)−0.01 (−0.06, 0.04)0.62Head circumference gain (cm/week)1.1 (1.0, 1.1)1.1 (1.0,1.1)0.007 (−0.05, 0.06)0.791.1 (1.1, 1.1)1.1 (1.1, 1.1)−0.004 (−0.06, 0.05)0.88Weight at study end (g) 32658 (2544, 2771)2757 (2632, 2883)−100 (−251, 50)0.192646 (2489, 2805)2815 (2675, 2955)−157 (−341, 28) 0.1Length at study end (cm)45.2 (44.5, 45.9)45.8 (45.0, 46.6)−0.5 (−1.3, 0.3)0.1945.2 (44.4, 46.0)46.3 (45.6, 47)−0.86 (−1.85, 0.12)0.09Head circumference at study end (cm)33.1 (32.5, 33.6)33.0 (32.4, 33.7)0.03 (−0.6, 0.7)0.9233.3 (32.7, 33.9)33.6 (33.0, 34.1)−0.16 (−0.90, 0.57)0.66Data are presented as mean, (95% CI); 1 For inclusion in ‘per protocol’ analysis, infants must have consumed 70% or more of their trial group HMF; 2 adjusted for sex and gestational age; 3 study end defined as removal of naso-gastric tube or term equivalent, whichever came first.nutrients-10-00634-t003_Table 3Table 3Feeding and clinical management.VariableHigh Protein (n = 31)Standard Protein (n = 29)\np\nInfant required enteral protein supplementation 101 (3.4)0.48Feeding interrupted 211 (35)6 (21)0.01Days receiving parenteral nutrition10 (7, 13)9 (7, 11)0.34Days of intravenous lipid4 (3, 7)4 (3, 6)0.72Days to full enteral feeds 38 (6, 10)8 (7, 10)0.72Confirmed necrotizing enterocolitis1 (3.2)0>0.99Oxygen at discharge2 (6.5)1 (3.4)0.15Late onset sepsis1 (3.2)0>0.99Data are reported as n (%) or mean (95% CI).1 One infant in the standard protein group was prescribed a protein supplement (Protifar) 2 Feeding interrupted was defined as one of more feeds not given in a day; 3 Full enteral feeds was defined as 150 mL/kg/day).", 'title': 'The Effect of Increasing the Protein Content of Human Milk Fortifier to 1.8 g/100 mL on Growth in Preterm Infants: A Randomised Controlled Trial.', 'date': '2018-05-19'}, '28727654': {'article_id': '28727654', 'content': "J Pediatr Gastroenterol NutrJ. Pediatr. Gastroenterol. NutrJPGAJournal of Pediatric Gastroenterology and Nutrition0277-21161536-4801Lippincott Williams & Wilkins287276545625962JPGN-16-82510.1097/MPG.000000000000168600025Original Articles: NutritionGrowth and Nutritional Biomarkers of Preterm Infants Fed a New Powdered Human Milk Fortifier: A Randomized TrialRigoJacques∗HascoëtJean-Michel†BilleaudClaude‡PicaudJean-Charles§MoscaFabio||RubioAmandine¶SalibaElie#RadkëMichaël∗∗SimeoniUmberto††GuilloisBernard‡‡de HalleuxVirginie∗JaegerJonathan§§AmeyeLaurent||||HaysNicholas P.¶¶SpalingerJohannes##∗Department of Neonatology, University of Liège, CHR Citadelle, Liège, Belgium†Maternité Régionale Universitaire A. Pinard, Nancy‡CIC Pédiatrique 1401 INSERM-CHU, Bordeaux§Service de Neonatologie, Hôpital de la Croix Rousse, Lyon, France||Neonatal Intensive Care Unit, Department of Clinical Science and Community Health, Fondazione IRCCS “Ca’ Granda” Ospedale Maggiore Policlinico, University of Milan, Milan, Italy¶Hôpital Couple Enfant, CHU de Grenoble, Grenoble#Hôpital Clocheville, CHU de Tours, Tours, France∗∗Klinikum Westbrandenburg GmbH, Potsdam, Germany††Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland‡‡Hôpital Clemenceau, CHU de Caen, Caen, France§§Nestlé Clinical Development Unit, Lausanne, Switzerland||||Nestlé Nutrition R&D, Vevey, Switzerland¶¶Nestlé Nutrition R&D, King of Prussia, PA##Children's Hospital of Lucerne, Lucerne, Switzerland.Address correspondence to Jacques Rigo, MD, PhD, Service Universitaire de Néonatologie, CHR de la Citadelle, Boulevard du Douzième de Ligne, 1 4000 Liège, Belgium (e-mail: J.Rigo@ulg.ac.be); Address reprint or protocol requests to: Nicholas P. Hays, PhD, 3000 Horizon Dr., Suite 100, King of Prussia, PA 19406 (e-mail: Nicholas.Hays@rd.nestle.com).1020172292017654e83e93231120162952017Copyright © The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition2017This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0ABSTRACTObjectives:The aim of this study was to assess growth and nutritional biomarkers of preterm infants fed human milk (HM) supplemented with a new powdered HM fortifier (nHMF) or a control HM fortifier (cHMF). The nHMF provides similar energy content, 16% more protein (partially hydrolyzed whey), and higher micronutrient levels than the cHMF, along with medium-chain triglycerides and docosahexaenoic acid.Methods:In this controlled, multicenter, double-blind study, a sample of preterm infants ≤32 weeks or ≤1500\u200ag were randomized to receive nHMF (n\u200a=\u200a77) or cHMF (n\u200a=\u200a76) for a minimum of 21 days. Weight gain was evaluated for noninferiority (margin\u200a=\u200a–1\u200ag/day) and superiority (margin\u200a=\u200a0\u200ag/day). Nutritional status and gut inflammation were assessed by blood, urine, and fecal biochemistries. Adverse events were monitored.Results:Adjusted mean weight gain (analysis of covariance) was 2.3\u200ag/day greater in nHMF versus cHMF; the lower limit of the 95% CI (0.4\u200ag/day) exceeded both noninferiority (P\u200a<\u200a0.001) and superiority margins (P\u200a=\u200a0.01). Weight gain rate (unadjusted) was 18.3 (nHMF) and 16.8\u200ag\u200a·\u200akg−1\u200a·\u200aday−1 (cHMF) between study days 1 and 21 (D1–D21). Length and head circumference (HC) gains between D1 and D21 were not different. Adjusted weight-for-age z score at D21 and HC-for-age z score at week 40 corrected age were greater in nHMF versus cHMF (P\u200a=\u200a0.013, P\u200a=\u200a0.003 respectively). nHMF had higher serum blood urea nitrogen, pre-albumin, alkaline phosphatase, and calcium (all within normal ranges; all P\u200a≤\u200a0.019) at D21 versus cHMF. Both HMFs were well tolerated with similar incidence of gastrointestinal adverse events.Conclusions:nHMF providing more protein and fat compared to a control fortifier is safe, well-tolerated, and improves the weight gain of preterm infants.Keywordsgrowthhuman milklow birth weightSTATUSONLINE-ONLYOPEN-ACCESSTRUEWhat Is KnownDue in part to variability in human milk composition, incidence of postnatal growth restriction is more frequently reported in very-low-birth-weight infants fed fortified human milk compared to those fed preterm formulas.The optimal composition of human milk fortifier and nutritional recommendations for preterm infants fed fortified human milk are still debated.What Is NewA new human milk fortifier containing partially hydrolyzed protein, fat, and carbohydrate provides a higher protein:energy ratio while achieving lower osmolality versus a current fortifier.In preterm infants, the new fortifier improves weight gain and reduces postnatal growth restriction compared to the current fortifier.Feeding of human milk (HM) rather than preterm formulas provides many benefits to preterm infants (eg, accelerated gut maturation (1); protection against infections (2), sepsis (3), necrotizing enterocolitis (2), and retinopathy of prematurity (4); possible protective effect on neurodevelopment (5)) that are mediated by protective biomolecules and trophic factors in HM. HM, however, provides inadequate protein and micronutrients to support the rapid growth and bone mineralization of preterm infants. These deficits are particularly acute in the smallest infants (birthweight <1500\u200ag) who have the highest protein and mineral needs (6). Fortification of mother's own milk or banked HM is therefore recommended for all preterm infants with birthweight <1800\u200ag to improve nutrient accretion and in-hospital growth (7,8).Feeding fortified HM helps support adequate growth and bone mineralization (9), and is associated with favorable neurodevelopmental outcomes (10), although evidence for improved outcomes other than in-hospital growth is limited (11). The nutritional content, however, of some currently available fortifiers may be inadequate for many preterm infants. Incidence of postnatal growth restriction is more frequently reported in very-low-birth-weight infants fed fortified HM compared to those fed preterm formulas (12,13). In addition, the nutritional profile of HM from mothers of premature infants varies greatly (14) and may differ from published reference compositional data, which may lead to less-than-recommended intakes of protein and energy (15,16). These nutritional inadequacies may worsen with use of donor HM, which is often from mothers of term infants >1-month postpartum (17).A new powdered HM fortifier has been developed with a higher protein:energy ratio (protein provided as partially hydrolyzed whey), non-protein energy from lipids and carbohydrate, and higher electrolyte and vitamin levels (enriching HM in line with ESPGHAN (18) and expert group (19) recommendations) versus a control fortifier. When mixed with HM containing 1.5\u200ag protein/100\u200amL (2–4 week milk) (20–22), it provides 3.6\u200ag protein/100 kcal (within the ESPGHAN-recommended ranges (18) for protein and energy intakes for a minimal intake volume of 140\u200amL/kg/day in very-low-birth-weight infants up to 1.8\u200akg body weight), with osmolality below the recommended threshold of 450\u200amOsm/kg (23,24).This study evaluated growth and nutritional biomarkers during a 21-day interval in clinically stable preterm infants receiving the new HM fortifier (nHMF) compared to infants fed a control fortifier (cHMF). The primary objective was to assess weight gain velocity (grams per day); evaluations of other growth parameters (including weight gain velocity in gram per kilograms per day) and intervals (eg, to 40 weeks corrected age [W40CA]), feeding tolerance, adverse events, time to full fortification/full enteral feeding, and markers of protein-energy, electrolytes, bone metabolic status, gut inflammation, and maturity of gastrointestinal (GI) function were also conducted as secondary outcomes. We hypothesized that weight gain of infants fed nHMF would be both noninferior (lower limit of 95% confidence interval [CI] of mean difference >–1\u200ag/day) and superior (lower limit of 95% CI of mean difference >0\u200ag/day) to that of infants fed cHMF.METHODSStudy design and participantsThis was a controlled, double-blind, randomized, parallel-group study conducted in neonatal intensive care units (NICUs) at 11 metropolitan hospitals in France, Belgium, Germany, Switzerland, and Italy. NICU size ranged from 25 to 45 beds. Clinically stable male and female preterm infants with gestational age ≤32 weeks or birthweight ≤1500\u200ag and born to mothers who had agreed to provide expressed or donor breastmilk for the entire 21-day study duration were enrolled in the study from April 2011 to March 2014. Infants were excluded if they had a history of or current systemic, metabolic, or chromosomic disease, any congenital anomalies of the GI tract, were small for gestational age (defined in this study as bodyweight ≤5th percentile (25)), or were receiving steroids or preterm formula during the study period. For multiple births, the first sibling was randomized and other siblings were allocated to the same group. The study was reviewed and approved by an institutional review board/independent Ethics Committee at each study site. Each subject's parent/legal representative provided written informed consent before participating in the study.Infants tolerating ≥100\u200amL\u200a·\u200akg−1\u200a·\u200aday−1 of HM for >24\u200ahours were randomized to receive either nHMF or cHMF for a minimum of 21 days; infants continued to receive their allocated study fortifier (or were transitioned to a routine/standard fortifier) until NICU discharge or medical decision to stop fortification, and fortification was stopped after discharge. The fortifiers were both cow's milk-based and provided similar energy supplementation (17\u200akcal/100\u200amL of HM). For every 100\u200amL of HM, nHMF provided 1.4\u200ag partially hydrolyzed whey protein, 0.7\u200ag lipids (primarily medium chain triglycerides and docosahexaenoic acid), 1.3\u200ag carbohydrate (maltodextrin), with a blend of micronutrients. cHMF (FM85 Human Milk Fortifier, Nestlé, Switzerland) provided 1.0\u200ag extensively hydrolyzed whey protein, no lipids, 3.3\u200ag carbohydrate (lactose and maltodextrin), with a blend of micronutrients. nHMF contained higher concentrations of some vitamins and electrolytes compared to cHMF, but both contained similar levels of minerals, including calcium (as calcium glycerophosphate and calcium phosphate) and phosphorus. Table 1 presents the estimated composition and osmolality of preterm HM (22) fortified with each fortifier. Fortifiers were fed beginning at half-strength (Fortification Strength Increase day 1; FSI1), then advanced per hospital practice, with full-strength fortification occurring once infants could maintain intakes of 150 to 180\u200amL\u200a·\u200akg−1\u200a·\u200aday−1 (ie, full enteral feeds; study day 1 [D1]). A study plan schematic is presented in Figure 1.FIGURE 1Study design. cHMF\u200a=\u200acontrol human milk fortifier; D1\u200a=\u200astudy day 1; D7\u200a=\u200astudy day 7; D10/11\u200a=\u200astudy day 10/11; D14\u200a=\u200astudy day 14; D21\u200a=\u200astudy day 21; DC\u200a=\u200adischarge (note that infants continued to receive their allocated study fortifier [or were transitioned to a routine/standard fortifier] until neonatal unit discharge or medical decision to stop fortification if length of stay was >21 days, and fortification was stopped after discharge) ; FSI1\u200a=\u200afortification strength increase day 1; HC\u200a=\u200ahead circumference; HM\u200a=\u200ahuman milk; nHMF\u200a=\u200anew human milk fortifier; W40CA\u200a=\u200aweek 40 corrected age.Study ProceduresGrowthInfant nude weight (to the nearest 1\u200ag) was measured daily by trained nursery personnel using a calibrated electronic scale (Baby Scale 717, Seca, Semur-en-Auxois, France). Recumbent length and head circumference (HC; both to the nearest 0.1\u200acm) were measured at FSI1, D1, and weekly thereafter. At least 2 trained examiners measured recumbent length using a length board (Mobile Measuring Board 417, Seca, Semur-en-Auxois, France) while maintaining proper body alignment and full body extension with feet flexed. HC was measured using a nonelastic measuring tape (Measuring Tape 212 or 218, Seca, Semur-en-Auxois, France) placed over the largest circumference of the skull (above the supraorbital ridges while covering the most prominent part of the frontal bulge anteriorly). The same calibrated equipment was used for anthropometric measures for each infant at all sites. Weight-for-age, length-for-age, and HC-for-age z scores were calculated using Fenton (25). Weight gain velocity (grams per kilograms per day) was calculated using the average of the start and end weights as the denominator.Markers of Protein-energy, Electrolyte, and Bone Metabolic StatusBlood and urine samples were collected at D1, D10/11, and D21 and analyzed for serum creatinine and prealbumin, blood urea nitrogen (BUN), urinary urea, hemoglobin, hematocrit, electrolyte status, and bone metabolic status. All blood and urine parameters were analyzed as part of routine clinical assessments at each NICU. Since 24-hour urine collections were not performed in this study owing to logistical infeasibility, urinary markers were corrected for 24-hour creatinine excretion (26) assuming a standard urinary excretion in preterm infants of 10\u200amg\u200a·\u200akg−1\u200a·\u200aday−1(27).Feeding Tolerance and Adverse EventsFeeding tolerance was evaluated by trained nursery staff who recorded daily milk intake (milliliters), stool pattern (defecation frequency and stool consistency [5\u200a=\u200ahard, 4\u200a=\u200aformed, 3\u200a=\u200asoft, 2\u200a=\u200aliquid, or 1\u200a=\u200awatery]), presence of abdominal distention, and incidence of spitting-up (defined as return of a small amount of swallowed food, usually a mouthful, and usually occurring during or shortly after feeding) and vomiting (defined as return of a larger amount of food with more complete emptying of the stomach, and usually occurring sometime after feeding). In addition, frequency, type, and attribution to fortifier intake of adverse events (AEs; including clinical and laboratory) were evaluated using physician-reported information recorded using standardized forms from enrollment to W40CA. AEs were categorized by the reporting investigator as “serious” in accordance with International Conference on Harmonization criteria (28) and as “related to the intervention” based on detailed, standardized criteria provided in the protocol.Statistical AnalysisSample size was based on a previous study (29), which investigated growth and zinc status in preterm infants fed fortified HM. In the present trial, a group-sequential design was chosen (Wang and Tsiatis) (30) with 1 interim analysis. To detect a noninferior weight gain in infants fed with nHMF versus cHMF from D1 to D21 (noninferiority margin –1\u200ag/day, expected weight gain difference 2\u200ag/day, standard deviation 4.73\u200ag/day, type I error 5%, power 80%) (29), 192 subjects (males and females combined) were needed. A computer-generated list of random numbers was used to allocate group assignments. Minimization algorithm with allocation ratio 1:1 and second best probability of 15% was used. Stratification factors were center, sex, and birthweight (100g intervals). Group coding was used with 2 nonspeaking codes per group; fortifier packaging was coded accordingly but otherwise identical in appearance. Infants were enrolled and assigned to their intervention by the study investigators or trained delegates. All study personnel (both site- and sponsor-based) and participants (infants’ families) were blind to group assignment. Noninferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference in weight gain from D1 to D21 was larger than the noninferiority margin. Superiority was evaluated if noninferiority was demonstrated. Weight gain was analyzed in the intent-to-treat (ITT) and per-protocol populations by analysis of covariance (ANCOVA) adjusting for D1 postmenstrual age and weight, sex, and center (random effect). Sensitivity analyses were conducted using ANCOVA models that adjusted for covariates that were determined post hoc to be significantly different between groups and which may have confounded the primary results (eg, mother smoking status). Secondary endpoints were analyzed in the ITT population only. For noninferiority and superiority tests, 1-sided P values are provided and should be compared to a reference value of 0.025. For other tests, 2-sided P values are provided and should be compared to a reference value of 0.05. 95% CIs provide estimates for feeding effects on all endpoints. Based on prespecified guidelines in the independent Data Monitoring Committee's (DMC) charter, a single interim analysis was conducted when 134 subjects had completed their D21 visit. The interim analysis was planned to occur when the first 100 infants completed at least 21 days of full fortification; however, the analysis was conducted using data from 134 infants owing to unforeseen delays in conducting the analysis (eg, performing statistical programming, data cleaning, and query resolution) while recruitment continued. The type 1 error rate was adjusted to account for the analysis being conducted at ∼70% enrollment rather than the planned 52%. The DMC consisted of independent experts (2 clinicians, 1 biostatistician) who reviewed growth, formula intake, and key biochemical data as well as AEs. The purpose of the interim analysis was to examine unblinded growth velocity results and determine whether the trial could be stopped early for success or futility, or whether the targeted sample size required adjustment (the interim statistical analysis plan was finalized before unblinding, and the analysis was unblinded only to the DMC to facilitate ethical decision-making) (31). On April 2, 2014, the DMC recommended to stop the trial, as noninferiority and superiority in regard to the primary outcome had been demonstrated. The sponsor was notified of this decision on April 3, 2014, and the final study population included infants enrolled through March 31, 2014.RESULTSA total of 274 infants were screened, with 153 enrolled and randomized to either nHMF (n\u200a=\u200a77) or cHMF (n\u200a=\u200a76) (Fig. 2). Demographic and baseline anthropometry data are summarized in Table 2. There was no evidence of imbalance between the 2 groups with respect to infant characteristics. A significantly lower percentage of mothers and fathers of infants in the nHMF group, however, smoked during pregnancy. Number of twins was similar in each group.FIGURE 2Flow of study participants. AE\u200a=\u200aadverse event; cHMF\u200a=\u200acontrol human milk fortifier; D21\u200a=\u200astudy day 21; ITT\u200a=\u200aintent-to-treat; NEC\u200a=\u200anecrotizing enterocolitis; nHMF\u200a=\u200anew human milk fortifier; NICU\u200a=\u200aneonatal intensive care unit; PP\u200a=\u200aper-protocol; SAE\u200a=\u200aserious adverse event. ∗Although screening procedures were standardized across sites, some variability in prescreening procedures did occur. Based on the typical clinical characteristics of infants who were admitted to each NICU during the study interval, the total number of infants who would have been theoretically considered eligible for the study was higher than the number shown here.The majority (84% and 87% by volume in nHMF and cHMF, respectively) of milk provided to infants was pasteurized. Donor milk was always pasteurized and accounted for 49% and 51% of the fortified HM volume provided in the nHMF and cHMF groups, respectively. There was no significant difference in mean volume of fortified milk intake between groups (152.7\u200a±\u200a13.0 and 152.6\u200a±\u200a17.2\u200amL\u200a·\u200akg−1\u200a·\u200aday−1 in nHMF and cHMF, respectively). Protein intake estimated using standard values for preterm HM composition per 100\u200amL (22) was significantly greater in nHMF compared to cHMF (4.48\u200a±\u200a0.38 vs 3.81\u200a±\u200a0.43\u200ag\u200a·\u200akg−1\u200a·\u200aday−1, respectively; P\u200a<\u200a0.001) because of higher protein content of the nHMF. Estimated energy intake was not significantly different between groups (125\u200akcal\u200a·\u200akg−1\u200a·\u200aday−1 in both groups). There was no significant difference in number of days between FSI1 and D1, but adjusted time between birth and D1 was significantly shorter in nHMF (16.8\u200a±\u200a5.4 vs 18.7\u200a±\u200a8.8 days; −8.5% [95% CI: −15.0%, −1.0%]).GrowthIn the ITT population, adjusted weight gain from D1 to D21 was 2.3\u200ag/day higher in nHMF, with the 95% CI ranging from 0.4 to 4.2\u200ag/day, demonstrating noninferiority (P\u200a<\u200a0.001) and superiority (P\u200a=\u200a0.01) of nHMF. Per-protocol results were similar. Weight gain from D1 to D21 remained significantly higher in nHMF when expressed in grams per kilogram per day (Table 3). Weight-for-age z scores (Fig. 3) remained stable from FSI1 to D21 in nHMF, but continued to decrease in cHMF (P\u200a=\u200a0.007 vs D1). At D21, weight-for-age z score was significantly higher in nHMF compared to cHMF (0.12 [95% CI: 0.03, 0.22]). Length and HC gains during the D1 to D21 period were not significantly different between groups (Table 3), with comparable results observed from analyses of unadjusted means (Table 4). Length-for-age z scores at D21 (Fig. 3) were significantly lower than D1 values in cHMF (P\u200a=\u200a0.041). Additionally, at W40CA, adjusted HC-for-age z scores were significantly higher in nHMF compared to cHMF (0.41 [95% CI: 0.14, 0.68]). Mean weight, length, and HC at D1, D21, and W40CA are summarized in Table 5.FIGURE 3Mean\u200a±\u200aSD weight-for-age (panel A), length-for-age (panel B), and head circumference-for-age (panel C) z scores for the overall ITT population. Circle symbols/solid line represents nHMF. Triangle symbols/dashed line represents cHMF. FSI1\u200a=\u200afortification strength increase day 1; ITT\u200a=\u200aintent-to-treat; SD\u200a=\u200astandard deviation; W40CA\u200a=\u200aweek 40 corrected age; z scores calculated using Fenton preterm growth chart (25). ∗P\u200a=\u200a0.013 vs cHMF (by analysis of covariance, adjusting for value at D1, sex, and center); †P\u200a=\u200a0.007 vs day 1 (by t test); ‡P\u200a=\u200a0.041 vs day 1 (by t test); ∗∗P\u200a=\u200a0.003 vs cHMF (by analysis of covariance, adjusting for value at D1, sex, and center).Protein-Energy StatusBUN decreased progressively in cHMF (P\u200a=\u200a0.004 for D21 vs D1), whereas it increased in nHMF (P\u200a<\u200a0.001 for D10/11 vs D1 [data not shown]) and remained stable up to D21 (Table 6). Prealbumin levels were similar at D1 and increased in both groups during the study (Table 6). The increase from D1 to D21, however, was only significant in nHMF (P\u200a=\u200a0.004). At D21, adjusted mean prealbumin in nHMF was significantly higher (+11.8% [95%CI: +2.3%, +22.2%]) than in cHMF. Urinary urea excretion (corrected for creatinine excretion) at D1 was similar in the 2 groups (Table 6). Urea excretion remained steady in cHMF but increased sharply in nHMF (P\u200a<\u200a0.001 for D10/11 vs D1 [data not shown]), after which it remained stable (to D21). At D21, urea excretion was significantly higher in nHMF versus cHMF (+108.7% [95% CI: +66.0%, +162.5%]).Bone Metabolic StatusSerum calcium concentrations were generally stable during the study (Table 6), with mean values for both groups within the normal range (32). Nevertheless, adjusted mean serum calcium concentration in nHMF was minimally but significantly higher than in cHMF at D21 (+1.9% [95% CI: +0.3%, +3.5%]). Serum phosphorus increased slightly in the 2 groups (Table 6). At D1, relative hypophosphatemia (<1.55\u200ammol/L) was observed in 13 infants in both groups; this was corrected in 11 infants by D10/11 and 12 infants by D21. At D1, serum alkaline phosphatase was not significantly different in nHMF versus cHMF (P\u200a=\u200a0.208). Thereafter, serum alkaline phosphatase decreased significantly in both groups (D21 vs D1: P\u200a=\u200a0.005 for nHMF, P\u200a<\u200a0.001 for cHMF), with mean values significantly higher in nHMF versus cHMF at D10/11 (+8.6% [95% CI: +1.0%, +16.8%]; data not shown) and D21 (+12.1% [95% CI: +2.8%, +22.3%]) (Table 6). Declines from baseline were significantly greater in cHMF versus nHMF at D10/11 (P\u200a<\u200a0.001; data not shown) and D21 (P\u200a=\u200a0.035). At D1, spot urinary excretions of calcium and phosphorus corrected for urinary creatinine excretion were similar in the 2 groups (Table 6). Calcium excretion tended to increase slowly during the study in both groups, with mean concentration significantly lower in nHMF compared to cHMF at D21 (P\u200a=\u200a0.011). Phosphorus excretion increased in both groups, resulting in a decreased median urinary calcium:phosphorus molar ratio in both groups (Table 6).ElectrolytesSerum electrolyte concentrations were stable during the study and similar in both groups (Table 6). Urinary sodium and potassium concentrations were significantly higher (sodium: +31.1% [95% CI: +1.7%, +68.9%], potassium: +22.5% [95% CI: +1.0%, +48.6%]) in nHMF compared to cHMF at D21 (Table 7).Stool Characteristics and Feeding ToleranceStool frequency from D1 to D21 was not significantly different in nHMF and cHMF (3.9\u200a±\u200a1.05 vs 3.6\u200a±\u200a0.93\u200astools/day; 0.29 [95% CI: −0.05, 0.63]). Stool consistency was slightly more “formed” in nHMF compared to cHMF during this interval (3.1\u200a±\u200a0.26 vs 3.0\u200a±\u200a0.27; 0.12 [95% CI: 0.02, 0.21]). Most infants (>90%) had stool consistency scores of “soft.” There were no significant differences between groups in frequencies of spitting-up, vomiting, or abdominal distention. There also were no group differences in incidence of AEs indicative of feeding intolerance (all P\u200a≥\u200a0.25).Adverse EventsThe overall incidence of AEs was significantly larger in nHMF (103 events in 56 infants, including 26 events categorized as GI disorders, 18 as infections or infestations, and 5 as metabolism and nutrition disorders) compared to cHMF (78 events in 41 infants, including 21 events categorized as GI disorders, 18 as infections or infestations, and 1 as metabolism and nutrition disorder; odds ratio: 2.26 [95% CI: 1.10, 4.47]). Other AEs that occurred more frequently in nHMF included several that were classified by study investigators as unlikely to be related to consumption of milk fortifiers (eg, cardiac disorders [16 events in nHMF vs 5 in cHMF], eye disorders [10 events in nHMF vs 3 in cHMF]). The number of AEs considered related to study product intake as determined by physician report was low (3 events in nHMF [2 events of hyponatremia, 1 of vomiting] and 0 events in cHMF). No significant difference was demonstrated in overall incidence of serious AEs between the 2 groups (7 events in 7 infants [including 2 events of necrotizing enterocolitis, 0 events of bronchopulmonary dysplasia, 0 events of sepsis, 0 events of retinopathy] in nHMF and 12 events in 11 subjects [including 4 events of necrotizing enterocolitis, 1 event of bronchopulmonary dysplasia, 0 events of sepsis, 0 events of retinopathy] in cHMF; odds ratio: 0.54 [95% CI: 0.17, 1.58]).DISCUSSIONThis study demonstrated that weight gain from D1 of full fortification until D21 in preterm infants fed HM fortified with a new fortifier designed to add 1.4\u200ag partially hydrolyzed protein and 0.7\u200ag fat to 100\u200amL of HM was significantly greater than weight gain in infants fed HM fortified with an isocaloric control fortifier designed to add 1.0\u200ag extensively hydrolyzed protein and no fat. The mean difference was 2.3\u200ag/day or 1.2\u200ag\u200a·\u200akg−1\u200a·\u200aday−1, consistent with our hypothesized difference of 2\u200ag/day, and which indicates the superiority of the new fortifier compared to the control with regard to weight gain. In addition, the weight gain benefit tended to persist until discharge, with a significantly higher adjusted weight gain difference in the nHMF group compared to cHMF from FSI1 to W40CA (2.01\u200ag/day; P\u200a=\u200a0.009). In the nHMF group, weight-for-age z scores were stable from FSI1 to D21 and average weight gain exceeded 18\u200ag\u200a·\u200akg−1\u200a·\u200aday−1, matching recommended rates of postnatal weight gain to mimic intrauterine growth (33,34). Consistent with the increased protein content of the new fortifier, the nHMF group had significantly higher serum prealbumin concentrations, suggesting an increase in nitrogen retention compared to cHMF. The lack of difference, however, in length gain during the study may be in part the result of the relatively limited period of protein supplementation (only 21 days) or because mean length gains in both groups were already quite high (ie, ≥1.1\u200acm/week), whereas the significantly higher HC-for-age z score at W40CA in the nHMF group may be because of the increased protein and lipid content of the new fortifier. In contrast, the absence of a significant difference at earlier timepoints could be attributable to the relatively high variability of HC gain (31% and 27% for nHMF and cHMF, respectively, from D1 to D21) induced by the natural dolichocephalic evolution of the skull that occurs in preterm infants (35). Feeding tolerance and stool patterns were similar in each group, and AEs related to feeding were low and not significantly different between groups, consistent with fortified HM osmolality values slightly lower in nHMF versus cHMF and below the recommended cutoff (23,24) in both groups.Although there was no evidence of imbalance between the 2 fortifier groups with respect to infant baseline characteristics, significant differences in maternal weight gain, smoking, and alcohol usage during pregnancy were observed. As these may be confounding factors in the analysis of weight gain, post hoc ANCOVAs including these parameters were performed. The post hoc results were essentially the same as the main results, indicating that differences in maternal baseline characteristics did not confound the results. Additionally, to determine the possible impact of including clustered data from twins in the analyses, a sensitivity analysis on weight gain (grams per day) from D1 to D21 accounting for the correlated multiple-birth data was performed. Again, these results were similar to those of the main analysis (weight gain 3.2\u200ag/day higher in nHMF [95% CI: 0.5, 5.9\u200ag/day]).Our results are consistent with those of previous studies (36–42). A recent meta-analysis of 5 studies (comprising 352 infants with birthweight ≤1750\u200ag and gestational age ≤34 weeks) compared growth of infants fed HM fortified with either lower-protein or higher-protein fortifier (43). Infants receiving higher-protein fortifier had significantly greater weight (mean difference 1.77\u200ag/kg/day), length (0.21\u200acm/week), and HC gains (0.19\u200acm/week) compared to those receiving lower-protein fortifier (43). Miller et al (39) used a higher-protein fortifier similar in protein content to the one used in the present study, and reported a higher bodyweight at study end among infants in the higher-protein HMF group (mean difference 220\u200ag), but no significant differences in length or HC. In contrast, Moya et al (40) observed a significantly higher achieved weight, length, and HC in the experimental group compared to controls, but their fortifier had a slightly higher protein content (3.2\u200ag/100\u200amL) versus the one used in the present study (3.04\u200ag/100\u200amL), plus the intervention lasted 28 rather than 21 days.Energy and protein content of HM samples were not analyzed in this study but estimated according to Tsang et al (22). Variability of protein, fat, and energy content of HM fed to preterm infants in the NICU is high (15,21). In addition, fat content may be reduced during processing of HM from expression to administration (44), which could be exacerbated with the use of continuous tube feeding (45). In our study, percentage of intake from mother's own milk, donor milk, and pasteurized HM was assessed. Pasteurized donor milk accounted for 51% of the fortified HM provided during the study, whereas 56% of mother's own milk was also pasteurized. Considering that protein content of donor HM is lower than that of mother's own milk (46) and that all the required processing steps (eg, collection, transfer, refrigeration, pasteurization, tube feeding) may significantly decrease fat and energy content (47), the characteristics of the HM used in the present study suggests that protein and energy content could be overestimated when based on a theoretical composition of preterm HM.In the present study, the mean increase in protein supplementation provided by nHMF compared to cHMF was 0.65\u200ag\u200a·\u200akg−1\u200a·\u200aday−1 or 7.4\u200ammol\u200a·\u200akg−1\u200a·\u200aday−1 of nitrogen, from which approximately 6.14\u200ammol\u200a·\u200akg−1\u200a·\u200aday−1 of nitrogen (83%) is absorbed (based on data from balance studies) (48). During the study, urea production increased significantly in the nHMF group leading to an increase in BUN of 1.7\u200ammol/L at D21 and in urea excretion of 2.3\u200ammol\u200a·\u200akg−1\u200a·\u200aday−1 (2.3\u200ammol/10\u200amg creatinine). These data suggest that the nitrogen balance was improved to ∼3.8\u200ammol nitrogen (52% of nitrogen intake) in preterm infants fed nHMF compared to control. This relatively limited protein utilization could result from reduced energy bioavailability of HM, and an increase in energy supply could improve protein utilization in preterm infants fed fortified HM. These data also suggest that specific nutritional recommendations should be formulated for infants fed fortified HM. Nevertheless, the increase in nitrogen retention (∼3.8\u200ammol\u200a·\u200akg−1\u200a·\u200aday−1) appears to be higher than the nitrogen content of the higher weight gain observed with the nHMF (12% of the 1.5\u200ag\u200a·\u200akg−1\u200a·\u200aday−1 corresponding to 2\u200ammol\u200a·\u200akg−1\u200a·\u200aday−1 of nitrogen), suggesting an increase in lean body mass accretion and a moderate reduction in fat mass gain as previously demonstrated in preterm infants fed protein-fortified HM (49).Indices of bone metabolism were satisfactory in both groups, with a significant decrease in serum alkaline phosphatase observed in both groups and 98% of the infants having normal serum phosphorus concentrations at D21. Adequate postnatal bone mineralization is difficult to obtain in preterm infants owing to the interruption of mineral transplacental transfer (50). Although elevated alkaline phosphatase activity may be associated with reduced bone mineralization when mineral intake is deficient (51), the decrease in enzyme levels observed in the presence of normal serum phosphorus values, as well as the low urinary calcium and moderate urinary phosphorus excretion observed in both groups in this study, suggest that intakes were adequate to promote bone mineralization and limit postnatal osteopenia. Mean serum creatinine concentration decreased significantly in both groups suggesting a similar maturation of renal function during this period. Urinary electrolyte concentrations were higher in nHMF versus cHMF at D21, likely in parallel with the higher electrolyte content of nHMF.A lack of HM composition data (allowing estimation of nutritional balance) is a limitation of our study, although standardized accurate techniques are still not available in the NICU. Additionally, the composition of the faster weight gain can only be estimated as lean body mass and/or bone mineralization were not determined. As a result, nutrient absorption and metabolism can only be estimated from serum and urinary metabolite concentrations. Lastly, the results need to be confirmed in a broader population of preterm infants commonly admitted to the NICU including SGA infants and partially breast-fed infants, as these infants were excluded by design. Strengths of this study include the size and multiple sites (11 pediatric hospitals in 4 European countries), which enhances external validity.In conclusion, these results indicate that the new HM fortifier, made with partially hydrolyzed whey protein and a higher protein:energy ratio is safe, well-tolerated, and improves weight gain of preterm infants compared to control fortifier. Providing some energy as fat and replacing extensively hydrolyzed with partially hydrolyzed protein in the new HM fortifier allows a reduction in osmolality <400\u200amOsm/kg immediately after fortification. Protein intakes from HM supplemented with the new fortifier are within the range of the most recent nutritional recommendations for preterm infants.AcknowledgmentsThe authors thank the families of the infants who participated in the study, as well as the research staff at each participating institution. The authors also thank Christelle Perdrieu and Samir Dahbane from the Clinical Development Unit at the Nestlé Research Center for assistance with trial management and Philippe Steenhout, Medical Director at Nestlé Nutrition, for input on study design and assistance with trial supervision.This study was sponsored by Nestlé Nutrition. J.J., L.A., and N.P.H. are employees of Nestlé SA. J.R., J.M.H., C.B., J.C.P., F.M., A.R., E.S., M.R., U.S., B.G., and J.S. received research funding from Nestlé Nutrition. J.R., J.C.P., and C.B. are consultants for Nestlé Nutrition. U.S. has been a speaker, consultant, and expert panel participant for Nestlé, Danone, and Bledina over the past 3 years. V.d.H. has no conflicts of interest to declare.www.clinicaltrials.gov NCT01771588This study was sponsored by Nestlé Nutrition.Portions of these data were presented in abstract form at the 1st Congress of joint European Neonatal Societies, Budapest, Hungary, 15–20 September 2015.REFERENCES1.GarciaCDuanRDBrevaut-MalatyV\nBioactive compounds in human milk and intestinal health and maturity in preterm newborn: an overview. Cell Mol Biol (Noisy-le-grand)\n2013; 59:108–131.253266482.CorpeleijnWEKouwenhovenSMPaapMC\nIntake of own mother's milk during the first days of life is associated with decreased morbidity and mortality in very low birth weight infants during the first 60 days of life. Neonatology\n2012; 102:276–281.229226753.PatelALJohnsonTJEngstromJL\nImpact of early human milk on sepsis and health-care costs in very low birth weight infants. J Perinatol\n2013; 33:514–519.233706064.ManzoniPStolfiIPedicinoR\nHuman milk feeding prevents retinopathy of prematurity (ROP) in preterm VLBW neonates. Early Hum Dev\n2013; 89\nsuppl 1:S64–S68.238093555.KooWTankSMartinS\nHuman milk and neurodevelopment in children with very low birth weight: a systematic review. Nutr J\n2014; 13:94.252313646.CarlsonSWojcikBBarkerA\nGuidelines for the use of human milk fortifier in the neonatal intensive care unit. University of Iowa Neonatology Handbook. 2011. Available at: http://www.uichildrens.org/iowa-neonatology-handbook/feeding/human-milk\nAccessed on January 22, 2017.7.AdamkinDHRadmacherPG\nFortification of human milk in very low birth weight infants (VLBW <1500\u200ag birth weight). Clin Perinatol\n2014; 41:405–421.248738408.MoroGEArslanogluSBertinoE\nXII. Human milk in feeding premature infants: consensus statement. J Pediatr Gastroenterol Nutr\n2015; 61\nsuppl 1:S16–S19.262959999.EinloftPRGarciaPCPivaJP\nSupplemented vs. unsupplemented human milk on bone mineralization in very low birth weight preterm infants: a randomized clinical trial. Osteoporos Int\n2015; 26:2265–2271.2597168610.GibertoniDCorvagliaLVandiniS\nPositive effect of human milk feeding during NICU hospitalization on 24 month neurodevelopment of very low birth weight infants: an Italian cohort study. PLoS ONE\n2015; 10:e0116552.2559063011.BrownJVEmbletonNDHardingJE\nMulti-nutrient fortification of human milk for preterm infants. Cochrane Database Syst Rev\n2016; 5:CD000343.12.SchanlerRJShulmanRJLauC\nFeeding strategies for premature infants: beneficial outcomes of feeding fortified human milk versus preterm formula. Pediatrics\n1999; 103\n(6 pt 1):1150–1157.1035392213.O’ConnorDLJacobsJHallR\nGrowth and development of premature infants fed predominantly human milk, predominantly premature infant formula, or a combination of human milk and premature formula. J Pediatr Gastroenterol Nutr\n2003; 37:437–446.1450821414.WeberALouiAJochumF\nBreast milk from mothers of very low birthweight infants: variability in fat and protein content. Acta Paediatr\n2001; 90:772–775.1151998015.CorvagliaLAcetiAPaolettiV\nStandard fortification of preterm human milk fails to meet recommended protein intake: bedside evaluation by near-infrared-reflectance-analysis. Early Hum Dev\n2010; 86:237–240.2044777916.ArslanogluSMoroGEZieglerEE\nPreterm infants fed fortified human milk receive less protein than they need. J Perinatol\n2009; 29:489–492.1944423717.ArslanogluSCorpeleijnWMoroG\nDonor human milk for preterm infants: current evidence and research directions. J Pediatr Gastroenterol Nutr\n2013; 57:535–542.2408437318.AgostoniCBuonocoreGCarnielliVP\nEnteral nutrient supply for preterm infants: commentary from the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr\n2010; 50:85–91.1988139019.KoletzkoBPoindexterBUauyR\nRecommended nutrient intake levels for stable, fully enterally fed very low birth weight infants. World Rev Nutr Diet\n2014; 110:297–299.2475163820.GidrewiczDAFentonTR\nA systematic review and meta-analysis of the nutrient content of preterm and term breast milk. BMC Pediatr\n2014; 14:216.2517443521.de HalleuxVRigoJ\nVariability in human milk composition: benefit of individualized fortification in very-low-birth-weight infants. Am J Clin Nutr\n2013; 98\nsuppl:529S–535S.2382472522.TsangRCUauyRKoletzkoB\nNutrition of the Preterm Infant, Scientific Basis and Practical Guidelines. Cincinnati: Digital Educational Publishing, Inc; 2005.23.KreisslAZwiauerVRepaA\nEffect of fortifiers and additional protein on the osmolarity of human milk: is it still safe for the premature infant?\nJ Pediatr Gastroenterol Nutr\n2013; 57:432–437.2385734024.BilleaudCSenterreJRigoJ\nOsmolality of the gastric and duodenal contents in low birth weight infants fed human milk or various formulae. Acta Paediatr Scand\n1982; 71:799–803.718044925.FentonTRKimJH\nA systematic review and meta-analysis to revise the Fenton growth chart for preterm infants. BMC Pediatr\n2013; 13:59.2360119026.NewmanDJPugiaMJLottJA\nUrinary protein and albumin excretion corrected by creatinine and specific gravity. Clin Chim Acta\n2000; 294:139–155.1072768027.Al-DahhanJStimmlerLChantlerC\nUrinary creatinine excretion in the newborn. Arch Dis Child\n1988; 63:398–402.336500928.ICH Expert Working Group. Guideline for good clinical practice E6(R1). 1996\nAvailable at: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guideline.pdf\nAccessed on January 22, 2017.29.SpalingerJHSchmidtMBergerTM\nComparison of two human milk fortifiers: effects on growth and zinc status in premature infants. J Pediatr Gastroenterol Nutr\n2004; 39\nsuppl 1:1126.30.WangSKTsiatisAA\nApproximately optimal one-parameter boundaries for group sequential trials. Biometrics\n1987; 43:193–199.356730431.KnottnerusJASpigtMG\nWhen should an interim analysis be unblinded to the data monitoring committee?\nJ Clin Epidemiol\n2010; 63:350–352.1976221032.NicholsonJFPesceMA\nNelsonWEBehrmanREKliegmanRArvinAM\nLaboratory Testing and Reference Values (Table 670-2) in Infants and Children. Nelson Textbook of Pediatrics. Philadelphia: W.B. Saunders; 1996\n2031–2084.33.FentonTRNasserREliasziwM\nValidating the weight gain of preterm infants between the reference growth curve of the fetus and the term infant. BMC Pediatr\n2013; 13:92.2375880834.EhrenkranzRADusickAMVohrBR\nGrowth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants. Pediatrics\n2006; 117:1253–1261.1658532235.McCartyDBPeatJRMalcolmWF\nDolichocephaly in preterm infants: prevalence, risk factors, and early motor outcomes. Am J Perinatol\n2016; 34:372–378.2758893336.PorcelliPSchanlerRGreerF\nGrowth in human milk-fed very low birth weight infants receiving a new human milk fortifier. Ann Nutr Metab\n2000; 44:2–10.1083846037.ReisBBHallRTSchanlerRJ\nEnhanced growth of preterm infants fed a new powdered human milk fortifier: a randomized, controlled trial. Pediatrics\n2000; 106:581–588.1096910638.BersethCLVan AerdeJEGrossS\nGrowth, efficacy, and safety of feeding an iron-fortified human milk fortifier. Pediatrics\n2004; 114:e699–e706.1554561639.MillerJMakridesMGibsonRA\nEffect of increasing protein content of human milk fortifier on growth in preterm infants born at <31 wk gestation: a randomized controlled trial. Am J Clin Nutr\n2012; 95:648–655.2230193340.MoyaFSiskPMWalshKR\nA new liquid human milk fortifier and linear growth in preterm infants. Pediatrics\n2012; 130:e928–e935.2298787741.AlanSAtasayBCakirU\nAn intention to achieve better postnatal in-hospital-growth for preterm infants: adjustable protein fortification of human milk. Early Hum Dev\n2013; 89:1017–1023.2403503942.ThoeneMHansonCLydenE\nComparison of the effect of two human milk fortifiers on clinical outcomes in premature infants. Nutrients\n2014; 6:261–275.2439453843.LiuTTDangDLvXM\nHuman milk fortifier with high versus standard protein content for promoting growth of preterm infants: A meta-analysis. J Int Med Res\n2015; 43:279–289.2595615644.VieiraAASoaresFVPimentaHP\nAnalysis of the influence of pasteurization, freezing/thawing, and offer processes on human milk's macronutrient concentrations. Early Hum Dev\n2011; 87:577–580.2159268845.IgawaMMuraseMMizunoK\nIs fat content of human milk decreased by infusion?\nPediatr Int\n2014; 56:230–233.2484751446.WojcikKYRechtmanDJLeeML\nMacronutrient analysis of a nationwide sample of donor breast milk. J Am Diet Assoc\n2009; 109:137–140.1910333547.de HalleuxVPeiltainCSanterreT\nUse of donor milk in the neonatal intensive care unit. Semin Fetal Neonatal Med\n2017; 22:23–29.2764999548.PicaudJCPutetGRigoJ\nMetabolic and energy balance in small- and appropriate-for-gestational-age, very low-birth-weight infants. Acta Paediatr Suppl\n1994; 405:54–59.773479249.PutetGRigoJSalleB\nSupplementation of pooled human milk with casein hydrolysate: energy and nitrogen balance and weight gain composition in very low birth weight infants. Pediatr Res\n1987; 21:458–461.358808250.PieltainCde HalleuxVSenterreT\nPrematurity and bone health. World Rev Nutr Diet\n2013; 106:181–188.2342869951.RuskC\nRickets screening in the preterm infant. Neonatal Netw\n1998; 17:55–57.TABLE 1Calculated∗ nutrient composition of fortified preterm human milkPreterm HM\u2009+\u2009nHMFPreterm HM\u2009+\u2009cHMF4\u2009g fortifier alone4\u2009g fortifier per 100\u2009kcal milk4\u2009g fortifier per 100\u2009mL milk5\u2009g fortifier alone5\u2009g fortifier per 100\u2009kcal milk5\u2009g fortifier per 100\u2009mL milkRecommended intake range (per 100\u2009kcal)†NutrientEnergy, kcal17.410084.617.410084.5Protein, g1.423.63.041.03.102.623.2–4.1Protein sourcePartially hydrolyzed wheyExtensively hydrolyzed wheyFat, g0.725.004.230.024.163.524.4–6MCT, g0.500.590.50000DHA, mg6.319.316.3011.810.0(16.4–) 50–55Carbohydrate, g1.3010.178.603.3012.5310.6010.5–12Carbohydrate sourceMaltodextrinLactose and maltodextrinCalcium, mg7611910175118100109–182Phosphorus, mg44695845705955–127Magnesium, mg4.08.67.32.46.75.77.3–13.6Sodium, mg36.776.564.720.056.848.063–105Potassium, mg48.4116.498.442.0108.892.071–177Chloride, mg32.1106.690.117.088.775.095–161Iron, mg1.802.231.891.301.641.391.8–2.7Zinc, mg0.941.551.310.801.381.171.3–2.3Manganese, μg8.089.988.445.006.345.360.9–13.6Copper, mg0.050.110.090.040.090.080.09–0.21Iodine, μg16.936.630.915.034.329.09–50Selenium, μg3.77.26.11.54.63.94.5–9Vitamin A, IU1183175414835009468001217–3333Vitamin D, IU150187158100128108100–350Vitamin E, IU4.45.64.72.23.02.52.2–11.1Vitamin K, μg8.09.88.34.05.14.34–25Thiamin, mg0.150.190.160.050.070.060.13–0.27Riboflavin, mg0.200.270.230.100.150.130.18–0.36Vitamin B6, mg0.130.160.140.050.070.060.05–0.27Vitamin B12, μg0.200.260.220.100.140.120.09–0.73Niacin, mg1.502.021.710.801.191.010.9–5Folic acid, μg40.051.043.140.051.043.132–91Pantothenic acid, mg0.701.100.930.400.740.630.45–1.9Biotin, μg3.504.784.043.004.193.541.5–15Vitamin C, mg20.028.924.410.017.014.418–50Osmolality‡, mOsm/kg390441cHMF\u2009=\u2009control human milk fortifier; DHA\u2009=\u2009docosahexaenoic acid; HM\u2009=\u2009human milk; nHMF\u2009=\u2009new human milk fortifier; MCT\u2009=\u2009medium chain triglycerides.*Calculated based on preterm human milk composition from Tsang et al, 2005 (22).†Recommended nutrient intakes for fully enterally fed preterm very low birth weight infants (19).‡Measured immediately after fortification at room temperature (25°C).TABLE 2Demographic and baseline characteristics of infants and parentsnHMF (n\u2009=\u200976)cHMF (n\u2009=\u200974)Infant characteristicsSex\u2003Boys38 (50)35 (47)Delivery type\u2003Vaginal24 (32)20 (27)Twin18 (24)16 (22)Birth weight, g1147\u2009±\u20092581156\u2009±\u2009289Birth weight by birth weight category\u2003<1000\u2009g\u2003\u2003n (%)24 (32)26 (35)\u2003\u2003Birth weight, g850.5\u2009±\u2009118.9847.3\u2009±\u2009105.1\u2003≥1000\u2009g\u2003\u2003Birth weight, g1283.6\u2009±\u2009175.41323.9\u2009±\u2009206.2Birth length, cm37.1\u2009±\u20092.737.1\u2009±\u20093.1Birth head circumference, cm26.5\u2009±\u20092.726.7\u2009±\u20092.5Gestational age at birth, weeks28.8\u2009±\u20092.128.7\u2009±\u20091.8Postnatal age at study time points, days*\u2003FSI113 (11, 18)14 (10, 20)\u2003Day 116 (13, 20)17 (13, 23)\u2003Day 2136 (33, 40)37 (33, 43)\u2003Week 40 corrected age76 (66, 91)76 (67, 83)Apgar score\u20031 min5.8\u2009±\u20092.55.8\u2009±\u20092.3\u20035 min8.0\u2009±\u20091.87.7\u2009±\u20091.9Parent characteristicsSmoking status\u2003Mother smoker during pregnancy6 (9)18 (29)\u2003Father smoker3 (5)12 (21)\u2003Mother drank alcohol during pregnancy0 (0)4 (6)Mother's age, y31.1\u2009±\u20095.130.8\u2009±\u20095.5Mother's BMI before pregnancy, kg/m2*23.2 (20.6, 27.2)21.3 (19.7, 26.1)Mother's weight gain during pregnancy, kg11.2\u2009±\u20096.89.2\u2009±\u20095.2BMI\u2009=\u2009body mass index; cHMF\u2009=\u2009control human milk fortifier; FSI1\u2009=\u2009fortification strength increase day 1; nHMF\u2009=\u2009new human milk fortifier . Data are presented as n (%) for categorical variables and mean\u2009±\u2009SD for continuous variables except where noted.*Data are presented as median (Q1, Q3).TABLE 3Anthropometric gains from D1 to D21Treatment groupnnHMFncHMFP*Weight gain, g\u2009·\u2009kg−1\u2009·\u2009day−16418.3\u2009±\u20093.76716.8\u2009±\u20093.70.013†Length gain, cm/wk551.23\u2009±\u20090.62651.18\u2009±\u20090.490.842HC gain, cm/wk571.04\u2009±\u20090.32650.96\u2009±\u20090.260.125cHMF\u2009=\u2009control human milk fortifier; D1\u2009=\u2009study day 1 (first day of full-strength fortification); D21\u2009=\u2009study day 21; HC\u2009=\u2009head circumference; nHMF\u2009=\u2009new human milk fortifier. Data are presented as unadjusted mean\u2009±\u2009SD.*One-sided superiority P value based on analysis of covariance model adjusted for postmenstrual age and relevant anthropometric measure at D1, sex, and center.†Adjusted difference in weight gain (nHMF–cHMF): mean difference\u2009=\u20091.18\u2009g\u2009·\u2009kg−1\u2009·\u2009day−1; 95% CI\u2009=\u20090.14, 2.21.TABLE 4Body length and head circumference gains between study days 1 and 21, by infant sex and by birth weight categoryUnadjusted length gain, cm/wk*Unadjusted head circumference gain, cm/wk*nHMFcHMFnHMFcHMFnMean\u2009±\u2009SDnMean\u2009±\u2009SDP†nMean\u2009±\u2009SDnMean\u2009±\u2009SDP†Overall551.23\u2009±\u20090.62651.18\u2009±\u20090.490.842571.04\u2009±\u20090.32650.96\u2009±\u20090.260.126Boys271.40\u2009±\u20090.65281.18\u2009±\u20090.490.364281.12\u2009±\u20090.28280.99\u2009±\u20090.220.062Girls281.08\u2009±\u20090.56371.17\u2009±\u20090.500.510290.97\u2009±\u20090.35370.93\u2009±\u20090.290.598<1000\u2009g191.07\u2009±\u20090.52211.27\u2009±\u20090.520.563191.04\u2009±\u20090.34210.94\u2009±\u20090.280.223≥1000\u2009g361.32\u2009±\u20090.66441.13\u2009±\u20090.480.499381.05\u2009±\u20090.32440.96\u2009±\u20090.260.270cHMF\u2009=\u2009control human milk fortifier; nHMF\u2009=\u2009new human milk fortifier.*Data are presented as unadjusted mean\u2009±\u2009SD.†Superiority P value for gain differences adjusted for postmenstrual age and the relevant anthropometric measure at D1, sex, and center by analysis of covariance.TABLE 5Weight, length, and head circumference at selected study time pointsnHMFcHMFVariablenMeanSDnMeanSDWeight, g\u2003D1721346271741347270\u2003D21641884336671863328\u2003W40CA603076519632897416Length, cm\u2003D16738.72.57438.72.8\u2003D215841.82.46542.02.7\u2003W40CA6047.62.66247.32.5Head circumference, cm\u2003D16827.72.57327.61.9\u2003D215930.22.26630.32.0\u2003W40CA5935.31.46434.61.5cHMF\u2009=\u2009control human milk fortifier; D1\u2009=\u2009study day 1; D21\u2009=\u2009study day 21; nHMF\u2009=\u2009new human milk fortifier; SD\u2009=\u2009standard deviation; W40CA\u2009=\u2009week 40 corrected age.TABLE 6Markers of protein-energy status, electrolytes, and bone metabolic status at study days 1 and 21nHMFcHMFVariablenMedianIQRGeometric meannMedianIQRGeometric meanP*Serum creatinine, μmol/L\u2003D16944.036.2–48.041.57044.138.0–51.843.50.303\u2003D216328.023.5–32.026.76530.025.0–35.029.50.001BUN, mmol/L\u2003D1703.101.70–4.562.89712.501.65–4.672.730.585\u2003D21633.903.05–4.653.89642.151.50–2.632.15<0.001Serum prealbumin, mg/L\u2003D15110080–12096.8469080–10087.80.073\u2003D214611691.3–140113.84110090–12098.10.015Urinary urea†, mmol/10\u2009mg creatinine\u2003D1472.72.0–4.72.8532.51.9–3.32.50.302\u2003D21425.84.6–6.85.1402.82.0–3.32.7<0.001Serum calcium, mmol/L\u2003D1502.442.31–2.532.41542.472.38–2.562.440.445\u2003D21502.472.40–2.542.46482.432.34–2.532.430.019Serum phosphorus, mmol/L\u2003D1681.991.85–2.221.96711.941.76–2.251.940.816\u2003D21622.101.93–2.232.05642.121.93–2.262.080.681Alkaline phosphatase, U/L\u2003D167353.0298.5–459.5377.963333.0250.0–438.5343.80.208\u2003D2162320.5273.3–405.5337.562270.5233.0–354.3297.50.010Urinary calcium †, mmol/10\u2009mg creatinine\u2003D1600.110.07–0.190.12690.140.09–0.200.120.985\u2003D21550.140.09–0.230.15540.210.13–0.320.190.011Urinary phosphorus†, mmol/10\u2009mg creatinine\u2003D1590.410.12–0.660.22650.340.14–0.650.230.867\u2003D21520.680.44–1.100.53520.710.40–0.920.580.896Urinary calcium:phosphorus molar ratio\u2003D1590.390.15–0.900.50640.410.16–1.340.470.824\u2003D21530.220.12–0.480.28530.310.19–0.600.340.054Serum sodium, mmol/L\u2003D171138.0137.0–140.0138.672138.6136.6–140.0138.50.891\u2003D2165138.0136.4–140.0138.064138.0137.0–139.9138.30.449Serum potassium, mmol/L\u2003D1714.734.30–5.324.83724.774.40–5.104.780.685\u2003D21644.744.29–5.104.72644.514.14–4.884.540.091Serum chloride, mmol/L\u2003D171106.0104.0–109.0106.172105.0102.8–108.0105.20.148\u2003D2163105.0103.0–107.0104.662105.0104.0–107.0105.30.111BUN\u2009=\u2009blood urea nitrogen; cHMF\u2009=\u2009control human milk fortifier; D1\u2009=\u2009study day 1; D21\u2009=\u2009study day 21; IQR\u2009=\u2009interquartile range; nHMF\u2009=\u2009new human milk fortifier.*D1 geometric mean values were log-transformed and analyzed using t test; D21 geometric mean values were log-transformed and analyzed using analysis of covariance (adjusting for the relevant biochemical parameter at D1, sex, and center).†Corrected for urinary creatinine excretion of 10\u2009mg/kg body weight/day.TABLE 7Markers of kidney function, blood count, and urinary electrolyte status at study days 1 and 21nHMFcHMFVariablenMedianIQRGeometric meannMedianIQRGeometric meanP*Urinary creatinine, μmol/L\u2003D1631300.0785.5–1685.51224.7691105.0900.0–1500.01182.3\u2003D21571030.0660.0–1609.01000.355854.0618.0–1273.0900.80.447Serum hemoglobin, mmol/L\u2003D1682.081.84–2.292.14722.021.84–2.262.18\u2003D21631.711.56–1.911.83661.691.50–1.981.760.936Serum hematocrit, %\u2003D1680.400.35–0.430.39720.390.35–0.430.38\u2003D21630.320.29–0.380.33660.330.28–0.380.330.805Urinary sodium, mmol/L\u2003D16637.023.3–57.337.56932.019.4–54.031.2\u2003D215934.021.1–48.033.35623.014.3–36.424.00.037Urinary potassium, mmol/L\u2003D16625.913.6–37.023.66921.815.0–32.220.0\u2003D215930.016.9–45.027.65722.916.9–30.422.80.040Urinary chloride, mmol/L\u2003D16037.026.3–60.040.26733.020.5–55.034.2\u2003D215431.017.8–43.830.75526.018.0–39.527.80.558cHMF\u2009=\u2009control human milk fortifier; D1\u2009=\u2009study day 1; D21\u2009=\u2009study day 21; IQR\u2009=\u2009interquartile range; nHMF\u2009=\u2009new human milk fortifier .*D21 geometric mean values were log-transformed and analyzed using analysis of covariance (adjusting for the relevant biochemical measure at D1, sex, and center).", 'title': 'Growth and Nutritional Biomarkers of Preterm Infants Fed a New Powdered Human Milk Fortifier: A Randomized Trial.', 'date': '2017-07-21'}}
| 0
|
Pediatrics & Neonatology
|
19
|
Is mortality higher, lower, or the same when comparing rapid ART to standard initiation?
|
lower
|
very low
|
yes
|
['28742880', '27658873', '29509839', '27163694', '29136001', '29112963', '28542080']
| 31,206,168
| 2,019
|
{'28742880': {'article_id': '28742880', 'content': 'PLoS MedPLoS MedplosplosmedPLoS Medicine1549-12771549-1676Public Library of ScienceSan Francisco, CA USA28742880552652610.1371/journal.pmed.1002357PMEDICINE-D-17-00266Research ArticleBiology and Life SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesPublic and Occupational HealthPreventive MedicineVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesImmunodeficiency VirusesHIVBiology and life sciencesOrganismsVirusesRNA virusesRetrovirusesLentivirusHIVBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVBiology and Life SciencesOrganismsVirusesViral PathogensRetrovirusesLentivirusHIVMedicine and health sciencesDiagnostic medicineHIV diagnosis and managementBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVHIV-1Medicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVHIV-1Biology and Life SciencesOrganismsVirusesViral PathogensImmunodeficiency VirusesHIVHIV-1Biology and Life SciencesOrganismsVirusesImmunodeficiency VirusesHIVHIV-1Biology and life sciencesOrganismsVirusesRNA virusesRetrovirusesLentivirusHIVHIV-1Biology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVHIV-1Medicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVHIV-1Biology and Life SciencesOrganismsVirusesViral PathogensRetrovirusesLentivirusHIVHIV-1Medicine and Health SciencesHealth CareHealth Care ProvidersMedical DoctorsPhysiciansPeople and PlacesPopulation GroupingsProfessionsMedical DoctorsPhysiciansPeople and placesGeographical locationsNorth AmericaCaribbeanHaitiBiology and Life SciencesMicrobiologyVirologyViral Transmission and InfectionViral LoadMedicine and health sciencesDiagnostic medicineHIV clinical manifestationsSame-day HIV testing with initiation of antiretroviral therapy versus standard care for persons living with HIV: A randomized unblinded trialSame-day HIV testing and antiretroviral therapy initiationhttp://orcid.org/0000-0001-7464-275XKoenigSerena P.ConceptualizationFunding acquisitionInvestigationMethodologySupervisionWriting – original draftWriting – review & editing12*DorvilNancyInvestigationMethodologyProject administrationSupervisionWriting – review & editing1DévieuxJessy G.ConceptualizationFunding acquisitionInvestigationMethodologySupervisionWriting – original draftWriting – review & editing3http://orcid.org/0000-0002-9689-5413Hedt-GauthierBethany L.ConceptualizationFormal analysisFunding acquisitionMethodologySoftwareSupervisionValidationVisualizationWriting – review & editing4RiviereCynthiaInvestigationMethodologyProject administrationSupervisionWriting – review & editing1FaustinMikerlyneInvestigationMethodologyProject administrationSupervisionWriting – review & editing1LavoileKerlyneInvestigationMethodologyProject administrationSupervisionWriting – review & editing1PerodinChristianFormal analysisInvestigationMethodologySoftwareValidationVisualizationWriting – review & editing1ApollonAlexandraConceptualizationInvestigationMethodologyProject administrationSupervisionWriting – review & editing1DuvergerLimatheInvestigationMethodologyProject administrationSupervisionWriting – review & editing1McNairyMargaret L.MethodologyWriting – review & editing56HennesseyKelly A.Formal analysisMethodologySoftwareValidationVisualizationWriting – review & editing1SouroutzidisAriadneFormal analysisMethodologySoftwareValidationVisualizationWriting – review & editing7CremieuxPierre-YvesFormal analysisMethodologySoftwareValidationVisualizationWriting – review & editing7SeverePatriceConceptualizationFunding acquisitionInvestigationMethodologyProject administrationSupervisionWriting – review & editing1PapeJean W.ConceptualizationFunding acquisitionInvestigationMethodologyProject administrationSupervisionWriting – review & editing151\nHaitian Study Group for Kaposi’s Sarcoma and Opportunistic Infections (GHESKIO), Port-au-Prince, Haiti2\nDivision of Global Health Equity, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America3\nAIDS Prevention Program, Florida International University, Miami, Florida, United States of America4\nDepartment of Global Health and Social Medicine, Harvard Medical School, Harvard University, Boston, Massachusetts, United States of America5\nCenter for Global Health, Department of Medicine, Weill Cornell Medical College, Cornell University, New York, New York, United States of America6\nDivision of General Internal Medicine, Department of Medicine, Weill Cornell Medical College, Cornell University, New York, New York, United States of America7\nAnalysis Group, Boston, Massachusetts, United States of AmericaGengElvin H.Academic EditorUniversity of California, San Francisco, UNITED STATESThe authors have declared that no competing interests exist.* E-mail: skoenig@bwh.harvard.edu257201772017147e100235724120171662017© 2017 Koenig et al2017Koenig et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThe science of rapid start—From the when to the how of antiretroviral initiation\nBackgroundAttrition during the period from HIV testing to antiretroviral therapy (ART) initiation is high worldwide. We assessed whether same-day HIV testing and ART initiation improves retention and virologic suppression.Methods and findingsWe conducted an unblinded, randomized trial of standard ART initiation versus same-day HIV testing and ART initiation among eligible adults ≥18 years old with World Health Organization Stage 1 or 2 disease and CD4 count ≤500 cells/mm3. The study was conducted among outpatients at the Haitian Group for the Study of Kaposi’s Sarcoma and Opportunistic infections (GHESKIO) Clinic in Port-au-Prince, Haiti. Participants were randomly assigned (1:1) to standard ART initiation or same-day HIV testing and ART initiation. The standard group initiated ART 3 weeks after HIV testing, and the same-day group initiated ART on the day of testing. The primary study endpoint was retention in care 12 months after HIV testing with HIV-1 RNA <50 copies/ml. We assessed the impact of treatment arm with a modified intention-to-treat analysis, using multivariable logistic regression controlling for potential confounders. Between August 2013 and October 2015, 762 participants were enrolled; 59 participants transferred to other clinics during the study period, and were excluded as per protocol, leaving 356 in the standard and 347 in the same-day ART groups. In the standard ART group, 156 (44%) participants were retained in care with 12-month HIV-1 RNA <50 copies, and 184 (52%) had <1,000 copies/ml; 20 participants (6%) died. In the same-day ART group, 184 (53%) participants were retained with HIV-1 RNA <50 copies/ml, and 212 (61%) had <1,000 copies/ml; 10 (3%) participants died. The unadjusted risk ratio (RR) of being retained at 12 months with HIV-1 RNA <50 copies/ml was 1.21 (95% CI: 1.04, 1.38; p = 0.015) for the same-day ART group compared to the standard ART group, and the unadjusted RR for being retained with HIV-1 RNA <1,000 copies was 1.18 (95% CI: 1.04, 1.31; p = 0.012). The main limitation of this study is that it was conducted at a single urban clinic, and the generalizability to other settings is uncertain.ConclusionsSame-day HIV testing and ART initiation is feasible and beneficial in this setting, as it improves retention in care with virologic suppression among patients with early clinical HIV disease.Trial registrationThis study is registered with ClinicalTrials.gov number NCT01900080In a randomized unblinded trial in Port-au-Prince, Haiti, Serena Koenig and colleagues investigate whether initiating ART on the day of HIV diagnosis improved retention in care and viral suppression.Author summaryWhy was this study done?Multiple visits for counseling, laboratory testing, and other procedures to prepare patients for initiation of antiretroviral therapy (ART) are burdensome and contribute to the high rate of attrition during the period from HIV testing to ART initiation.The World Health Organization (WHO) recently changed their guidelines to recommend ART for all persons living with HIV, facilitating ART initiation.This study was conducted to determine if ART initiation on the day of HIV diagnosis could improve treatment initiation rates, retention in care, and HIV viral suppression for patients with asymptomatic or minimally symptomatic HIV disease.What did the researchers do and find?We randomly assigned patients who presented for HIV testing at a clinic in Port-au-Prince, Haiti to standard ART initiation or same-day HIV testing and ART initiation (356 in the standard and 347 in the same-day groups).The standard group had 3 weekly visits with a social worker and physician and then started ART 21 days after the date of HIV diagnosis; the same-day ART group initiated ART on the day of HIV diagnosis.All participants in the same-day ART group and 92% of participants in the standard group initiated ART.At 12 months after HIV testing, a higher proportion of participants in the same-day ART group were retained in care (80% versus 72%), and a higher proportion were retained in care with viral load <50 copies/ml (53% versus 44%) and viral load <1,000 copies/ml (61% versus 52%).What do these findings mean?This study demonstrates that it is feasible to initiate ART on the day of HIV diagnosis for patients with early HIV clinical disease and that same-day treatment leads to increased ART uptake, retention in care, and viral suppression.Though same-day ART initiation improves outcomes, retention in care and viral suppression remain suboptimal, so further interventions to maximize long-term outcomes will be essential.The study is limited by being conducted at 1 clinic in urban Haiti. Further study will be necessary to determine if this strategy will be effective in other settings.http://dx.doi.org/10.13039/100000060National Institute of Allergy and Infectious DiseasesR01AI104344http://orcid.org/0000-0001-7464-275XKoenigSerena P.This project was supported by the National Institute of Allergy and Infectious Diseases, grant number R01AI104344. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Data AvailabilityWe have included the anonymized dataset as a Supporting Information file (S1 Data).Data AvailabilityWe have included the anonymized dataset as a Supporting Information file (S1 Data).IntroductionThe Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 targets state that 90% of HIV-infected persons know their status, 90% initiate antiretroviral therapy (ART), and 90% achieve virologic suppression by the year 2020 to curb the AIDS epidemic [1]. In 2015, the World Health Organization (WHO) updated their guidelines to recommend ART for all persons living with HIV based on evidence that earlier treatment improves outcomes and decreases transmission [2–4]. To achieve these goals, patients must be promptly linked to HIV services, initiated on ART, and retained in lifelong care [5].Attrition rates are particularly high during the period from HIV testing to ART initiation, with one-quarter to one-third of patients lost in the process of starting ART [6–9]. Even if many of these patients re-engage in care at a later date, they will return with more advanced disease. Though there are many factors that contribute to pretreatment attrition, the current standard of care in most settings, which requires multiple sequential visits for HIV testing and counseling, laboratory testing, and adherence counseling prior to ART initiation, creates barriers to treatment initiation. As of June 2016, WHO guidelines note inadequate evidence to support a recommendation of same-day HIV testing and ART initiation [2]. However, the availability of point-of-care tests, the fact that CD4 cell counts are no longer necessary prior to ART initiation, and the provision of same-day counseling can accelerate treatment initiation, potentially reducing attrition [10–12]. We conducted a randomized trial in Haiti to determine whether same-day HIV testing and ART initiation, as compared with standard ART initiation, improves retention in care with viral suppression.MethodsStudy design and settingWe conducted an unblinded, randomized controlled trial of standard ART initiation versus same-day HIV testing and ART initiation among HIV-infected adults at the Haitian Group for the Study of Kaposi’s Sarcoma and Opportunistic infections (GHESKIO) in Port-au-Prince, Haiti. Haiti is the poorest country in the Western Hemisphere, with adult HIV prevalence of 1.7% [13,14]. GHESKIO is a Haitian nongovernmental organization and the largest provider of HIV care in the Caribbean, treating up to 700 patients per day for HIV and/or tuberculosis (TB). All care is provided free of charge. The study was approved by the institutional review boards at Partners Healthcare, GHESKIO, Weill Cornell Medical College, and Florida International University. See supporting information files S1 Text for the study protocol and S2 Text for the CONSORT checklist.ParticipantsParticipants were recruited from the HIV voluntary counseling and testing center at GHESKIO from August 2013 to October 2015. They received HIV testing and posttest counseling; those with a positive HIV test were referred for same-day physician evaluation, CD4 count (FACS Count, Becton-Dickinson, Franklin Lakes, New Jersey), WHO staging, and chest radiograph. Patients were eligible for study inclusion if they were infected with HIV-1, ≥18 years of age, and had WHO Stage 1 or 2 disease and CD4 count ≤500 cells/mm3. Initially, enrollment was limited to patients with CD4 count ≤350 cells/mm3, but in February 2014, the cutoff was increased to ≤500 cells/mm3 in response to revised WHO and Haitian guidelines [15]. Patients were excluded if they were already aware of their HIV diagnosis, had received ART previously, were pregnant or breastfeeding, lived outside of the greater Port-au-Prince metropolitan area, planned to transfer care during the study period, or failed to demonstrate preparedness on an ART readiness survey, which was administered by a social worker prior to study enrollment. The survey includes a 5-point scale, with respondents ranking their preparedness from “not at all ready” to “completely ready” in response to 7 questions. Study inclusion required a response of “somewhat ready” or “completely ready” for all 7 questions (S3 Text) [16].Randomization and maskingAfter the patients had provided written informed consent, the study team performed a screening evaluation for study exclusion criteria, and eligible participants were enrolled and randomized on the day of HIV testing. Participants were randomly assigned with the use of a computer-generated random-number list to either standard ART or same-day ART initiation in a 1:1 ratio, with allocation concealment. The randomization sequence was generated by a computer in the GHESKIO data management unit by a data manager who had no other involvement in study procedures. Participants were enrolled in the study and assigned to groups by a study physician. Participants, site personnel, and study statisticians were not masked to group assignment.ProceduresAfter randomization, the standard group participants received ART initiation procedures that mirror national guidelines. Participants were referred to return on Day 7 for baseline laboratory tests (creatinine, alanine aminotransferase, aspartate aminotransferase, complete blood count, purified protein derivative [PPD]), physician evaluation, and counseling with a social worker. On Day 10, they received interpretation of PPD results, and on Days 14 and 21, they were seen by a physician and social worker for additional counseling, test results, and ongoing evaluations for opportunistic infections. Participants started ART on Day 21 and had an additional social worker and physician visit at Week 5 (Fig 1). The ART regimen was the same as that for nonstudy patients at GHESKIO. First-line therapy included a single combination tablet including tenofovir disoproxil fumarate, lamivudine, and efavirenz.10.1371/journal.pmed.1002357.g001Fig 1Study interventions for the standard ART and same-day ART groups.The same-day ART group had identical laboratory tests as the standard ART group, a 30-minute counseling session with a social worker, and physician evaluation, and then initiated the same ART regimen as the standard ART group. They returned on Day 3 for physician and social worker visits and receipt of baseline laboratory test results; those with creatinine clearance <50 mL/minute as calculated by the Cockcroft-Gault equation were switched from tenofovir to zidovudine or abacavir. They returned on Days 10 and 17 for additional physician and social worker visits and on Day 24 for a physician visit. The same number of scheduled physician visits and counseling sessions were provided to each group so that the only difference in care was in the schedule of visits during the first 5 weeks of the study and the timing of ART initiation.All care was delivered by GHESKIO clinic staff, and the same providers (physicians, nurses, social workers, pharmacists, and field workers) cared for both groups. A counseling manual was followed with an outline for the social workers to follow at each scheduled counseling visit; these were identical between groups, except for the timing of ART initiation, and each session took about 30 minutes. All counseling was provided for individual patients, rather than for groups. The counseling sessions were audiotaped and systematically evaluated for quality control purposes. If a participant in either group missed a study visit that included a scheduled social worker counseling session, the counseling was provided at the next visit.Participants in both groups had monthly physician visits throughout the follow-up period and received the same package of services provided to all HIV-infected patients at GHESKIO, including prophylactic treatment with trimethoprim-sulfamethoxazole and isoniazid. Field workers phoned patients who missed a visit and attempted a home visit for those not reachable by phone. Participants received a transportation subsidy of 100 Haitian gourdes (US$1.70) per visit.OutcomesThe primary endpoint was retention in care with HIV-1 RNA <50 copies/ml at 12 months after HIV testing. Retention was defined as attending the 12-month visit (1 clinic visit between 12 and 15 months after HIV testing). Lost to follow-up (LTFU) was defined as failure to attend the 12-month visit. Deaths were ascertained by review of medical records or report from family members. A National Institutes of Health Division of AIDS Expedited Adverse Event Form was filled out within 48 hours after the study team became aware of any death. Transfers were ascertained by confirmation that the participant was receiving care at a different site. Secondary outcomes include survival, ART initiation, retention in care with HIV-1 RNA <1,000 copies/ml at 12 months after HIV testing, adherence as measured by pharmacy refill records and self-report, and cost and cost-effectiveness of standard and same-day ART; the adherence and cost-effectiveness evaluations will be reported in separate manuscripts.Statistical analysisDemographic, clinical, and laboratory data from the electronic medical record and study forms were de-identified, entered into an Excel spreadsheet, and exported into Stata v14 software (StataCorp, 2011, College Station, Texas) for analysis. After study completion, all participants who were LTFU were recontacted to determine their vital status.The study was powered to detect a 10% absolute difference in the rate of retention with virologic suppression between the 2 groups at 12 months after enrollment (65% in the standard and 75% in the same-day ART group). At the α = 0.05 significance level, we estimated that we would need to enroll 349 participants per group (698 in total) to achieve 80% power to detect this difference. Because patients who transferred during the study period were excluded, we increased the total sample size to 762 participants. For all analyses, a modified intention-to-treat approach was used, in which all patients were analyzed according to their assignment group, excluding patients who transferred to another facility during the follow-up period, according to protocol.Baseline characteristics were summarized using simple frequencies and proportions and medians with interquartile ranges (IQRs) stratified by treatment arm. Among participants who died, baseline CD4 count was compared using the Wilcoxon rank-sum test. We compared the proportion of participants who were retained in care with HIV-1 RNA <50 copies/ml (primary endpoint), retained with HIV-1 RNA <1,000 copies/ml, retained regardless of HIV-1 RNA, initiated ART, and died (secondary endpoints) at 12 months after enrollment using a chi-square test. We conducted multivariable logistic regression including all covariates listed in Table 1 to control for any residual confounding. We present unadjusted and adjusted risk ratios (RR) with 95% confidence intervals. Because of the change in enrollment criteria mid-study, we conducted a sensitivity analysis that included only the participants who met the original enrollment criteria of CD4 count ≤350 cells/mm3. In response to a reviewer’s request, we also plotted retention in care, regardless of viral load, for both groups and compared the distributions with the log-rank test. The study is registered with ClinicalTrials.gov number NCT01900080.10.1371/journal.pmed.1002357.t001Table 1Baseline characteristics of study participants by group.CharacteristicStandard Group (n = 356)Same-Day ART Group (n = 347)Age (years)—Median (IQR)37 (30, 45)37 (29, 46)Female sex—no. (%)181 (51)166 (48)Education—no. (%)\xa0\xa0\xa0\xa0No school90 (25)93 (27)\xa0\xa0\xa0\xa0Primary school110 (31)111 (32)\xa0\xa0\xa0\xa0Secondary school or more156 (44)143 (41)Income—no. (%)\xa0\xa0\xa0\xa0No income92 (26)90 (26)\xa0\xa0\xa0\xa0>$0 to $1/day176 (49)159 (46)\xa0\xa0\xa0\xa0>$1 to $2/day67 (19)76 (22)\xa0\xa0\xa0\xa0>$2/day21 (6)22 (6)Marital status—no. (%)\xa0\xa0\xa0\xa0Single71 (20)71 (20)\xa0\xa0\xa0\xa0Currently married/living with partner222 (62)211 (61)\xa0\xa0\xa0\xa0Formerly married63 (18)65 (19)WHO Stage—no. (%)\xa0\xa0\xa0\xa0WHO Stage 1117 (33)101 (29)\xa0\xa0\xa0\xa0WHO Stage 2239 (67)246 (71)CD4 count (cells/mm3)—Median (IQR)247 (150, 349)249 (143, 336)Body mass index—Median (IQR)*21.6 (19.7, 23.9)20.9 (19.3, 23.5)* Body mass index differed significantly between the 2 groups (p = 0.025).ART, antiretroviral therapy; IQR, interquartile range, WHO, World Health Organization.ResultsA total of 821 patients were screened, and 762 were enrolled in the study and underwent randomization (Fig 2). After randomization, 59 participants (28 in the standard ART and 31 in same-day ART group) transferred to another clinic and were excluded from all analyses, as per protocol. The median age was 37 years old (IQR: 30–45 years), 347 (49%) were women, and the median CD4 count was 248 cells/mm3 (IQR: 148, 345).10.1371/journal.pmed.1002357.g002Fig 2Screening, randomization, and follow-up.Of the 356 participants in the standard group, 256 (72%) were retained in care, 20 (6%) died, and 80 (23%) were LTFU (Table 2). Among the 256 participants retained in the standard ART group, 156 (61% of retained and 44% overall) had HIV-1 RNA <50 copies/ml. Of the 347 participants in the same-day ART group, 277 (80%) were retained in care, 10 (3%) died, and 60 (17%) were LTFU. Among the 277 participants retained in the same-day ART group, 184 (66% of retained and 53% overall) had HIV-1 RNA <50 copies/ml. The unadjusted RR of being retained in care at 12 months and achieving HIV-1 RNA <50 copies/ml was 1.21 (95% CI: 1.04, 1.38; p = 0.015) for the same-day ART group compared to the standard group (Table 3); the adjusted RR for this comparison was 1.24 (95% CI: 1.06, 1.41; p = 0.008).10.1371/journal.pmed.1002357.t002Table 2Study outcomes by group.OutcomeStandard ART Group (n = 356)Same-Day ART Group (n = 347)Unadjusted Risk Difference (95% CI)p-valuePrimary OutcomeRetained in care at 12 months with VL <50 copies/ml156 (43.8%)184 (53.0%)9.2% (1.8%, 16.6%)0.015†Secondary OutcomesRetained in care at 12 months with VL <1,000 copies/ml184 (51.7%)212 (61.1%)9.4% (2.1%, 16.7%)0.012‡Retained in care at 12 months, regardless of VL results256 (71.9%)277 (79.8%)7.9% (1.6%, 14.2%)0.014††Died20 (5.6%)10 (2.9%)Lost to follow-up80 (22.5%)60 (17.3%)† p-value comparing the proportion of all patients who were retained in care with viral load <50 copies/ml between the 2 arms.‡ p-value comparing the proportion of all patients who were retained in care with viral load <1,000 copies/ml between the 2 arms.†† p-value comparing the proportion of all patients who were retained in care between the 2 arms.ART, antiretroviral therapy; VL, viral load.10.1371/journal.pmed.1002357.t003Table 3Unadjusted and adjusted risk ratios of study outcomes.UnadjustedAdjusted for All Baseline Co-variatesRR95% CIp-valueRR95% CIp-valueRetained in care with viral load <50 copies/mlStandard ART Group1.01.0Same-Day ART Group1.21(1.04, 1.38)0.0151.24(1.06, 1.41)0.008Retained in care with viral load <1,000 copies/mlStandard ART Group1.01.0Same-Day ART Group1.18(1.04, 1.31)0.0121.20(1.05, 1.33)0.008Mortality during study periodStandard ART Group1.01.0Same-Day ART Group0.51(0.24, 1.08)0.0730.43(0.19, 0.94)0.033ART, antiretroviral therapy; RR, risk ratio.In the standard ART group, 184 (72% of retained and 52% overall) participants who were retained in care had HIV-1 RNA <1,000 copies/ml. In the same-day ART group, 212 (77% of retained and 61% overall) participants who were retained in care had HIV-1 RNA <1,000 copies/ml. The unadjusted RR of being retained in care at 12 months and achieving HIV-1 RNA <1,000 copies/ml was 1.18 (95% CI: 1.04, 1.31; p = 0.012) for the same-day ART group compared to the standard ART group (Table 3); the adjusted RR for this comparison was 1.20 (95% CI: 1.05, 1.33; p = 0.008). In the sensitivity analysis that included only participants who met the original enrollment criteria (CD4 count ≤350 cells/mm3), the adjusted RR of being retained in care at 12 months and achieving HIV-1 RNA <50 copies/ml was 1.19 (95% CI: 0.99, 1.38; p = 0.060), and the adjusted RR of being retained in care at 12 months and achieving HIV-1 RNA < 1,000 copies/ml was 1.18 (95% CI: 1.01, 1.34; p = 0.035).Vital status at the end of the study was known for 328 (92%) participants in the standard ART group and 329 (95%) in the same-day ART group. The unadjusted RR for mortality was 0.51 (95% CI: 0.24, 1.08; p = 0.073) for the same-day group compared to the standard group; the adjusted RR for this comparison was 0.43 (95% CI: 0.19, 0.94; p = 0.033). In the sensitivity analysis that included only participants with CD4 count ≤350 cells/mm3, the adjusted RR for mortality was 0.41 (95% CI: 0.18, 0.93; p = 0.033). Among the participants who died, the median baseline CD4 count was 100 cells/mm3 (IQR: 45, 192) in the standard and 207 cells/mm3 (IQR: 112, 291) in the same-day ART group (p = 0.078). Eight of 20 (40%) deaths in the standard ART group occurred in participants who were LTFU prior to ART, 8 (40%) deaths occurred in those LTFU after starting ART, and 4 (20%) occurred while in care; the causes of death for those in care were stroke, trauma, and cancer in 3, and the fourth had pain and died after seeing a traditional healer. Three of the 10 (30%) deaths in the same-day ART group occurred in participants who were LTFU after starting ART; among the 7 (70%) participants who died while in care, 1 of each died of stroke, pneumonia, malaria, renal failure, and sudden death, and 2 died of gastroenteritis. No deaths for those in care were attributed to immune reconstitution syndrome or an opportunistic infection that was missed at ART initiation. In Fig 3, the Kaplan-Meier curve plots the retention in care, regardless of viral load, for both groups. The log-rank test comparing the curves between the standard and same-day ART group indicates a significant difference (p = 0.028).10.1371/journal.pmed.1002357.g003Fig 3Retention in care by study group.In the same-day ART group, 344 of 347 (99%) participants started ART on the day of HIV testing, and the remaining 3 patients started ART within the subsequent week. During the Day 3 follow-up visit, 13 patients (4%) in the same-day ART group had adjustments in their ART regimens (replacement of tenofovir with zidovudine or abacavir) because they had creatinine clearance <50 mL/minute on baseline testing. In the standard group, 281 (79%) participants initiated ART by Day 28, the end of the time window for the 3-week ART initiation visit. Thirty-six (10%) standard group participants initiated ART from Day 29 to Day 90, and 12 (3%) initiated ART after Day 90 due to late or missed visits. Twenty-seven (8%) standard group participants never started ART during the study period because they were LTFU or died prior to initiating treatment. Isoniazid prophylaxis was initiated for 337 (95%) participants in the standard group and 340 (98%) in the same-day group. Eight cases of TB were diagnosed during the first 3 months after ART initiation; 6 of these occurred in the standard group and 2 in the same-day ART group.DiscussionThe results of this randomized controlled trial show that among HIV-infected adults with early WHO Stage disease and CD4 count ≤500 cells/mm3, same-day HIV testing and ART initiation, as compared to standard care, improves retention in care with virologic suppression and, in the multivariable analysis, decreases mortality. These results are important given recent WHO 2016 guidelines stating the lack of evidence in support of same-day ART initiation.Our findings suggest that ART initiation as soon as possible after HIV testing may be beneficial for clinically stable patients. In resource-poor settings with fragile delivery systems, such as Haiti, the provision of immediate support by care providers at the time of HIV diagnosis can have both structural and individual impact. In addition to making treatment initiation logistically easier for patients, we believe that same-day counseling and ART initiation increase the sense of hope, optimism, and overall connectedness to the healthcare system for patients, which have been shown to be important for retention [17–20].Our findings are consistent with the results of the RapIT study, a randomized trial that included participants in South Africa with WHO Stage 3 or 4 disease or CD4 count ≤350 cells/mm3 [11]. Participants in the standard group in that study generally started ART at the sixth visit, and 72% of participants in the rapid group started ART on the day of study enrollment. Rapid ART initiation resulted in a 17% improvement in retention and 13% improvement in viral suppression. A stepped-wedge cluster-randomized trial in Uganda found an increase in ART initiation within 2 weeks after eligibility by implementing a multicomponent intervention to streamline ART initiation that included training healthcare workers, providing point-of-care CD4 count testing platforms, eliminating mandatory multiple preinitiation sessions, and giving feedback to facilities on their ART initiation rates [21]. A weighted proportion of 80% in the intervention group had started ART within 2 weeks after eligibility compared with 38% in the control group. A cohort study of same-day ART initiation in pregnant women in South Africa also found high rates of treatment initiation, with 91% initiating ART on the day of referral to the service [22]. In the intervention group of the Sustainable East Africa Research on Community Health (SEARCH) HIV test-and-treat study, a cluster-randomized controlled trial conducted in Kenya and Uganda, HIV-infected patients who were identified through community testing were referred to HIV care upon diagnosis and then offered immediate ART initiation; retention was high (89%) among patients newly linking to care [23].At ART initiation, it is critical that patients are ready to start lifelong therapy, that TB screening is conducted, and that renal function is evaluated to avoid the use of tenofovir in patients with renal insufficiency. In this study, ART readiness was remarkably high, with over 99% of patients screened for the study reporting they were ready to start lifelong ART. This is a particularly significant and timely finding for the provision of recommended universal ART because the majority of people living with HIV have early clinical disease, and there has been prior concern that healthier patients may be less willing to accept lifelong therapy [4]. Most patients with early clinical disease do not have TB symptoms (cough, fever, night sweats, or weight loss), so they do not require further work up to exclude TB, according to WHO guidelines [2]. With the exclusion of patients with a baseline chest x-ray that was suspicious for TB, we found that less than 1% of participants in the same-day ART group had TB that was missed at the time of ART initiation. We found that 4% of participants in the same-day ART group had creatinine clearance <50 mL/minute; ART regimens were adjusted on Day 3 for these patients.Both groups in our study received high-level care, with multiple counseling and physician visits in the first month, followed by monthly physician visits. At the time the study was started, this was the standard of care in Haiti. However, this standard has shifted over the past few years towards decreased frequency of visits and nonphysician providers [2,24–27]. We believe that same-day ART can be provided with fewer follow-up visits if proper counseling is provided during the early period after ART initiation. However, clinic-level procedures play a major role in the effectiveness of accelerated ART initiation strategies, as illustrated in Malawi, where among nearly 22,000 pregnant women who started ART for mother-to-child prevention, LTFU rates ranged from 0% to 58% between facilities and were highest among women who initiated ART on the day of HIV testing at large clinics [28].Though lower than anticipated, retention in both groups in our study was higher than reports of standard ART initiation from other resource-poor settings. Two studies from South Africa found that approximately one-third of patients remained in care from HIV testing through 12 months of ART, and systematic reviews of African studies have found high rates of pre-ART attrition [6,8,29,30]. In Haiti, data on pre-ART outcomes are limited, but 12-month retention after ART initiation is 73% nationwide [31]. We attribute the higher retention in our study in large part to faster ART initiation, even in the standard group, compared to many other HIV programs. We surmise that retention would have been lower in the standard group if there had been longer delays in ART initiation [5,11,30].The rates of retention with viral suppression in our study are lower than those reported from clinical trial cohorts, including at GHESKIO. In the GHESKIO Clinical Trials Unit, with a median monthly average of 483 subjects participating in NIH-funded clinical trials, retention is 97%. We attribute the lower retention and viral suppression rates in our study to 2 major reasons. First, nearly all patients meeting WHO stage and CD4 criteria were enrolled in the study on the day of HIV testing, including those with substantial barriers to retention in care and adherence. In contrast, over one-third of patients are generally lost to care prior to ART initiation or enrollment in clinical trials [6,8,29,30]. Second, the care that was provided in this study was similar to that received by nonstudy patients at GHESKIO, with the aim of producing findings that could be reproduced in other resource-poor settings. In order to achieve the UNAIDS 90-90-90 targets, it will be important to evaluate reasons for attrition and implement new strategies to improve retention in care. One approach that has been successful in a cohort of nonresearch patients at GHESKIO has been expedited follow-up care, with fewer visits of shorter duration for clinically stable patients [32]. Streamlined care has also been associated with high rates of retention in the SEARCH study, which is described above [23].Our study was conducted in a large urban clinic, which may limit the generalizability of our findings. In addition, though our study included patients with early clinical disease, the CD4 counts in our population were lower than would be expected with the provision of universal ART. It is possible that patients with higher CD4 counts may experience less benefit from same-day ART. It is also noteworthy that we conducted a chest x-ray prior to enrollment; if same-day ART is provided without a chest x-ray, it is possible that TB cases will be missed. Our study was not blinded. All participants in both groups received the same number of visits and the same retention plan, but we cannot exclude the possibility that awareness of study group impacted provider behavior.In conclusion, in a population of asymptomatic or minimally symptomatic HIV-infected patients, same-day HIV testing and ART initiation decreased mortality and improved the rate of retention in care with virologic suppression compared with standard ART initiation. Furthermore, human and material resources provided to each group were similar, so same-day ART is not expected to increase treatment costs. The new WHO recommendations to provide ART to all HIV-infected patients should facilitate same-day test and treat.Supporting informationS1 TextStudy protocol.(DOCX)Click here for additional data file.S2 TextCONSORT checklist.(DOC)Click here for additional data file.S3 TextHIV medication readiness scale.(PDF)Click here for additional data file.S1 DataAnonymized dataset.(XLSX)Click here for additional data file.Presented in part at the 21st International AIDS Conference, Durban, South Africa, July 18 to 22, 2016. We thank all of the patients who participated in this study and all of the GHESKIO staff who cared for them. We thank Drs. Paul Farmer, Daniel Fitzgerald, Martin Hirsch, Warren Johnson, Daniel Kuritzkes, and Paul Sax for expert advice on study design and Kaya Hedt and Anshul Saxena for manuscript formatting and preparation. We also thank Drs. Carlos del Rio, Kenneth Mayer, and Larry Moulton for serving on the data safety monitoring board and providing oversight of the study.AbbreviationsARTantiretroviral therapyGHESKIOHaitian Group for the Study of Kaposi’s Sarcoma and Opportunistic infectionsIQRinterquartile rangeLTFUlost to follow-upPPDpurified protein derivativeRRrisk ratioSEARCHSustainable East Africa Research on Community HealthUNAIDSThe Joint United Nations Programme on HIV/AIDSWHOWorld Health OrganizationReferences1UNAIDS Fast-Track, Ending the AIDS Epidemic by 2030. Accessed May 24, 2017 at: http://www.unaids.org/en/resources/campaigns/World-AIDS-Day-Report-2014.2Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection. Recommendations for a Public Health Approach. Second Edition, World Health Organization, 2016. Accessed May 24, 2017 at: http://www.who.int/hiv/pub/arv/arv-2016/en/.3The INSIGHT START Study Group, LundgrenJD, BabikerAG, GordinF, EmeryS, GrundB, et al\nInitiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. New Engl J Med. 2015;373(9):795–807. doi: 10.1056/NEJMoa1506816\n261928734The TEMPRANO ANRS 12136 Study Group. A Trial of Early Antiretrovirals and Isoniazid Preventive Therapy in Africa. New Engl J Med. 2015;373(9):808–22. doi: 10.1056/NEJMoa1507198\n261931265FoxMP, RosenS. Retention of Adult Patients on Antiretroviral Therapy in Low- and Middle-Income Countries: Systematic Review and Meta-analysis 2008–2013. J Acquir Immune Defic Syndr. 2015;69(1):98–108. doi: 10.1097/QAI.0000000000000553\n259424616ClouseK, PettiforAE, MaskewM, BassettJ, Van RieA, BehetsF, et al\nPatient retention from HIV diagnosis through one year on antiretroviral therapy at a primary health care clinic in Johannesburg, South Africa. 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PLoS ONE. 2016;11(2):e0146903\ndoi: 10.1371/journal.pone.0146903\n2690179510SiednerMJ, LankowskiA, HabererJE, KembabaziA, EmenyonuN, TsaiAC, et al\nRethinking the "pre" in pre-therapy counseling: no benefit of additional visits prior to therapy on adherence or viremia in Ugandans initiating ARVs. PLoS ONE. 2012;7(6):e39894\ndoi: 10.1371/journal.pone.0039894\n2276192411RosenS, MaskewM, FoxMP, NyoniC, MongwenyanaC, MaleteG, et al\nInitiating Antiretroviral Therapy for HIV at a Patient\'s First Clinic Visit: The RapIT Randomized Controlled Trial. PLoS Med. 2016;13(5):e1002015\ndoi: 10.1371/journal.pmed.1002015\n2716369412JaniIV, SitoeNE, AlfaiER, ChongoPL, QuevedoJI, RochaBM, et al\nEffect of point-of-care CD4 cell count tests on retention of patients and rates of antiretroviral therapy initiation in primary health clinics: an observational cohort study. Lancet. 2011;378(9802):1572–9. doi: 10.1016/S0140-6736(11)61052-0\n2195165613UNAIDS—Haiti profile. Accessed May 24, 2017 at: http://www.unaids.org/en/regionscountries/countries/haiti.14International Human Development Indicators, Haiti Country Profile. United Nations Development Program. Accessed May 24, 2017 at: http://hdr.undp.org/en/countries/profiles/HTI.15Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection. Recommendations for a Public Health Approach. World Health Organization, 2013. Accessed May 24, 2017 at: http://www.who.int/hiv/pub/guidelines/arv2013/en/.16BalfourL, TascaGA, KowalJ, CoraceK, CooperCL, AngelJB, et al\nDevelopment and validation of the HIV Medication Readiness Scale. Assessment. 2007;14(4):408–16. doi: 10.1177/1073191107304295\n1798665817WareNC, WyattMA, GengEH, KaayaSF, AgbajiOO, MuyindikeWR, et al\nToward an understanding of disengagement from HIV treatment and care in sub-Saharan Africa: a qualitative study. PLoS Med. 2013;10(1):e1001369\ndoi: 10.1371/journal.pmed.1001369\n2334175318BernaysS, RhodesT, BarnettT. Hope: a new way to look at the HIV epidemic. AIDS. 2007;21\nSuppl 5:S5–11.19BarnettT, WestonM. Wealth, health, HIV and the economics of hope. AIDS. 2008;22\nSuppl 2:S27–34.20MasquillierC, WoutersE, MortelmansD, Booysen FleR. Families as catalysts for peer adherence support in enhancing hope for people living with HIV/AIDS in South Africa. J Int AIDS Soc. 2014;17:18802\ndoi: 10.7448/IAS.17.1.18802\n2470279721AmanyireG, SemitalaFC, NamusobyaJ, KaturamuR, KampiireL, WallentaJ, et al\nEffects of a multicomponent intervention to streamline initiation of antiretroviral therapy in Africa: a stepped-wedge cluster-randomised trial. Lancet HIV. 2016;3(11):e539–e48. doi: 10.1016/S2352-3018(16)30090-X\n2765887322MyerL, ZulligerR, BlackS, PienaarD, BekkerLG. Pilot programme for the rapid initiation of antiretroviral therapy in pregnancy in Cape Town, South Africa. AIDS Care. 2012;24(8):986–92. doi: 10.1080/09540121.2012.668173\n2251956123BrownLB, HavlirDV, AyiekoJ, MwangwaF, OwaraganiseA, KwarisiimaD, et al\nHigh levels of retention in care with streamlined care and universal test and treat in East Africa. AIDS. 2016;30(18):2855–64. doi: 10.1097/QAD.0000000000001250\n2760329024SanneI, OrrellC, FoxMP, ConradieF, IveP, ZeineckerJ, et al\nNurse versus doctor management of HIV-infected patients receiving antiretroviral therapy (CIPRA-SA): a randomised non-inferiority trial. Lancet. 2010;376(9734):33–40. doi: 10.1016/S0140-6736(10)60894-X\n2055792725LongL, BrennanA, FoxMP, NdibongoB, JaffrayI, SanneI, et al\nTreatment outcomes and cost-effectiveness of shifting management of stable ART patients to nurses in South Africa: an observational cohort. PLoS Med. 2011;8(7):e1001055\ndoi: 10.1371/journal.pmed.1001055\n2181140226HumphreysCP, WrightJ, WalleyJ, MamvuraCT, BaileyKA, NtshalintshaliSN, et al\nNurse led, primary care based antiretroviral treatment versus hospital care: a controlled prospective study in Swaziland. BMC Health Serv Res. 2010;10:229\ndoi: 10.1186/1472-6963-10-229\n2068795527FairallL, BachmannMO, LombardC, TimmermanV, UebelK, ZwarensteinM, et al\nTask shifting of antiretroviral treatment from doctors to primary-care nurses in South Africa (STRETCH): a pragmatic, parallel, cluster-randomised trial. Lancet. 2012;380(9845):889–98. doi: 10.1016/S0140-6736(12)60730-2\n2290195528TenthaniL, HaasAD, TweyaH, JahnA, van OosterhoutJJ, ChimbwandiraF, et al\nRetention in care under universal antiretroviral therapy for HIV-infected pregnant and breastfeeding women (\'Option B+\') in Malawi. AIDS. 2014;28(4):589–98. doi: 10.1097/QAD.0000000000000143\n2446899929FoxMP, ShearerK, MaskewM, Meyer-RathG, ClouseK, SanneI. Attrition through Multiple Stages of Pre-Treatment and ART HIV Care in South Africa. PLOS ONE. 2014;9(10):e110252\ndoi: 10.1371/journal.pone.0110252\n2533008730MugglinC, EstillJ, WandelerG, BenderN, EggerM, GsponerT, et al\nLoss to programme between HIV diagnosis and initiation of antiretroviral therapy in sub-Saharan Africa: systematic review and meta-analysis. Trop Med Int Health. 2012;17(12):1509–20. doi: 10.1111/j.1365-3156.2012.03089.x\n2299415131Bulletin de Surveillance, Epidemiologique VIH/SIDA, Programme National de Lutte contre les IST/VIH/SIDA, Juin, 2016.32Guiteau Moise C, Bellot C, Hennessey K, Rivera V, Severe P, Aubin D, et al. Retention of clinically stable ART patients in a rapid model of care in Haiti. Conference on Retroviruses and Opportunistic Infections (CROI), Boston, MA, USA, 2016.', 'title': 'Same-day HIV testing with initiation of antiretroviral therapy versus standard care for persons living with HIV: A randomized unblinded trial.', 'date': '2017-07-26'}, '27658873': {'article_id': '27658873', 'content': "In Africa, up to 30% of HIV-infected patients who are clinically eligible for antiretroviral therapy (ART) do not start timely treatment. We assessed the effects of an intervention targeting prevalent health systems barriers to ART initiation on timing and completeness of treatment initiation.\nIn this stepped-wedge, non-blinded, cluster-randomised controlled trial, 20 clinics in southwestern Uganda were randomly assigned in groups of five clinics every 6 months to the intervention by a computerised random number generator. This procedure continued until all clinics had crossed over from control (standard of care) to the intervention, which consisted of opinion-leader-led training and coaching of front-line health workers, a point-of-care CD4 cell count testing platform, a revised counselling approach without mandatory multiple pre-initiation sessions, and feedback to the facilities on their ART initiation rates and how they compared with other facilities. Treatment-naive, HIV-infected adults (aged ≥18 years) who were clinically eligible for ART during the study period were included in the study population. The primary outcome was ART initiation 14 days after first clinical eligibility for ART. This study is registered with ClinicalTrials.gov, number NCT01810289.\nBetween April 11, 2013, and Feb 2, 2015, 12\u2008024 eligible patients visited one of the 20 participating clinics. Median CD4 count was 310 cells per μL (IQR 179-424). 3753 of 4747 patients (weighted proportion 80%) in the intervention group had started ART by 2 weeks after eligibility compared with 2585 of 7066 patients (38%) in the control group (risk difference 41·9%, 95% CI 40·1-43·8). Vital status was ascertained in a random sample of 208 patients in the intervention group and 199 patients in the control group. Four deaths (2%) occurred in the intervention group and five (3%) occurred in the control group.\nA multicomponent intervention targeting health-care worker behaviour increased the probability of ART initiation 14 days after eligibility. This intervention consists of widely accessible components and has been tested in a real-world setting, and is therefore well positioned for use at scale.\nNational Institute of Allergy and Infectious Diseases (NIAID) and the President's Emergency Fund for AIDS Relief (PEPFAR).", 'title': 'Effects of a multicomponent intervention to streamline initiation of antiretroviral therapy in Africa: a stepped-wedge cluster-randomised trial.', 'date': '2016-10-30'}, '29509839': {'article_id': '29509839', 'content': 'Home-based HIV testing is a frequently used strategy to increase awareness of HIV status in sub-Saharan Africa. However, with referral to health facilities, less than half of those who test HIV positive link to care and initiate antiretroviral therapy (ART).\nTo determine whether offering same-day home-based ART to patients with HIV improves linkage to care and viral suppression in a rural, high-prevalence setting in sub-Saharan Africa.\nOpen-label, 2-group, randomized clinical trial (February 22, 2016-September 17, 2017), involving 6 health care facilities in northern Lesotho. During home-based HIV testing in 6655 households from 60 rural villages and 17 urban areas, 278 individuals aged 18 years or older who tested HIV positive and were ART naive from 268 households consented and enrolled. Individuals from the same household were randomized into the same group.\nParticipants were randomly assigned to be offered same-day home-based ART initiation (n\u2009=\u2009138) and subsequent follow-up intervals of 1.5, 3, 6, 9, and 12 months after treatment initiation at the health facility or to receive usual care (n\u2009=\u2009140) with referral to the nearest health facility for preparatory counseling followed by ART initiation and monthly follow-up visits thereafter.\nPrimary end points were rates of linkage to care within 3 months (presenting at the health facility within 90 days after the home visit) and viral suppression at 12 months, defined as a viral load of less than 100 copies/mL from 11 through 14 months after enrollment.\nAmong 278 randomized individuals (median age, 39 years [interquartile range, 28.0-52.0]; 180 women [65.7%]), 274 (98.6%) were included in the analysis (137 in the same-day group and 137 in the usual care group). In the same-day group, 134 (97.8%) indicated readiness to start ART that day and 2 (1.5%) within the next few days and were given a 1-month supply of ART. At 3 months, 68.6% (94) in same-day group vs 43.1% (59) in usual care group had linked to care (absolute difference, 25.6%; 95% CI, 13.8% to 36.3%; P\u2009<\u2009.001). At 12 months, 50.4% (69) in the same-day group vs 34.3% (47) in usual care group achieved viral suppression (absolute difference, 16.0%; 4.4%-27.2%; P\u2009=\u2009.007). Two deaths (1.5%) were reported in the same-day group, none in usual care group.\nAmong adults in rural Lesotho, a setting of high HIV prevalence, offering same-day home-based ART initiation to individuals who tested positive during home-based HIV testing, compared with usual care and standard clinic referral, significantly increased linkage to care at 3 months and HIV viral suppression at 12 months. These findings support the practice of offering same-day ART initiation during home-based HIV testing.\nclinicaltrials.gov Identifier: NCT02692027.', 'title': 'Effect of Offering Same-Day ART vs Usual Health Facility Referral During Home-Based HIV Testing on Linkage to Care and Viral Suppression Among Adults With HIV in Lesotho: The CASCADE Randomized Clinical Trial.', 'date': '2018-03-07'}, '27163694': {'article_id': '27163694', 'content': 'PLoS MedPLoS MedplosplosmedPLoS Medicine1549-12771549-1676Public Library of ScienceSan Francisco, CA USA27163694486268110.1371/journal.pmed.1002015PMEDICINE-D-15-03455Research ArticleBiology and Life SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesPublic and Occupational HealthPreventive MedicineVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesImmunodeficiency VirusesHIVBiology and life sciencesOrganismsVirusesRNA virusesRetrovirusesLentivirusHIVBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVBiology and Life SciencesOrganismsVirusesViral PathogensRetrovirusesLentivirusHIVPeople and placesGeographical locationsAfricaSouth AfricaBiology and Life SciencesAnatomyBody FluidsBloodBlood CountsMedicine and Health SciencesAnatomyBody FluidsBloodBlood CountsBiology and Life SciencesPhysiologyBody FluidsBloodBlood CountsMedicine and Health SciencesPhysiologyBody FluidsBloodBlood CountsMedicine and Health SciencesHematologyBloodBlood CountsMedicine and Health SciencesHealth CareHealth Care ProvidersNursesPeople and PlacesPopulation GroupingsProfessionsNursesBiology and Life SciencesMicrobiologyVirologyViral Transmission and InfectionViral LoadMedicine and Health SciencesInfectious DiseasesBacterial DiseasesTuberculosisMedicine and Health SciencesTropical DiseasesTuberculosisMedicine and Health SciencesPharmaceuticsDrug TherapyInitiating Antiretroviral Therapy for HIV at a Patient’s First Clinic Visit: The RapIT Randomized Controlled TrialSingle-Visit ART InitiationRosenSydney\n1\n\n2\n*MaskewMhairi\n2\nFoxMatthew P.\n2\n\n3\nNyoniCynthia\n2\nMongwenyanaConstance\n2\nhttp://orcid.org/0000-0003-1473-880XMaleteGiven\n2\nSanneIan\n2\nhttp://orcid.org/0000-0001-5800-1960BokabaDorah\n4\nSaulsCeleste\n2\nhttp://orcid.org/0000-0002-1180-8764RohrJulia\n1\nLongLawrence\n2\n\n1\nDepartment of Global Health, Boston University School of Public Health, Boston, Massachusetts, United States of America\n\n2\nHealth Economics and Epidemiology Research Office, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa\n\n3\nDepartment of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, United States of America\n\n4\nHealth Department, City of Johannesburg, Johannesburg, South Africa\nBinagwahoAgnesAcademic Editor\nRwanda Ministry of Health, RWANDA\nThe authors have declared that no competing interests exist.Conceived and designed the experiments: SR LL MM IS MPF. Performed the experiments: CN CM DB CS JR. Analyzed the data: MM GM SR. Wrote the first draft of the manuscript: SR MM. Contributed to the writing of the manuscript: SR MM LL MPF. Enrolled patients: CN. Agree with the manuscript’s results and conclusions: SR MM LL MPF CN CM GM IS DB CS JR. All authors have read, and confirm that they meet, ICMJE criteria for authorship.* E-mail: sbrosen@bu.edu105201652016135e1002015171120152232016© 2016 Rosen et al2016Rosen et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.BackgroundHigh rates of patient attrition from care between HIV testing and antiretroviral therapy (ART) initiation have been documented in sub-Saharan Africa, contributing to persistently low CD4 cell counts at treatment initiation. One reason for this is that starting ART in many countries is a lengthy and burdensome process, imposing long waits and multiple clinic visits on patients. We estimated the effect on uptake of ART and viral suppression of an accelerated initiation algorithm that allowed treatment-eligible patients to be dispensed their first supply of antiretroviral medications on the day of their first HIV-related clinic visit.Methods and FindingsRapIT (Rapid Initiation of Treatment) was an unblinded randomized controlled trial of single-visit ART initiation in two public sector clinics in South Africa, a primary health clinic (PHC) and a hospital-based HIV clinic. Adult (≥18 y old), non-pregnant patients receiving a positive HIV test or first treatment-eligible CD4 count were randomized to standard or rapid initiation. Patients in the rapid-initiation arm of the study (“rapid arm”) received a point-of-care (POC) CD4 count if needed; those who were ART-eligible received a POC tuberculosis (TB) test if symptomatic, POC blood tests, physical exam, education, counseling, and antiretroviral (ARV) dispensing. Patients in the standard-initiation arm of the study (“standard arm”) followed standard clinic procedures (three to five additional clinic visits over 2–4 wk prior to ARV dispensing). Follow up was by record review only. The primary outcome was viral suppression, defined as initiated, retained in care, and suppressed (≤400 copies/ml) within 10 mo of study enrollment. Secondary outcomes included initiation of ART ≤90 d of study enrollment, retention in care, time to ART initiation, patient-level predictors of primary outcomes, prevalence of TB symptoms, and the feasibility and acceptability of the intervention. A survival analysis was conducted comparing attrition from care after ART initiation between the groups among those who initiated within 90 d. Three hundred and seventy-seven patients were enrolled in the study between May 8, 2013 and August 29, 2014 (median CD4 count 210 cells/mm3). In the rapid arm, 119/187 patients (64%) initiated treatment and were virally suppressed at 10 mo, compared to 96/190 (51%) in the standard arm (relative risk [RR] 1.26 [1.05–1.50]). In the rapid arm 182/187 (97%) initiated ART ≤90 d, compared to 136/190 (72%) in the standard arm (RR 1.36, 95% confidence interval [CI], 1.24–1.49). Among 318 patients who did initiate ART within 90 d, the hazard of attrition within the first 10 mo did not differ between the treatment arms (hazard ratio [HR] 1.06; 95% CI 0.61–1.84). The study was limited by the small number of sites and small sample size, and the generalizability of the results to other settings and to non-research conditions is uncertain.ConclusionsOffering single-visit ART initiation to adult patients in South Africa increased uptake of ART by 36% and viral suppression by 26%. This intervention should be considered for adoption in the public sector in Africa.Trial RegistrationClinicalTrials.gov NCT01710397, and South African National Clinical Trials Register DOH-27-0213-4177.In the RapIT randomized controlled trial, Sydney Rosen and colleagues investigate whether accelerated initiation of antiretroviral therapy can improve viral suppression for HIV patients in South Africa.Author SummaryWhy Was This Study Done?One of the most persistent operational challenges facing antiretroviral therapy (ART) programs for HIV/AIDS in sub-Saharan Africa is late presentation of patients for care and high rates of attrition from care between HIV testing and ART initiation.One reason for this is that starting ART in many countries is a lengthy and burdensome process, imposing long waits and multiple clinic visits on patients; in South Africa, the country with the world’s largest HIV treatment program, patients must typically make five or six clinic visits, starting with an HIV test, before they receive medications.There have not yet been any controlled evaluations of an integrated, rapid HIV treatment initiation algorithm that allows patients to initiate ART in a single clinic visit, so the RapIT trial was done to find out if “same-day initiation” of ART would increase the number of patients starting treatment and improve overall health outcomes, compared to current practices.What Did the Researchers Do and Find?We randomly assigned 377 adult patients at two public clinics in Johannesburg, South Africa, who had provided consent to participate in the study to one of two groups.Patients in the group assigned to receive rapid treatment initiation were offered the chance to start treatment on the same day as their first clinic visit, using rapid, point-of-care laboratory tests and an accelerated sequence of other steps, including a physical exam, education, and counseling.Patients in the group assigned to receive standard treatment initiation followed the standard schedule for treatment initiation used by the clinics, which usually required three to five additional clinic visits over a 2–4 wk period.After the study enrollment visit, patients were followed up by reviewing their regular clinic medical records, to determine how many did start treatment and how many were still in care and had good outcomes, as indicated by a suppressed viral load, 10 mo later.We found that 97% of patients in the rapid initiation group had started ART by 90 d after study enrollment—three-quarters of them on the same day—compared to 72% of patients in the standard initiation group.By 10 mo after study enrollment, 64% of patients in the rapid group had good outcomes compared to 51% in the standard group.Rapid initiation group patients spent roughly two and a half hours in the clinic to complete all the steps required before they got their medications.What Do These Findings Mean?The RapIT (Rapid Initiation of Treatment) trial showed that it is possible to initiate nearly all eligible patients on HIV therapy, and to do so in a much shorter time interval than previously required.By showing that offering the opportunity to start treatment on the spot, without delay, overcomes many barriers patients would otherwise face, this study demonstrates that same-day ART initiation is an effective strategy for improving health outcomes.More patients in the rapid initiation group dropped out of care after starting treatment than in the standard initiation group; although the rapid initiation group still had better health outcomes overall, adherence support after starting treatment remains essential.The findings of this study are limited because the study took place in only two clinics in one part of South Africa and was carried out by study staff, not by regular clinic staff.Based on this study’s results, consideration could be given to accelerating the process of ART initiation in many different settings and for different types of patients.http://dx.doi.org/10.13039/100000060National Institute of Allergy and Infectious Diseases1U01AI100015RosenSydneyFunding for this study was provided by the U.S. National Institutes of Health (National Institute of Allergy and Infectious Diseases) under the terms of grant 1U01AI100015 to Boston University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Data AvailabilityData will be made publicly available in the Dryad repository (http://www.datadryad.org/) after the protocol has been closed (anticipated closure June 2018). Until then, data will remain under the supervision of the University of the Witwatersrand Human Research Ethics Committee (HREC). Requests should be sent to the HREC Research Administrator at: https://www.wits.ac.za/research/about-our-research/ethics-and-research-integrity/human-research-ethics-committee-medical/.Data AvailabilityData will be made publicly available in the Dryad repository (http://www.datadryad.org/) after the protocol has been closed (anticipated closure June 2018). Until then, data will remain under the supervision of the University of the Witwatersrand Human Research Ethics Committee (HREC). Requests should be sent to the HREC Research Administrator at: https://www.wits.ac.za/research/about-our-research/ethics-and-research-integrity/human-research-ethics-committee-medical/.IntroductionOne of the most persistent operational challenges facing antiretroviral therapy (ART) programs for HIV/AIDS in sub-Saharan Africa is late presentation of patients for care and high rates of attrition from care between HIV testing and ART initiation, with baseline median CD4 cell counts remaining well below 200 cells/mm3 in the region despite steadily rising eligibility thresholds [1]. Even among those who have been diagnosed and found to be treatment-eligible, loss to care before starting ART has consistently been estimated at a third to a quarter of patients [2,3]. While many of those who drop out of care prior to ART initiation will make their way back at a later time, they will almost certainly have lower CD4 counts and more symptoms of illness than when they first tested positive. Some will be very sick or die before treatment can be started, and those who do eventually start will have a poorer prognosis on treatment than if they had begun treatment earlier [4,5]. Offering ART to all who test positive regardless of CD4 count, as is now recommended by the World Health Organization [6], will make little difference if those who test positive fail to initiate treatment.There are likely many causes of loss to care before treatment initiation, but one reason observed is that starting ART in many countries is a lengthy and burdensome process, requiring long waits and multiple clinic visits [7,8]. In South Africa, the country with the world’s largest HIV treatment program [9], the process typically includes an HIV test (visit 1), determination of treatment eligibility (visit 2), adherence education and counseling and baseline blood tests (visits 3, 4, and 5), and physical examination and dispensing of antiretrovirals (ARVs) (visit 6). The proliferation of visits has three main causes. First, clinic receipt of printed test results from centralized laboratories typically takes several days, if not longer. Second, a belief remains that to ensure adherence, patients must participate in multiple preparatory educational and counseling sessions [2,10,11]. And third, clinics have had little motivation to accelerate the initiation process for patients who are not critically ill, as standard performance indicators do not include the proportion of eligible patients who actually initiate ART, nor the time required to do so.If patients are deterred from starting treatment by the complexity of the process, then one strategy for reducing loss of patients prior to ART initiation and encouraging earlier treatment initiation may be to shorten the time period, reduce the number of visits, and simplify the steps required before medications are dispensed. This strategy depends critically on two factors: a clinic’s willingness and ability to adjust its schedules and procedures to compress and accelerate the required steps, and the availability of rapid, point-of care (POC) laboratory assays that eliminate delays in receiving whatever lab results are required for initiation. There have not yet been any rigorous, controlled evaluations of an integrated, rapid HIV treatment initiation algorithm incorporating procedural changes and POC tests for adult, non-pregnant patients. We therefore conducted a randomized controlled trial of rapid ART initiation that allowed patients in public sector clinics in Johannesburg, South Africa to have treatment eligibility determined, all treatment preparation steps performed, and ARV medications dispensed on the day of their first HIV-related clinic visit.MethodsRapIT (Rapid Initiation of Treatment) was an unblinded, individually randomized, controlled trial of a service delivery intervention. It was approved by the Institutional Review Board of Boston University Medical Campus (H-31880) and the Human Research Ethics Committee (Medical) of the University of the Witwatersrand (M120843) and is registered with ClinicalTrials.gov, number NCT01710397.Study Sites, Infrastructure, and StaffingRapIT was conducted at two public sector outpatient clinics. Site 1 is a primary health clinic serving an urban informal settlement population on the edge of Johannesburg. Site 2 is a large, hospital-based HIV clinic serving an urban formal and informal population within Johannesburg. Both sites follow South African national treatment guidelines for ART initiation, ARV regimens, and monitoring [12]. During the period of study enrollment, May 8, 2013–August 29, 2014, the prevailing threshold for ART eligibility was a CD4 count ≤ 350 cells/mm3 or a WHO Stage 3/4 clinical condition. Requirements for care prior to initiating ART are not standardized in South Africa [13], but both sites generally required four to five clinic visits between HIV testing and dispensing the first month’s supply of ARVs.At each site, a small clinic room with security bars, running water, and basic furnishings was designated for study equipment and supplies, POC instruments, and files. As all the POC instruments were designed as desktop devices, no separate laboratory was needed. An outdoor booth for safe collection of sputum samples from tuberculosis (TB) suspects was constructed at Site 1 and made available for both study arms; existing facilities for this purpose were used at Site 2. Clinical procedures were performed by study nurses with the same level of clinical certification as existing primary health care nurses at the sites. Non-clinical procedures (consent, questionnaire, education, counseling, patient flow management) were implemented by study assistants with qualifications comparable to those of experienced lay counselors at the sites. All study staff received study and instrument-specific training. A small stipend (R1000/month, equivalent to US$86 at the exchange rate at the time of the study) was paid to clinic lay counselors at Site 1 and a messenger at Site 2 who assisted by referring potential study participants to the study assistant.Study PopulationThe study enrolled adult (≥18 y old), non-pregnant patients who presented to have an HIV test, provide a blood sample for a CD4 count if already known to be HIV-infected, or receive the results of the patient’s first treatment-eligible CD4 count. During pre-screening and screening, patients who had previously been found to be eligible for ART, were already on ART or reported receiving it in the past 12 mo, indicated that they intended to seek HIV care during the next 12 mo at a different clinic, were judged by clinic or study staff to be physically or emotionally unable to provide consent or participate in all study procedures, or did not meet other study inclusion criteria were excluded. Potential participants whose visit purpose was to have an HIV test were enrolled; those found post-enrollment not to be eligible for ART were subsequently withdrawn upon determination of ineligibility. Potential participants whose visit purpose was to receive a CD4 count result and were not eligible for treatment on the basis of that CD4 count were not enrolled.Participants were individually randomized 1:1 to either rapid treatment initiation or standard-of-care treatment initiation, using block randomization in blocks of 6. Sealed, opaque envelopes containing the allocations were prepared by the local principal investigator and numbered sequentially. The envelopes were kept in sequential, numbered order at the study sites. After obtaining written informed consent, the study assistant opened the next sequentially numbered envelope to reveal the allocation.Study Design and ProceduresProcedures for each study arm are illustrated in Fig 1. Standard-of-care treatment initiation followed existing procedures at the sites as closely as possible. Study staff interaction with participants was limited to screening for study eligibility, obtaining written informed consent, administering a questionnaire, and referring patients to clinic staff for either a blood draw for a CD4 count or a next visit appointment if the patient already had results of a CD4 count in hand. After referral, patients in the standard-initiation arm of the study were followed passively, through medical record review, and had no further interaction with the study. Standard-of-care procedures for ART initiation at both study sites included a CD4 count to determine eligibility, TB symptom screening followed by a TB test and TB treatment initiation if required, pre-initiation blood tests (hemoglobin, creatinine, and alanine aminotransferase (ALT)), group and individual counseling and education sessions, and a physical examination. All samples for laboratory tests were sent to centralized public sector laboratories, requiring patients to make separate clinic visits to provide biological samples and to receive results. Once ART eligibility was determined, initiation typically required three to four more clinic visits over a period of 2–4 wk. Patients who were very ill or found to have low CD4 counts could be “fast-tracked,” with the schedule shown in Fig 1 completed in as little as one week.10.1371/journal.pmed.1002015.g001Fig 1Standard initiation of treatment and rapid initiation procedures and visit schedule.For patients randomized to rapid initiation, all the same procedures were performed, but the use of a compressed and accelerated schedule and rapid laboratory instruments at point of care allowed them all to be completed in a single visit (Box 1). Patients offered rapid initiation typically completed each step in order, with little or no waiting time in between unless a TB test was required, which entailed a wait to process the sample. Patients who enrolled in the study too late in the day for all steps to be completed before the clinic closed were asked to return the next day to finish study procedures. Patients who were randomized to rapid initiation but did not have time to participate on the day of enrollment or wished to delay for other reasons were given up to 30 d to return and be initiated under rapid procedures. Those returning beyond 30 d were offered standard initiation by the clinic.Box 1. Rapid Initiation ProceduresCD4 countPatients who enrolled in the study and did not already have CD4 count results from a test performed within the previous 6 mo were given a rapid CD4 count using the Alere Pima CD4 Test (http://alerehiv.com/hiv-monitoring/alere-pima-cd4/) with venous blood draw. This test, previously evaluated in several studies in Africa [14–18], provides a CD4 count result from a capillary or venous blood sample in 20 min. Following the test, patients with a CD4 count ≤ 350 cells mm3 or evident physical symptoms or complaints that suggested a Stage 3 or 4 condition continued with study procedures. Those not eligible for ART were withdrawn from the study at this point and referred to the clinic for standard pre-ART monitoring.TB symptom screen and testWhile awaiting CD4 count results, a TB symptom screen was administered using South Africa’s four-question screening tool. All patients who reported symptoms were then asked to provide a sputum sample, which was immediately processed using the Cepheid Xpert MTB/RIF test (http://www.cepheid.com/us/cepheid-solutions/clinical-ivd-tests/critical-infectious-diseases/xpert-mtb-rif). This is the technology currently used for TB diagnosis in the public sector throughout South Africa, but it is located in centralized laboratories rather than at point of care [19]. It generates a TB diagnosis in 90 min [20]. Two sputum samples were run simultaneously to increase the reliability of results. Any patient who received a positive Xpert test was escorted to the clinic TB nurse to initiate TB treatment, which under national guidelines required a delay of at least 2 wk before ART could be initiated. Patients initiated on TB treatment were asked to return 2 wk later to complete rapid ART initiation on a second visit.Baseline testsOnce eligibility for ART was established, pre-initiation blood tests (hemoglobin, creatinine, and ALT) were run on a point-of-care Reflotron Plus instrument (Roche, http://www.roche-diagnostics.co.in/Products/Pages/ReflotronPlusDry.aspx)[14] using the same blood sample dawn for the CD4 count. This instrument takes approximately 2 min to complete each test. A standard clinic urine dipstick pregnancy test was also conducted for female patients of child-bearing age.Physical examA standard physical examination was conducted by the study nurse to identify any specific conditions or concerns prior to initiating ART. Initiation was delayed in patients found to have conditions that required referral to a hospital or consultation with the clinic’s doctor.Education sessionA condensed version of HIV/ART/adherence education was developed using the study clinics’ materials and provided to study participants. It was delivered in a one-on-one session by the study counselor in approximately 20 min.Counseling sessionAfter completing all tests, physical examination, and education session, each patient met individually with the study nurse, who reviewed results with the patient and provided an opportunity for the patient to ask any remaining questions and confirm that she or he was indeed ready for treatment initiation.Dispensing of ARVsThe study nurses, like other qualified nurses in South Africa, were authorized to write prescriptions for ARVs, which could then be filled directly by the nurse from study room stock (Site 1) or at the on-site clinic pharmacy (Site 2). Study patients at Site 2 were served at the pharmacy immediately, rather than being required to wait in pharmacy queues to fill prescriptions. Once the initial 4 wk supply of ARVs was dispensed, study interaction with rapid group patients ceased. Patients were asked to return to the clinic for monitoring and prescription refill by clinic staff in 1 mo, consistent with routine practice.After the enrollment visit, or completion of rapid initiation procedures for patients in the rapid-initiation arm of the study (“rapid arm”) who delayed initiation but returned to complete it within 30 d, the study team had no further contact with study patients. Patients who started ART in either arm received standard-of care treatment management from the clinic, which called for monitoring visits and medication refills at 1, 2, 3, 6, and 12 mo after initiation, with a routine viral load test at the 6 mo visit.Outcomes and DataThe primary, protocol-defined outcome for the study was viral suppression (≤400 copies/ml) within 10 mo of study enrollment, a time period selected to capture the 6 mo routine monitoring visit called for by national guidelines. Ten months was selected as the endpoint to allow patients to take up to 3 mo to initiate ART and to be up to 1 mo late for the 6 mo routine visit. Because the study sites occasionally omitted the 6 mo viral load and performed the test only at 12 mo, we considered a patient with a suppressed viral load test result any time from 3 to 12 mo after study enrollment to have achieved viral suppression. In this analysis, missing viral load test results were regarded as failures; only patients with recorded, suppressed viral load results were defined as virally suppressed. To account for the possibility that viral load results could be missing due to clinic oversight in not ordering the test, rather than patient default, and to investigate the possibility that rapid initiation merely shifts attrition from before to after treatment initiation, we also report the secondary outcome of retention in care at 10 mo after study enrollment, with retention defined as any HIV-related clinic visit in months 5–10 after study enrollment, regardless of viral load.Although viral suppression was the primary outcome assessed, the pathway by which the study aimed to increase suppression was reduction of attrition between HIV testing and treatment initiation. We therefore report initiation of treatment within 90 d of study enrollment as a secondary outcome, with initiation defined as being dispensed a first month’s supply of ARVs. We also report uptake of treatment within 180 d, as a CD4 count result is considered to be valid under South African guidelines for 6 mo—after that, a patient must have a new CD4 count to establish eligibility for ART. Finally, we report the distribution of time (d) to treatment initiation in each group.Other secondary outcomes evaluated in the study included the feasibility of the intervention, as indicated by the ability of both study sites to implement the accelerated algorithm; acceptability of the intervention, as measured by the proportion of patients offered rapid initiation who accepted it; patient-level predictors of the primary outcome; and, in the rapid arm, the prevalence of TB symptoms and confirmed TB disease and ART initiation among patients with TB.After the enrollment visit, all data collection for both groups was by passive medical record review. Both study sites routinely utilized an electronic medical record system called TherapyEdge-HIV, into which patient data were entered retrospectively by data clerks from paper files (Site 1) or by a combination of clinicians in real time and data clerks from paper files (Site 2)[21]. This record system improved the completeness of the follow-up dataset used in the study. In instances of incomplete follow-up data—for example, if the database reported a clinic visit 6 mo after ART initiation but contained no viral load test result—study staff searched the clinics’ paper files and registers and the online data portal of the National Health Laboratory Service to determine if any additional information existed but had not been recorded in the clinics’ databases. The study team had no further contact with study participants after the enrollment visit so as not to have any influence on retention in care, a study outcome.Data AnalysisWe designed the study to detect a 20% difference in viral suppression rates between the arms at 10 mo after study enrollment. With an α of 0.05, power of 90%, 1:1 randomization, and an uncorrected Fisher’s exact test, we estimated that we would need to enroll at least 124 HIV positive ART-eligible participants per group (248 total). We increased this to a maximum of 200 per group (400 total) to allow for stratification by site, sex, or age.Characteristics at study enrollment of all randomized participants who met ART initiation and study inclusion criteria were summarized using simple proportions and medians with interquartile ranges (IQR) stratified by treatment arm. For the remaining analyses, we excluded patients who were found after randomization not to be eligible for ART or not to meet study inclusion criteria. We compared the proportions of patients achieving each dichotomized study outcome and present crude risk ratios (RR) and risk differences (RD) with 95% confidence intervals (CI) stratified by group. Baseline predictors of outcomes that appeared imbalanced by treatment arm were also adjusted for using log-linear regression models to estimate adjusted risk ratios (aRR). We estimated time to treatment initiation in days using a cumulative incidence curve. To investigate whether attrition after initiation of ART differed between the study arms, we performed a survival analysis comparing attrition from care after ART initiation among those who initiated within 90 d between the groups. Person-time accrued from ART initiation date to the earliest of loss to follow up, transfer, or 10 mo of follow up, and hazard ratios of attrition from care were estimated with Cox proportional hazards models. A stratified analysis was performed to detect effect measure modification by site or patient-level factors. Finally, to confirm that no imbalance was created by excluding patients after randomization for reasons other than ineligibility for ART or evidence of a previous eligible CD4 count, we conducted sensitivity analysis incorporating the excluded patients and assigning each a negative outcome.ResultsBetween May 8, 2013, and August 29, 2014, 603 patients were screened for study eligibility and 463 provided written informed consent and were enrolled in the study (Fig 2). Of the 140 screened but excluded prior to randomization, 109 did not meet study eligibility criteria, including 43 who resided outside study clinic catchment areas or intended to seek further care elsewhere; 24 who were determined by the study assistant to be too ill for consent and study procedures; 16 who were not eligible on the basis of a prior CD4 count, were ineligible for ART, or were already on ART; 12 who were determined by the study assistant to be too emotionally upset to provide consent; 9 who did not speak any of the languages spoken by the study team; 3 who were found to be pregnant; and 2 who were excluded for other reasons. An additional 31 patients refused participation; of these, 18 were in a hurry and did not have time for study procedures, six did not wish to participate in the study, five stated that they would prefer standard care, and two were not willing to initiate therapy. Follow-up ended 10 mo after the last patient was enrolled (June 28, 2015).10.1371/journal.pmed.1002015.g002Fig 2Study enrollment and randomization.Characteristics of patients in each study arm at time of enrollment are reported in Table 1. There were no important differences between the study arms in the variables shown. Just over half the participants were female and the median age was 35 y. The median CD4 count was less than 200 cells/mm3. Age, sex, and CD4 count characteristics of the study sample were similar to those of the overall non-pregnant patient populations initiating ART at the study clinics in 2014.10.1371/journal.pmed.1002015.t001Table 1Baseline characteristics of study sample (n = 463).VariableStandard armRapid arm\nn (randomized participants)229234Enrollment site (n)\xa0\xa0\xa0\xa0Site 1 (primary health clinic)124126\xa0\xa0\xa0\xa0Site 2 (hospital-based HIV clinic)105108Age (median, IQR)35.8 (29.5–41.6)34.2 (29.0–40.1)Sex (% female)132 (58%)129 (55%)CD4 count (cells/mm3) (median, IQR)195 (103–322)224 (128–327)Purpose of clinic visit (%)\xa0\xa0\xa0\xa0Have HIV test (diagnosed today)100 (44%)90 (38%)\xa0\xa0\xa0\xa0Provide blood sample for CD4 count8 (4%)10 (4%)\xa0\xa0\xa0\xa0Receive first CD4 count results109 (47%)112 (48%)\xa0\xa0\xa0\xa0Other11 (5%)22 (10%)Reason for treatment eligibility (%)\xa0\xa0\xa0\xa0CD4 count below threshold182 (79%)183 (78%)\xa0\xa0\xa0\xa0Clinical condition Stage 3 or 43 (1%)4 (2%)\xa0\xa0\xa0\xa0Excluded (not eligible for treatment or study)44 (20%)47 (20%)Household composition\xa0\xa0\xa0\xa0Live alone (% yes)36 (16%)41 (18%)\xa0\xa0\xa0\xa0# other persons in house (median, IQR)2 (1–4)2 (1–3)Household type (%)\xa0\xa0\xa0\xa0Formal house or flat146 (63%)165 (71%)\xa0\xa0\xa0\xa0Informal dwelling or shack83 (37%)69 (29%)Travel time to clinic (minutes) (median, IQR)18 (9–24)15 (9–27)Employment status (%)\xa0\xa0\xa0\xa0Employed formally68 (30%)90 (38%)\xa0\xa0\xa0\xa0Work informally62 (27%)54 (23%)\xa0\xa0\xa0\xa0Unemployed, seeking work91 (40%)84 (36%)\xa0\xa0\xa0\xa0Unemployed, not seeking work8 (3%)6 (3%)Marital status (%)\xa0\xa0\xa0\xa0Married or long-term partner173 (76%)157 (67%)\xa0\xa0\xa0\xa0Single, no long-term partner41 (18%)57 (24%)\xa0\xa0\xa0\xa0Other (widowed, divorced)15 (6%)20 (9%)Reasons for excluding patients during the study screening process are reported in Fig 2. The 603 patients screened represent a subset of those pre-screened by clinic counselors and then referred to the study assistant for screening. While pre-screening data, which were collected by the counselors and not by study staff, are of uncertain quality, they do provide some indication of the proportion of all patients presenting at clinics who could be eligible for rapid initiation. At Site 1, for which the pre-screening data are more complete, a total of 2,636 patients presenting at the clinic’s HIV counseling and testing service were pre-screened. More than half of these were HIV-negative (1,468/2,636, 56%) or known to have CD4 counts above the eligibility threshold or already on ART (114/2,636, 4%). Of the remaining 1,054, 325 (31%) were referred for study screening. Another 293/1,054 (28%) were judged by the counselors not to meet study protocol eligibility criteria (age, residence location, language, not first CD4 count) but would likely have been eligible for the intervention if it were offered as routine care. A fifth (225/1,054, 21%) were regarded by the counselors as too sick for study participation (not necessarily for ART initiation) and were referred to a clinic doctor or nurse for immediate care; it is not clear if they would have been eligible for the intervention or not. The remainder (20%) included patients who refused study participation (36/1,054, 3%) or refused any further care (12/1,054, 1%), were deemed too upset or emotionally distressed to participate (25/1,054, 2%), were referred directly to the clinic’s HIV or TB nurse rather than the study assistant (75/1,054, 7%), or were in a hurry or had no reason stated (63/1,254, 6%).Among 463 patients screened and found eligible for study participation, 234 patients were randomized to rapid initiation and 229 to standard initiation (Fig 2). Upon completion of a CD4 count, which occurred after randomization for those who did not already have one in hand, 37 patients in each group were determined not to be eligible for ART under South African guidelines and were excluded from further data collection and from the analysis. An additional 12 patients were excluded after randomization, for reasons indicated in Fig 2. One hundred and ninety patients in the standard group and 187 in the rapid group (n = 377 total) were offered full study procedures and are included in the analysis below, with sensitivity analysis incorporating the six who were excluded after randomization for a reason other than ineligibility for ART or evidence of a prior eligible CD4 count.The protocol-defined primary outcome for the study was viral suppression within 10 mo of study enrollment. As presented in Table 2, viral suppression by 10 mo was 64% (119/187) in the rapid arm and 51% (96/190) in the standard arm, indicating a risk difference of 13% (3%–33%) and a crude relative risk of 1.26 (1.05–1.50).10.1371/journal.pmed.1002015.t002Table 2ART initiation, 10-mo retention in care, and 10-mo viral suppression.OutcomeStandard arm(%)n = 190Rapid arm(%)n = 187Crude risk difference(95% CI)Crude relative risk(95% CI)Initiated ≤ 90 d and suppressed by 10 mo (primary outcome)96 (51%)119 (64%)13% (3%–23%)1.26 (1.05–1.50)\xa0\xa0\xa0\xa0Of those\nnot\ninitiated ≤ 90 d and suppressed by 10 mo\n\n94 (49%)\n\n68 (36%)\n\n\xa0\xa0\xa0\xa0\xa0\xa0Not initiated\n\n54 (28%)\n\n5 (3%)\n\n\xa0\xa0\xa0\xa0\xa0\xa0Initiated but not suppressed\n\n40 (21%)\n\n63 (34%)\n\n\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0Of those initiated but not suppressed:\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0Retained, unsuppressed viral load test reported\n\n11 (6%)\n\n17 (9%)\n\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0Retained, no viral load test reported\n\n14 (7%)\n\n16 (9%)\n\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0Transferred to another clinic\n\n1 (1%)\n\n6 (3%)\n\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0Died\n\n3 (2%)\n\n0 (0%)\n\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0Lost to follow-up\n\n11 (6%)\n\n24 (13%)\nInitiated ≤ 90 d136 (72%)182 (97%)25% (19%–33%)1.36 (1.24–1.49)Initiated ≤ 90 d and retained at 10 mo (secondary outcome)121 (64%)151 (81%)17% (5%–23%)1.27 (1.12–1.44)\xa0\xa0\xa0\xa0Of those not initiated ≤ 90 d and retained at 10 mo:\n69 (36%)\n\n36 (19%)\n\xa0\xa0\xa0\xa0\xa0\xa0Initiated but not retained\n\n15 (8%)\n\n31 (17%)\n\xa0\xa0\xa0\xa0\xa0\xa0Not initiated\n\n54 (28%)\n\n5 (3%)\nBy 90 d after study enrollment, 97% (182/187) of participants in the rapid arm and 72% (136/190) of participants in the standard arm had initiated ART, equating to a risk difference of 25% (95% CI 19%–33%) and a crude relative risk of 1.36 (1.24–1.49) (Table 2). In adjusted analysis (S1 Table), neither age, sex, nor baseline CD4 count affected these values. By 180 d, one additional patient in the rapid arm and two in the standard arm had initiated, leaving four patients in the rapid arm and 52 in the standard arm who did not initiate within the period of validity of their CD4 count results. In the rapid arm, all four were referred to a clinic nurse or doctor for clinical confirmation of TB and did not return for ART initiation. In the standard arm, 73% (38/52) of the patients who did not initiate within 180 d made no further visits to the site after the visit in which they were enrolled in the study.\nFig 3 shows the cumulative incidence of treatment initiation in each study arm over the 180 d following enrollment. In the rapid arm, 72% (135/187) of patients started ART on the same day as study enrollment, an additional 7% (13/187) on the next day, and 96% (179/187) within 1 mo. In the standard arm, 58% of patients initiated within one month. The median (IQR) time to initiation in the standard arm for the subset who did initiate within 90 d (n = 136) was 17 (11–26) d. For rapid arm patients who did not initiate on the same day (n = 48), the reasons for delay were the need for clinical confirmation of TB or a Stage 3 or 4 condition or for TB treatment (25/48, 52%), insufficient time to complete all steps on the same day (6/48, 13%), patient preferences (5/48, 10%), lack of electricity in the clinic (2/48, 4%), and unknown reasons (10/48, 21%). Time to treatment initiation in the standard arm was shorter for patients who already had CD4 count results available upon study enrollment (median days 16, [IQR 11–22]) compared to those who enrolled in the study at the time of having an HIV test (22 [IQR 10–35]); the median for both types of patients in the rapid arm was 0 d (i.e., same-day initiation).10.1371/journal.pmed.1002015.g003Fig 3Time to ART initiation, by study arm.Cumulative incidence of ART initiation in each study arm, by number of days since study enrollment.All patients in the rapid arm had the opportunity to initiate treatment on the day of study enrollment (same-day initiation) unless one of the reasons for delay listed above pertained to them. To explore whether a delay in initiation was associated with different post-initiation outcomes, we compared patients who did initiate on the same day to those who delayed for any reason. There were no differences in either the primary outcome of viral suppression or the secondary outcome of retention in care between these two groups of patients (S3 Table). Because this analysis was limited to rapid arm patients, however, it is not a randomized comparison and should be interpreted with caution.Retention in care, defined as making a clinic visit between months 5 and 10 after study enrollment, was 81% (151/187) in the rapid arm and 64% (121/190) in the standard arm, for a risk difference of 17% (5%–23%) and a crude relative risk of 1.27 (1.12–1.44). Table 2 also indicates that 86% (31/36) of patients in the rapid arm who were not retained were lost from care after ART initiation, compared to just 22% (15/69) in the standard arm; the fall-off in the standard arm, in contrast, was mainly among those who never initiated (54/69, 78%). Although there was less loss to follow-up after initiation in the standard arm (15/190, 8% versus 31/187, 17%), this was more than offset by the higher pre-initiation loss in the standard arm (54/190, 28% versus 5/187, 3%), resulting in an overall increase in retention of 17%. Among the patients lost to care after initiation (15 in the standard arm and 31 in the rapid arm), a large majority of patients who initiated ART but were not retained in care either never came back after their initiation visit (40% of patients in the standard arm (6/15) and 45% in the rapid arm (14/31)) or came back just once (47% (7/15) and 35% (11/31), respectively), suggesting that most of these patients were never “established” on ART.To explore further the rate of loss to care, we estimated attrition from care within the first 10 mo after initiation among the subsample of 318 patients who did initiate ART within 90 d. In the standard arm, during 1,250 mo of total person-time, 22/136 (16%) dropped out of care after ART initiation, for an attrition rate of 1.8 per 100 person-months. In the rapid arm, during 1,626 mo of total person-time, 30/182 (16%) dropped out of care, for a rate of 1.8 per 100 person-months. The hazard of attrition within the first 10 mo after ART initiation among those who initiated within 90 d did not differ between the treatment arms (HR 1.06; 95% CI 0.61–1.84). We note that this result is subject to selection bias and confounding, however, due to the exclusion of those who did not start treatment within 90 d.In pooled analysis of both study arms, none of the variables presented in Table 1 predicted any of the outcomes reported above, with three exceptions (S2 Table). A slightly higher proportion of patients with baseline CD4 counts below 100 cells/mm3 initiated ART, but this difference did not persist through retention or viral suppression at 10 mo. As might be expected, patients who enrolled in the study at the time of receiving their CD4 count results (thus their second HIV-related clinic visit overall), rather than at the time of having an HIV test, were slightly more likely to achieve all three outcomes, though only for retention in care was this difference statistically significant. Finally, patients who reported being employed at the time of study enrollment, while no more likely to initiate ART, had significantly better retention in care and viral suppression than did those who reported being unemployed.In stratified analysis (S4 Table) we observed non-significant differences in effect sizes for the primary outcome (viral suppression at 10 mo) by sex, age group, and study site. A larger effect was seen among men aged <35 y (risk difference [95% CI] 34% [12%–55%]), while little effect was seen among men or women ≥35 (5% [-9%–19%]). The effect size was also greater at the primary health clinic (21% [8%–34%]), while little effect was seen at the hospital-based HIV clinic (2% [-12%–17%]). As noted, these differences were not statistically significant, and the study was not powered to detect differences among subgroups.In the rapid arm, for which TB diagnostic data were available, 29/187 patients (16%) presented with TB symptoms and were tested for TB using Xpert MTB/RIF. Four patients (17% of those with symptoms and 2% of all rapid arm patients) had a confirmed TB diagnosis. All four initiated ART within the 90-d outcome defined above, with a range of 11–54 d between study enrollment and ART initiation.The results of the sensitivity analysis incorporating the six patients who were excluded after randomization for reasons other than ART eligibility or prior CD4 count, and assigning each a negative outcome, did not differ substantively from the findings presented above, with a relative risk of viral suppression by 10 mo of 1.22 [1.02–1.46].Rapid initiation, using the procedures described above and as implemented by the study, appeared acceptable to patients at the time it was offered and feasible to implement at both study sites. We were not able to assess acceptability after patients received the intervention, as the study had no post-initiation interaction with those enrolled, and thus can surmise acceptability only on the basis of acceptance of the intervention. The study refusal rate was very low (31/603, 5%); nearly four out of five (148/187, 79%) patients offered the intervention accepted initiation on the same day or the next day, and rapid arm patients consistently expressed appreciation for the opportunity to start immediately.All steps in the rapid initiation process were completed on the same day as study enrollment for 72% (135/187) of those in the rapid arm, demonstrating the feasibility of the intervention, at least within the context of the study. From provision of informed consent (study enrollment) to dispensing of the first supply of ARV medications, rapid initiation took a median of 2.4 (IQR 2.1–2.8) hours for those who initiated on the same day as study enrollment. This interval was shorter for patients who already had CD4 count results in hand at study enrollment (median 2.25 hours). It was longer (median 4.5 hours) for those who required a TB test and did initiate ART on the same day, but 15/20 patients requiring TB tests did not initiate on the same day. The only obstacle encountered in implementing rapid procedures was fairly frequent power outages, a common occurrence in South Africa, at Site 1, which did not have a generator for backup power supply. Most rapid instrument tests could not be performed during power outages. The rapid test instruments otherwise performed well throughout the study, and no major delays or problems arose in the acceleration of clinic procedures.DiscussionIn this randomized controlled trial, we evaluated the effectiveness of an accelerated ART initiation algorithm that combined compressed and accelerated clinic procedures with point-of-care laboratory testing technologies that allowed eligible patients to initiate ART in a single clinic visit. This intervention increased the proportion of patients eligible for ART at study enrollment who initiated ART within 90 d by 25%, to 97% of all eligible patients and 100% of patients who were not delayed for TB treatment. By 10 mo after study enrollment, the intervention increased viral suppression among all treatment-eligible patients by 13% and retention in care by 17%. It was feasible and appeared acceptable at both study sites.The trial demonstrated that it is possible to initiate nearly all eligible patients on ART, and to do so in a much shorter time interval than previously required. The net benefit for overall viral suppression was clinically meaningful and may underestimate the true benefits of the intervention. Both the study sites were relatively well-managed, public sector clinics, resulting in a higher rate of ART initiation in the standard arm (72%) than is found elsewhere in the country, for example in rural KwaZulu Natal Province where the rate was 59% [2]. In addition, we observed a larger effect at Site 1, the primary health clinic, than at Site 2, the hospital-based HIV clinic. Primary health clinics, which have fewer resources than hospital-based clinics but treat 85% of HIV patients in South Africa, may struggle more with loss to follow-up before treatment initiation than do hospital-based clinics, creating a greater opportunity for a service delivery intervention like RapIT to be effective. The potential for reaching younger men, who have been among the least likely to access ART under standard care [22], is another important potential benefit of rapid initiation. Additional research is needed to explore further the non-significant differences in effect that we observed in our study.The patients who likely benefited most from RapIT were those who would not otherwise have initiated treatment at all, or who would have waited until they were sick enough to compromise their prognosis on treatment. In the standard arm, most patients who did not start treatment did not return to the study clinics for even one more visit, underscoring the importance of taking full advantage of the first visit to get as many patients started on treatment as possible. For those who would have initiated treatment, just not as soon, there is some evidence that even relatively short delays may be harmful. A recent modeling exercise using South African data estimated that compared to immediate initiation, a delay in initiating ART of 70 d would lead to a 34% increase in 12-mo mortality [22]. Delaying treatment initiation thus both deters some patients from starting at all and jeopardizes outcomes for those who do start.We hypothesize that the delays and multiple visits patients must endure before starting ART directly deter treatment initiation. Patients who cannot afford transport fare for multiple visits, have childcare obligations at home, or risk job or wage loss if they miss too many days of work may be directly deterred from returning. Others may simply grow impatient or lose their courage or motivation, particularly if they are asymptomatic when diagnosed. These patients are likely to drift away and only return when their CD4 counts are lower and symptoms have started, or to die before treatment can be started. Our results suggest that offering the opportunity to start treatment on the spot, without delay, overcomes these barriers, without risking poorer outcomes later on.Among patients who did initiate ART, post-initiation loss to care was higher in the rapid arm than the standard arm. This difference disappeared in the survival analysis, which controlled for number of months on ART but does not reflect the benefits of randomization. We speculate that some patients who did not want or were not ready for treatment chose to accept immediate initiation simply because it was offered or they wanted to participate in the study. For these patients, attrition from care was simply shifted from before ART initiation to after. While the intervention was successful in increasing the overall proportion of treatment-eligible patients with successful outcomes (viral suppression and/or retention in care), the rate of post-initiation attrition is a reminder that early retention in care and adherence support once patients start treatment remain high priorities for further research and intervention.Other studies have gauged the impact on treatment uptake of a single POC technology [23] or changes in service delivery [24], but we found only one prior report of a “single-visit initiation” intervention that was similar, to some degree, to RapIT. That study enrolled pregnant women initiating ART for prevention of mother-to-child transmission in South Africa and found very high uptake of ART among women offered rapid initiation, but it did not have a comparison arm to allow an effect to be estimated [25]. A study in Tanzania and Zambia compared the effect of community support on a two-visit algorithm and reported 99% uptake of ART in both study arms [26]. Taken together, these studies imply that accelerating ART initiation is effective in a wide range of settings.Nothing in the rapid initiation procedures used in this study differed fundamentally from existing clinic procedures. The intervention was delivered by study nurses and counselors with the same qualifications as existing clinic staff, though with study-specific training and supervision. The intervention imposed no major burdens on site management, though managerial acquiescence to the study and operational flexibility were needed to adjust the schedule and content of patient visits, staff responsibilities, and record keeping to allow for rapid initiation [27]. The main technical training required was in the use of the POC test instruments, which also required a secure location within the clinic, temperature control, and electricity.Although South Africa has better clinic infrastructure than do many other countries in the region, the RapIT intervention does not require anything that most urban and many rural clinics cannot provide. We speculate that the RapIT intervention would be feasible and potentially even more effective in other high HIV prevalence areas, where patients travel farther to reach clinics and results from centralized laboratories take even longer to return. As the new WHO guidelines are adopted, moreover, laboratory test results may not be required prior to ART initiation for patients who are asymptomatic, reducing the need for POC technology.The generalizability of our results is limited in several ways. The study was conducted in only two clinics in one province of one country. The trial intervention was delivered by study staff; it is uncertain if clinic staff delivering the same intervention will achieve the same outcomes (and whether their outcomes will be better or worse than those observed in the trial). As is typical in individually randomized trials of service delivery interventions, the possibility exists that quality of care in the standard arm was improved by the presence of the study, as clinic staff providing care for the standard arm may have been motivated by the study to make treatment initiation more efficient. If this occurred, the effect reported here would understate the true improvement in ART initiation that could be expected under routine implementation. As with many studies in which retention in care is an endpoint, we do not know the true outcomes of study patients who were not retained nor whether rapid arm patients who were not retained and who agreed to start treatment solely due to the presence of the study, and would otherwise not have done so, are at increased risk of developing ARV resistance. Finally, as reported above, rapid initiation under the study algorithm took 2–3 hours to complete, making same-day initiation impractical for patients who arrive late in the day (and for clinics with large numbers of such patients).We also do not know how clinic and patient characteristics will affect the net cost and cost-effectiveness of the intervention. Most of the changes introduced in the RapIT intervention entailed only adjustments in schedules and staff time, and we speculate that these will not result in a major net change to service delivery costs. The POC instruments used in the trial require an up-front investment, but it may be possible to initiate ART in a single visit without any POC instruments if there is no CD4 count threshold for initiation, patients with TB symptoms are identified and managed separately, and ARV regimen adjustments are routinely made at the first refill visit, rather than before initiation. Costs saved by patients, who must make just one clinic visit rather than four or five, should also be taken into account.The RapIT intervention as designed and implemented showed clinically meaningful improvements in ART uptake and viral suppression, providing “proof of principle” for a single-visit treatment initiation algorithm. Follow-on studies are needed to evaluate effectiveness and cost-effectiveness in routine practice in a variety of settings, and variations on the algorithm could also be considered. The RapIT trial has demonstrated that accelerating ART initiation can be effective and feasible in this setting and appeared acceptable to patients to whom it was offered; the next challenge will be adapting it to the range of settings and conditions found in clinics throughout Africa.Supporting InformationS1 TableStudy outcomes adjusted for baseline CD4 count, age, and sex.(DOCX)Click here for additional data file.S2 TableCrude patient-level predictors of treatment uptake, viral suppression, and retention in care.(DOCX)Click here for additional data file.S3 TableStudy outcomes stratified by immediate versus delayed initiation (rapid arm patients initiating ≤90 d only).(DOCX)Click here for additional data file.S4 TableAbsolute and relative effect measure modification of primary outcome (initiated ≤90 d and suppressed by 10 mo).(DOCX)Click here for additional data file.S1 TextResearch protocol.(PDF)Click here for additional data file.S2 TextCONSORT statement.(PDF)Click here for additional data file.AbbreviationsALTalanine aminotransferaseaRRadjusted risk ratioARTantiretroviral therapyARVantiretroviralIQRinterquartile rangeCIconfidence intervalHRhazard ratioPHCprimary health clinicPOCpoint-of-careRapITRapid Initiation of TreatmentRDrisk differenceRRrelative riskTBtuberculosisReferences1\nSiednerMJ, NgCK, Bassett IV, KatzIT, BangsbergDR, TsaiAC. 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S Afr Med J. 2012; 102:805–807. 10.7196/SAMJ.5851\n23034211', 'title': "Initiating Antiretroviral Therapy for HIV at a Patient's First Clinic Visit: The RapIT Randomized Controlled Trial.", 'date': '2016-05-11'}, '29136001': {'article_id': '29136001', 'content': "PLoS MedPLoS MedplosplosmedPLoS Medicine1549-12771549-1676Public Library of ScienceSan Francisco, CA USA29136001568543710.1371/journal.pmed.1002433PMEDICINE-D-17-02016Research ArticleMedicine and health sciencesDiagnostic medicineHIV diagnosis and managementBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesImmunodeficiency VirusesHIVBiology and life sciencesOrganismsVirusesRNA virusesRetrovirusesLentivirusHIVBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVBiology and Life SciencesOrganismsVirusesViral PathogensRetrovirusesLentivirusHIVBiology and Life SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesPublic and Occupational HealthPreventive MedicineVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyResearch and Analysis MethodsDatabase and Informatics MethodsHealth InformaticsElectronic Medical RecordsMedicine and health sciencesEpidemiologyHIV epidemiologyResearch and Analysis MethodsResearch DesignSurvey ResearchQuestionnairesMedicine and Health SciencesDiagnostic MedicineClinical Laboratory SciencesClinical LaboratoriesPeople and PlacesGeographical LocationsAfricaMozambiqueA combination intervention strategy to improve linkage to and retention in HIV care following diagnosis in Mozambique: A cluster-randomized studyA combination intervention strategy to improve HIV care in Mozambiquehttp://orcid.org/0000-0001-6101-3073ElulBatyaConceptualizationFunding acquisitionMethodologyProject administrationSupervisionWriting – original draftWriting – review & editing12*LambMatthew R.ConceptualizationData curationFormal analysisFunding acquisitionMethodologyWriting – original draftWriting – review & editing12http://orcid.org/0000-0002-9748-9273LahuertaMariaMethodologyProject administrationSupervisionWriting – original draftWriting – review & editing12AbacassamoFatimaInvestigationProject administrationWriting – review & editing3AhouaLaurenceConceptualizationFunding acquisitionInvestigationMethodologyProject administrationWriting – review & editing1http://orcid.org/0000-0001-7915-8553KujawskiStephanie A.Data curationFormal analysisWriting – review & editing2TomoMariaMethodologyProject administrationWriting – review & editing3JaniIleshMethodologyWriting – review & editing41\nICAP at Columbia University, Mailman School of Public Health, Columbia University, New York, New York, United States of America2\nDepartment of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, United States of America3\nCenter for Collaboration in Health, Maputo, Mozambique4\nInstituto Nacional de Saúde, Maputo, MozambiqueLewinSharon R.Academic EditorUniversity of Melbourne, AUSTRALIAI have read the journal's policy and the authors of this manuscript have the following competing interests: FA and MT were employees of the Center for Collaboration in Health which was providing technical support to the study health facilities at the time of the study.* E-mail: be2124@columbia.edu141120171120171411e100243396201710102017© 2017 Elul et al2017Elul et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.BackgroundConcerning gaps in the HIV care continuum compromise individual and population health. We evaluated a combination intervention strategy (CIS) targeting prevalent barriers to timely linkage and sustained retention in HIV care in Mozambique.Methods and findingsIn this cluster-randomized trial, 10 primary health facilities in the city of Maputo and Inhambane Province were randomly assigned to provide the CIS or the standard of care (SOC). The CIS included point-of-care CD4 testing at the time of diagnosis, accelerated ART initiation, and short message service (SMS) health messages and appointment reminders. A pre–post intervention 2-sample design was nested within the CIS arm to assess the effectiveness of CIS+, an enhanced version of the CIS that additionally included conditional non-cash financial incentives for linkage and retention. The primary outcome was a combined outcome of linkage to care within 1 month and retention at 12 months after diagnosis. From April 22, 2013, to June 30, 2015, we enrolled 2,004 out of 5,327 adults ≥18 years of age diagnosed with HIV in the voluntary counseling and testing clinics of participating health facilities: 744 (37%) in the CIS group, 493 (25%) in the CIS+ group, and 767 (38%) in the SOC group. Fifty-seven percent of the CIS group achieved the primary outcome versus 35% in the SOC group (relative risk [RR]CIS vs SOC = 1.58, 95% CI 1.05–2.39). Eighty-nine percent of the CIS group linked to care on the day of diagnosis versus 16% of the SOC group (RRCIS vs SOC = 9.13, 95% CI 1.65–50.40). There was no significant benefit of adding financial incentives to the CIS in terms of the combined outcome (55% of the CIS+ group achieved the primary outcome, RRCIS+ vs CIS = 0.96, 95% CI 0.81–1.16). Key limitations include the use of existing medical records to assess outcomes, the inability to isolate the effect of each component of the CIS, non-concurrent enrollment of the CIS+ group, and exclusion of many patients newly diagnosed with HIV.ConclusionsThe CIS showed promise for making much needed gains in the HIV care continuum in our study, particularly in the critical first step of timely linkage to care following diagnosis.Trial registrationClinicalTrials.gov NCT01930084In a cluster-randomized trial done in Mozambique, Batya Elul and colleagues study a combined intervention for linkage to and retention of people with HIV in care.Author summaryWhy was this study done?In sub-Saharan Africa, HIV testing, care, and treatment programs have been widely scaled up over the past decade, but suboptimal outcomes across the HIV care continuum—particularly with regards to timely linkage to and sustained retention in care—compromise their effectiveness.Patients experience multiple barriers to linkage to and retention in HIV care including health system barriers, structural barriers, and behavioral barriers, yet prior studies have largely evaluated individual interventions targeting a single barrier to care.Our study was designed specifically to examine the effectiveness of a combination intervention strategy (CIS) composed of several scalable evidence-based interventions targeting the multiple and prevalent health system, structural and behavioral barriers that patients face across the HIV continuum.What did the researchers do and find?We randomly assigned 10 primary health facilities in the city of Maputo and Inhambane Province in Mozambique to provide the standard of care (SOC) or the CIS, which included point-of-care CD4 testing at the time of diagnosis, accelerated ART initiation, and short message service (SMS) health messages and appointment reminders. A pre–post intervention 2-sample design was nested within the intervention arm to assess the effectiveness of CIS+, an enhanced version of the CIS that additionally included conditional non-cash financial incentives for linkage and retention.We enrolled 2,004 adults diagnosed with HIV in the voluntary counseling and testing clinics of participating health facilities, and compared the proportion who achieved a combined outcome of linkage to HIV care within 1 month of diagnosis and retention in care at 12 months across the 3 study groups.We found an increased likelihood of achieving the combined outcome in the CIS group compared to the SOC group, driven primarily by very large increases in same-day linkage, but no difference between the CIS+ and CIS groups.What do these findings mean?The CIS may help improve outcomes across the HIV care continuum in high-burden settings, particularly in the critical first step of timely linkage to care following diagnosis.Further research is needed to understand whether financial incentives can be optimized in this setting, given their effectiveness in enhancing other health outcomes.http://dx.doi.org/10.13039/100000200United States Agency for International DevelopmentAID-OAA-A-12-00027http://orcid.org/0000-0001-6101-3073ElulBatyahttp://dx.doi.org/10.13039/100000060National Institute of Allergy and Infectious DiseasesT32 AI114398http://orcid.org/0000-0001-7915-8553KujawskiStephanieThis study was funded by the United States Agency for International Development (USAID), USAID Award Number: AID-OAA-A-12-00027 and the National Institute of Allergy & Infectious Diseases of the National Institutes of Health, T32 AI114398 (SAK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Data AvailabilityAll relevant data are within the paper and its Supporting Information files.Data AvailabilityAll relevant data are within the paper and its Supporting Information files.IntroductionAlthough the extraordinary scale-up of HIV testing, care, and treatment programs in sub-Saharan Africa over the past decade has resulted in more than 19 million persons accessing antiretroviral therapy (ART) [1], the effectiveness of these programs has been significantly hindered by high levels of attrition across the HIV care continuum. Observational studies and systematic reviews have repeatedly reported disturbing gaps in care as patients move from HIV testing clinics to HIV care clinics (i.e., linkage to care) and that patient dropout among those enrolled in HIV care is far too common, both before and after ART initiation (i.e., retention in care) [2–7]. Indeed, available data suggest that less than 1/3 of individuals who are diagnosed with HIV are successfully linked to and remain engaged in HIV care 12 months later [4,8].Barriers to timely linkage to and sustained retention in HIV care have been well documented, and include health system barriers (e.g., multiple HIV clinic visits for counseling and clinical and laboratory assessments prior to ART initiation), structural barriers (e.g., transport costs and distances, work and childcare constraints), and behavioral barriers (e.g., forgetting appointments, lack of understanding of required care) [9–14]. Prior studies have overwhelmingly evaluated individual interventions targeting a single barrier at a single point in the HIV care continuum such as mobile phone short message service (SMS) messaging to augment linkage to care following diagnosis, or point-of-care CD4 testing to enhance retention among patients enrolled in HIV care [15,16]. However, it is increasingly recognized that multi-component approaches composed of several practical, evidence-based interventions that simultaneously target the multiple and recurrent barriers that patients face as they navigate across the HIV care continuum are needed to maximize individual and population health [17,18]. Further, implementation science research that evaluates proposed multi-component approaches in real-world settings is needed to assess not only effectiveness, but also implementation outcomes including reach, adoption, and sustainability [19]. To this end, we designed a combination intervention strategy (CIS) composed of several scalable evidence-based interventions targeting prevalent health system, structural, and behavioral barriers across the HIV care continuum, and determined its effect on a combined outcome of linkage to and retention in HIV care among adults newly diagnosed with HIV in Mozambique, while also collecting information on its implementation and potential for broader scale-up [20]. Data regarding intervention feasibility and patient acceptability have been published [21], and thus we present here the effectiveness results. Because the interventions included in the CIS are expected to be implemented at the facility level, as opposed to targeted at specific individuals, should they be scaled up, we evaluated effectiveness using a cluster design, which best mirrors this implementation approach.MethodsA detailed description of the study protocol has been published [22].Ethics statementEthical approval was provided by Mozambique’s National Committee for Bioethics for Health and Columbia University’s institutional review board (IRB) (protocol AAAL1354). Informed written consent was obtained from all participants.Study designBetween April 22, 2013, and June 30, 2016, we conducted a 2-arm cluster-randomized study (effectiveness–implementation hybrid design, Type 1) [20] in health facilities in Maputo and Inhambane Province in Mozambique in order to assess the effectiveness of the CIS. Additionally, a pre–post intervention 2-sample design was nested within the intervention arm to assess the additional effectiveness of an enhanced version of the CIS, referred to as CIS+. Consequently, the standard of care (SOC) arm enrolled 1 cohort of patients, while the intervention arm enrolled 2 sequential cohorts of patients (CIS and CIS+). CIS+ participants were enrolled after CIS enrollment was completed at each facility randomized to the intervention arm.Study settingThe city of Maputo, the nation’s capital, has an area of 300 km2 and an estimated population of 1,225,868 [23], with an HIV prevalence of 16.9% among those aged 15 to 59 years [24]. The Maputo City Health Network has a total of 37 health facilities, 32 of which offered comprehensive HIV care and treatment services at the time of study implementation [25]. In contrast, Inhambane is a rural province, with an estimated 1,475,318 people spread across 68,615 km2 [23]. HIV prevalence among adults aged 15 to 59 years is 14.1% [24]. The ratio of doctors to population (5.96/100,000) is one of the lowest in the country [26]. Of the 135 health facilities in the province, 76 offered HIV care and treatment services when our study was initiated [25]. Suboptimal health facility infrastructure, long distances to facilities, and weak referral systems in the province are all believed to compromise health service uptake [26].RandomizationPrimary health facilities providing HIV testing, care, and treatment services and operated by the Ministry of Health with technical support from the Center for Collaboration in Health, a local PEPFAR implementing partner, were the unit of randomization. We focused on primary health facilities, rather than larger provincial hospitals, to reflect the increasingly decentralized nature of HIV service delivery in Mozambique. Ten facilities in Maputo (N = 4) and Inhambane Province (N = 6) were selected from the 66 primary health facilities receiving technical support from the Center for Collaboration in Health in those regions. Participating facilities were purposely chosen because they had the highest volume of adults testing HIV positive and enrolling in HIV care in the year prior to study start and thus were expected to have sufficient participants for appropriate power. Facilities were matched into pairs by region (Maputo or Inhambane), level of urbanicity (urban versus rural), and average number of patients testing HIV positive in voluntary counseling and testing (VCT) in the year prior to study initiation (high versus low), resulting in 5 matched pairs. Matched pairs were randomized by one of the authors (MRL) using a computerized random number generator to either the CIS arm or the SOC arm using matched-pair randomization. Sequences were concealed until interventions were assigned. The study was non-blinded.Study populationParticipants were enrolled in the SOC group beginning on April 22, 2013, and in the CIS group beginning on April 25, 2013. The last patient was enrolled in the SOC group on November 20, 2014, and the last patient in the CIS group was enrolled on February 11, 2015. Enrollment in the CIS+ group began after each clinic randomized to the intervention arm completed CIS enrollment, and ran from June 16, 2014, through June 30, 2015. All participants were followed for 12 months, with the last patient completing follow-up on June 30, 2016.Broad inclusion criteria were used to reflect as accurately as possible the population of adults newly diagnosed with HIV in VCT clinics at the participating health facilities. We focused on individuals newly diagnosed in VCT clinics, as opposed to those diagnosed in antenatal clinics and tuberculosis clinics, because the latter groups of patients typically follow a modified clinic flow. All adults testing HIV positive in the VCT clinics within the participating health facilities were informed of the study by HIV testing counselors following diagnosis, and those who were interested were referred to study staff for further information, eligibility screening, and consent procedures. Patients were excluded if they were less than 18 years of age, were pregnant, planned to move from their community of residence in the next 12 months, had enrolled in HIV care or initiated ART in the past 6 months, did not understand Portuguese or Xitsua, or were incapable of providing informed consent. Study participants agreed to be referred to HIV care and treatment services at the same facility where they were diagnosed (referred to as the “diagnosing facility”); to complete a baseline, 1-month, and 12-month interview; to be traced at their homes if they could not be reached by phone for follow-up interviews; to provide contact information for a family member or friend who could provide information on their vital status if they could not be located for a follow-up interview; and, if they enrolled in HIV care and treatment services at the diagnosing facility, to have their clinical data abstracted from the facility’s existing electronic medical records.Study interventionsStandard of careParticipants at health facilities randomized to receive the SOC were managed as per prevailing Ministry of Health guidelines [27]. Individuals diagnosed with HIV received post-test counseling in the VCT clinic and were referred verbally to HIV services, typically in the diagnosing facility. Patients presenting to the facility receptionist to schedule a clinical consultation for HIV care were referred to the laboratory for CD4 cell count, chemistry, and hematology testing, and provided with an appointment 2–4 weeks later to allow sufficient time for the laboratory results to be received. ART eligibility was determined at that first clinical consultation based on CD4 cell count ≤ 350 cells/mm3 and/or WHO stage 3/4. Those found to be eligible for ART received at least 1 individual counseling session before initiating treatment. For ART-eligible patients, the time interval between enrollment in HIV care and ART initiation was estimated at 1–2 months at the time the study started. Participants initiating ART were requested to return every 2 weeks for the first month, at 2 months, at 6 months, and every 6 months thereafter. ART-ineligible patients were instructed to return at 6 months for repeat clinical evaluation and laboratory testing.Combination intervention strategyAt facilities randomized to the intervention arm, we introduced 4 evidence-based interventions that simplified the clinic flow and encouraged linkage to and retention in care. These interventions targeted several known health system, structural, and behavioral barriers across the HIV care continuum, and were adapted for the on-the-ground realities—including practice norms, physical space, and available staffing—at the health facilities. First, we introduced Pima (Inverness Medical Innovations) CD4 assay machines in the VCT clinics to enable HIV testing counselors to provide real-time, point-of-care CD4 test results immediately following diagnosis, and thus addressed a health system barrier by reducing the number of visits required for CD4 testing. We also hypothesized that receipt of additional information on one’s health at the time of diagnosis would advance patient understanding of the need for care, a documented behavioral barrier [10,28]. All patients regardless of CD4 count were provided with a paper-based referral to on-site HIV services that included their CD4 count, and were instructed to present for their first clinical consultation within 1 week. Second, to address additional health system barriers, patients with Pima CD4 cell count ≤ 350 cells/mm3 were provided with accelerated ART initiation, with the ultimate goal of decreasing the HIV morbidity and mortality that contributes to significant attrition among ART-eligible patients [4]. These individuals received an individual ART preparatory counseling session in the VCT clinic immediately following CD4 testing, on the day of diagnosis. Facility receptionists were instructed to expedite appointments for these patients when they presented to schedule their clinical consultations. Although the patients were directed to the laboratory to have their blood drawn for baseline laboratory tests required by national ART guidelines, clinicians were encouraged to initiate ART at the first clinical visit rather than await the results of the laboratory tests unless the patient presented with comorbid conditions. Patients who initiated ART received a 2-week supply and followed the visit schedule dictated by national guidelines, similar to the SOC procedures. Once baseline laboratory results were available, they were reviewed by clinic staff, and if abnormalities were noted, the participant was contacted to return to the clinic. Third, participants received health messages and appointment reminders via SMS messaging to address behavioral barriers associated with deferring care engagement and forgetting appointments. The messages were sent from the central study office to the participant’s phone or to a friend or relative’s phone per participant preference, and did not refer to HIV or a specific health facility or reveal any personal information. The health messages encouraged participants to care for their health, and were sent weekly for 1 month following diagnosis and then monthly (e.g., “Hi. Your health is the most important thing. Please remember to come to the health center for health services.”). Appointment reminders were sent only to participants who linked to care at the diagnosing facility, and were sent 3–7 days before each scheduled clinic visit (e.g., “Hi. Your health is the most important thing. We expect to see you at your upcoming appointment scheduled for the day ___.”). Participants were not asked to confirm receipt or reply to the messages. Finally, patients in the CIS+ cohort received the CIS interventions plus a series of non-cash financial incentives (FIs) in the form of prepaid cellular air-time cards to offset structural barriers associated with the direct and indirect costs of coming to the health facility to receive HIV care. Air-time cards rather than cash were selected as the incentive based on discussion with the Ministry of Health. Each card was valued at approximately US$5 and was provided conditionally upon the following achievements: linkage to care within 1 month of diagnosis, retention in care 6 months after diagnosis, and retention in care 12 months after diagnosis, for a total of approximately US$15. Participants who completed each achievement received the card when presenting for routine services. Participants without cellular phones could opt to give them to a family member, sell them for cash, or trade them for other goods. Both the point-of-care CD4 testing and accelerated ART initiation interventions were provided by health facility staff to all individuals diagnosed with HIV in the VCT clinic regardless of whether they were enrolled in the study, while the SMS messages and FIs were provided by study staff and only to study participants.Data collection and outcomesSite assessmentsData on the configuration of HIV services at the 10 participating study sites were collected at the beginning and at the end of the study using a standardized site assessment form. The purpose of the site assessments was to identify important similarities and differences between participating health facilities, as well as to better understand how services at the site could impact study implementation.Baseline interviewParticipants completed closed-ended questionnaires administered by trained research assistants at the time of study enrollment. The questionnaire took about 30 minutes to complete, and gathered information on sociodemographic characteristics, social and family support, mental health, alcohol use, HIV testing history, HIV knowledge and beliefs, and anticipated stigma and barriers to care. Anticipated stigma was assessed through 6 items adapted from the 12-item anticipated HIV stigma index developed by Earnshaw and Chaudoir [29]. Stigma scores were summed, then dichotomized into 2 groups: highest (>75th percentile) versus lower anticipated stigma. Mental health was assessed via a 7-question evaluation based on the Kessler 10-item scale for psychological distress [30]. Mental health scores were summed, then dichotomized into 2 groups: highest (<75th percentile) versus lower level of distress. Perceived availability of social support was assessed with 4 questions adapted from a 9-item scale by Wortman and colleagues [31]. Social support scores were summed, then dichotomized into 2 groups: higher (>50th percentile) versus lower social support. Questions assessing HIV-related knowledge and attitudes were based on those used by one of the authors in a previous study [32]. HIV knowledge scores were summed, then dichotomized into 2 groups: higher (>50th percentile) versus lower knowledge. Baseline interview data were double-entered into a study database, and a computer program identified discrepant double-entered results for correction against the paper-based forms.Patient tracing and follow-up interviewsOne and 12 months after enrollment, up until June 30, 2016, trained research assistants contacted participants by phone to ascertain their vital status and HIV care status, and to administer follow-up questionnaires. If the participant could not be contacted by phone after 3 attempts, research assistants visited the participant’s home up to 3 times. Participants who were located completed closed-ended interviews that gathered updated information on key domains from the baseline questionnaire, as well as self-reported information on linkage to (1- and 12-month questionnaires) and retention in HIV care (12-month questionnaire only), reasons for linkage/non-linkage (1- and 12-month questionnaires) and retention/non-retention (12-month questionnaire only), ART status, hospitalizations, and anticipated stigma. In cases where the participant could not be located, research assistants contacted a friend or family member as specified by the participant at study enrollment. Research assistants did not refer to HIV or the health facility during contact tracing but rather attempted to determine whether the participant was alive or dead. For those whose vital status could not be determined through contact tracing, research assistants searched existing electronic medical records at other primary health facilities supported by the Center for Collaboration in Health in the same district to assess whether patients had enrolled in HIV care at another facility, and reviewed death registers at the municipal and provincial levels to ascertain their vital status. Similar data entry and reconciliation procedures to those used for the baseline interview data were used for the tracing and follow-up data.Abstraction of clinical data for patients linking to HIV care at the diagnosing facilityAs part of routine clinical practice for HIV patients, clinicians documented patient information at every clinic visit on national HIV care forms, and trained data clerks entered those data into an Access-based electronic medical record. In its role as a PEPFAR implementing partner supporting the study sites, the Center for Collaboration in Health assessed the completeness and accuracy of these electronic data every 4 months and initiated targeted interventions to enhance data quality if there was greater than 15% disagreement on key data elements between the electronic and paper-based systems. During the study period, research assistants reviewed the electronic medical records to identify study participants who had linked to care at their diagnosing facility. For those located, we extracted the complete electronic medical record, capturing information on visit dates, vital status, transfer status, ART status, laboratory test results, and opportunistic infections.OutcomesThe primary outcome was a combined outcome of linkage to HIV care within 1 month of diagnosis plus retention in care 12 months after diagnosis measured at the individual level. We used a combined outcome to reflect the fact that improvements are needed across the HIV care continuum in order to maximize individual and population health. Linkage to care was defined by at least 1 clinical consultation for HIV that included assessment of the patient’s medical history and a physical exam. Retention in care was defined by a clinic visit in the 90 days prior to the end of the 12-month study follow-up period, with no documentation that the patient had transferred to another facility or had died. We assessed the combined outcome from the perspective of the diagnosing health facility using data from the electronic medical records maintained by the HIV clinics. All study participants were included in these analyses, including those who did not complete follow-up interviews. Participants whose electronic medical records were not located were considered not to have achieved the combined outcome for this analysis. As a secondary approach, we evaluated the combined outcome from the perspective of the Mozambican health program by supplementing data from the electronic medical records with patient reports of linkage to and retention in care at HIV clinics at different health facilities (obtained during follow-up interviews) and information obtained from electronic medical records at other health facilities. In these analyses, participants whose self-reported linkage and retention status suggested they were linked to and/or retained at a health facility other than their diagnosing clinic were considered to have achieved the respective linkage/retention outcomes. Participants who either did not complete follow-up interviews or did not self-report linkage to or retention at another clinic maintained their initial outcome designation. All study participants were included in these analyses.Secondary outcomes included linkage to care at several predefined time points, ART eligibility assessment (defined as receipt of WHO staging and/or CD4 cell count), ART initiation, disease progression (defined as a new WHO stage 3/4 condition or hospitalization noted in the electronic medical records or self-reported during follow-up interviews), retention in care 6 and 12 months after diagnosis regardless of the timing of linkage, and death.Statistical analysisThe trial was designed and powered to measure outcomes at the individual level, with outcomes assessed within each cluster (5 clusters per arm). In our initial power calculations, we anticipated that an average of 200 patients per clinic (in the CIS and SOC arms) would be eligible for enrollment based on historical data on the annual number of adults testing positive in the VCT clinics at the participating health facilities. With 5 facilities per study arm, an average of 200 patients per facility, an intraclass correlation coefficient (ICC) of 0.05, and an alpha of 0.05 and assuming that 35% of participants in the SOC arm would achieve the primary outcome, we estimated that the study would have 80% power to detect as statistically significant 55% of participants in the CIS group achieving the primary outcome, and greater than 80% power to detect as statistically significant 75% of participants in the CIS+ group achieving the primary outcome. Because enrollment proceeded slower than originally planned, at study midpoint we assessed the implications for power if each health facility enrolled an average of 150 participants rather than 200. Our calculations revealed minimal change in power with this reduction in the number of participants per health facility. Calculations were performed using PASS 8.0 software for 2 independent proportions in a cluster randomization study design and a 2-sided Farrington and Manning Likelihood Score Test [33]. Our power estimations and statistical analyses did not take into account the pair matching prior to randomization but rather followed recommendations from Diehr et al. [34] to break matches in statistical analyses of clustered studies when the number of pairs is between 3 and 9.An intent-to-treat analysis determined the relative risk (RR) of achieving study outcomes between the CIS and SOC groups, and between the CIS+ and CIS groups. For analyses of the primary outcome, we used random-intercept multilevel log-Poisson models to account for clustering within health facilities with an empirical variance adjustment for small numbers of sampling units described by Morel et al. [35]. We also assessed whether the primary outcome differed after adjustment for patient-level factors by constructing propensity scores that estimated the probability of inclusion in the CIS, CIS+, and SOC groups by age, sex, region, education, income, employment status, marital status, religion, prior year history of being away from home for more than 1 month, travel time to clinic, tuberculosis status, past hospitalizations, diagnosis history, and whether another family member was known to be living with HIV. The propensity score was included as a covariate in the multivariable log-Poisson models (adjusted analyses). In post hoc analyses, we further estimated the likelihood of key subgroups achieving the primary outcome using interaction contrast ratios. The subgroups assessed included subgroups based on baseline age, sex, region of health facility, employment status, marital status, whether the participant was away from home for more than 1 month in the year prior to study enrollment, travel time to clinic, whether a household member was known to be HIV positive, and dichotomous variables based on scales for self-reported anticipated stigma, HIV knowledge, mental health, and perceived social support as described earlier. For analyses of secondary outcomes, log-Poisson models were used for dichotomous outcomes, and t tests and 2-way median tests as appropriate for continuous outcomes, adjusting for clustering but not for patient-level differences.ResultsHealth facility characteristicsAs noted above, 10 primary health facilities participated in the study, 4 in Maputo and 6 in Inhambane. At study start, the 5 health facilities randomized to the intervention arm reported that they had experienced disruptions of 3 or more days in VCT services in the prior 12 months, while only 1 facility randomized to the SOC arm reported experiencing a similar disruption. By study end, no facilities—whether in the intervention or SOC arm—had experienced such disruptions. Throughout the study, only intervention sites conducted point-of-care CD4 testing using Pima machines in the VCT clinic. Two SOC sites reported that they had Pima machines available in their laboratories but only used them to monitor CD4 counts after patients had enrolled in HIV care. None of the SOC sites used SMS messaging for health messages or appointment reminders on a routine basis for all patients, but 2 sites sent SMS appointment reminders for patients participating in community ART groups [36]. Though the 2013 national HIV treatment guidelines stipulate that 1 ART preparatory counseling session is required for ART-eligible patients, all the facilities participating in the study typically conducted 2 to 3 sessions prior to ART initiation, with a slight reduction in the number of sessions observed between study start and end.Enrollment and participant characteristicsFig 1 shows the enrollment, exclusion, and flow of the patients by study group. During the study period, 5,327 adults ≥18 years of age were diagnosed with HIV in the VCT clinics at the 10 study facilities. A total of 265 of those individuals were not referred to the study staff for further information on the study because they informed the HIV testing counselor that they were not interested in the study, were already receiving HIV services, or were not willing to be referred to the diagnosing health facility. Among the 5,062 who were referred to the study staff for further information, 3,058 did not meet study eligibility criteria. The main reasons for exclusion were inability to provide informed consent due to distress following diagnosis (19%), inability to understand Portuguese or Xitsua (12%), and refusal to be referred to the diagnosing health facility for HIV services (10%).10.1371/journal.pmed.1002433.g001Fig 1Flow chart for study participation.CIS, combination intervention strategy; SOC, standard of care; VCT, voluntary counseling and testing.A total of 2,004 adults ≥18 years of age enrolled in the study at the 10 health facilities: 744 (37%) in the CIS group, 493 (25%) in the CIS+ group, and 767 (38%) in the SOC group. The majority of participants were female (64%), and the median age of participants was 34 years of age, with no meaningful differences observed by study group (Table 1). More than half of the participants (53%) were living with a partner at the time of diagnosis, and 65% of participants had a primary or lower level of education. Most participants (74%) were employed, and 43% had a monthly income of less than 1,500 meticais (approximately US$50). One-quarter (27%) reported that another household member was living with HIV. While no serious adverse events were reported during the study period, there was 1 unanticipated event of a female participant reporting intimate partner violence. The Mozambican National Committee for Bioethics for Health and the Columbia University IRB were informed of this event, and the participant asked to remain in the study but to conduct all study interviews at the facility (i.e., no follow-up phone calls).10.1371/journal.pmed.1002433.t001Table 1Participant characteristics at study enrollment in the 3 study groups (N = 2,004).CharacteristicTotalN = 2,004CISN = 744CIS+N = 493SOCN = 767p-ValueRegionMaputo1,077 (54%)396 (53%)275 (56%)406 (53%)0.58Inhambane927 (46%)348 (47%)218 (44%)361 (47%)Sex0.50Female1,292 (64%)490 (66%)319 (65%)483 (63%)Male712 (36%)254 (34%)174 (35%)284 (37%)Age (years)34.2 (9.6)34.9 (9.8)33.8 (9.9)33.8 (9.3)0.04518–24265 (13%)90 (12%)70 (14%)105 (14%)0.1225–391,233 (62%)440 (59%)301 (61%)492 (64%)40–49348 (17%)148 (2%)87 (18%)113 (15%)50+158 (8%)66 (9%)35 (7%)57 (7%)Marital status<0.001Married/partner and living together1,068 (53%)376 (51%)255 (52%)437 (57%)Married/partner, but not living together222 (11%)101 (14%)86 (17%)35 (5%)Single713 (36%)266 (36%)152 (31%)295 (38%)Missing/refused1 (0%)1 (0%)0 (0%)0 (0%)Education0.003None164 (8%)59 (8%)33 (7%)72 (9%)Primary1,149 (57%)442 (59%)256 (52%)451 (59%)Secondary471 (24%)164 (22%)130 (26%)177 (23%)Above secondary219 (11%)78 (1%)74 (15%)67 (9%)Missing/refused1 (0%)1 (0%)0 (0%)0 (9%)Employment0.46Employed1,473 (74%)537 (72%)361 (73%)575 (75%)Unemployed531 (26%)207 (28%)132 (27%)192 (25%)Monthly income<0.001≤1,500 meticais871 (43%)342 (46%)165 (33%)364 (47%)>1,500 meticais936 (47%)343 (46%)271 (55%)322 (42%)Missing/refused197 (1%)59 (8%)57 (12%)81 (11%)Another household member has HIV0.28Yes550 (27%)187 (25%)144 (29%)219 (29%)No913 (46%)361 (49%)219 (44%)333 (43%)Don’t know539 (27%)196 (26%)130 (26%)213 (28%)Missing/refused2 (0%)0 (0%)0 (0%)2 (0%)Data given as N (percent).CIS, combination intervention strategy; SOC, standard of care.Intervention effect on linkage to and retention in HIV care at the diagnosing facilityAs shown in Table 2, the CIS was associated with statistically significant improvements in the combined outcome of linkage to care within 1 month of diagnosis and retention in care 12 months following diagnosis when compared to the SOC. Analyses using data from electronic medical records to examine linkage to and retention at the diagnosing health facility showed that 57% of participants in the CIS group achieved the primary outcome versus 35% of those in the SOC group (RRCIS vs SOC = 1.58, 95% CI 1.05–2.39). Post hoc calculation of the ICC for the primary outcome according to the methods of Snijders and Bosker for binary outcome data [37] estimated an ICC of 0.066, similar to but slightly higher than the assumed ICC of 0.05 used in power and sample size estimation. These results were robust to adjustment for patient-level differences (adjusted RR [aRR]CIS vs SOC = 1.55, 95% CI 1.07–2.25). As shown in Fig 2, the greatest intervention effects were observed among young adults age 18–24 years (RRCIS vs SOC = 2.39, 95% CI 1.51–3.80, p-value for interaction between age and treatment arm = 0.07), those in Maputo (RRCIS vs SOC = 2.31, 95% CI 1.90–2.79, p-value for interaction between region and treatment arm < 0.0001), those who did not report that another household member was living with HIV (RRCIS vs SOC = 1.81: 95% CI 1.52–2.16, p-value for interaction between household member with HIV and treatment arm = 0.11), and those reporting high levels of anticipated stigma at enrollment (RRCIS vs SOC = 1.95, 95% CI 1.53–2.49, p-value for interaction between stigma and treatment arm = 0.10).10.1371/journal.pmed.1002433.g002Fig 2Relative risk of the CIS compared to the SOC on the primary outcome at the diagnosing health facility by patient characteristics.a Fifteen patients with missing information were excluded from this estimate. A description of the variables examined and categories used are provided in the Methods section.10.1371/journal.pmed.1002433.t002Table 2Linkage to and retention in HIV care: CIS versus SOC and CIS+ versus CIS.CategoryOutcomeCISN = 744CIS+N = 493SOCN = 767RR1 (95% CI), p-ValueaRR2 (95% CI), p-ValueNPercentNPercentNPercentCIS versus SOCCIS+ versus CISCIS versus SOCCIS+ versus CISPrimary outcomeAt diagnosing facilityLinked to care within 1 month of diagnosis and retained 12 months after diagnosis42557%27355%26835%1.58 (1.05–2.39)p = 0.030.96 (0.81–1.16)p = 0.661.55 (1.07–2.25)p = 0.040.94 (0.76–1.18)p = 0.52At any health facilityLinked to care within 1 month of diagnosis and retained 12 months after diagnosis54774%36073%36347%1.47 (1.08–2.01)p = 0.020.98 (0.85–1.15)p = 0.911.46 (1.05–2.04)p = 0.030.96 (0.83–1.11)p = 0.52Secondary outcomesLinkage at diagnosing facilitySame day as HIV test65989%45793%12016%9.13 (1.65–50.40)p = 0.021.04 (0.92–1.20)p = 0.38N/AWithin 1 week of HIV test67891%46194%34946%2.43 (0.70–8.41)p = 0.141.03 (0.91–1.16)p = 0.59N/AWithin 1 month of HIV test70394%46795%48263%1.48 (0.93–2.35)p = 0.091.00 (0.89–1.13)p = 0.96N/AWithin 12 months of HIV test71696%46795%59277%1.23 (1.03–1.48)p = 0.030.98 (0.87–1.11)p = 0,74N/ARetention at diagnosing facility6 months after diagnosis46262%32265%40553%1.18 (1.00–1.39)p = 0.061.05 (0.88–1.26)p = 0.48N/A12 months after diagnosis43558%27355%34144%1.32 (1.12–1.54)p = 0.0040.95 (0.79–1.13)p = 0.45N/A1RR accounts for clustering within sites using random-intercept log-Poisson regression with empirical standard error estimates.2aRR adjusts for patient-level differences using propensity scores.aRR, adjusted relative risk; CIS, combination intervention strategy; N/A, not applicable; RR, relative risk; SOC, standard of care.Eighty-nine percent of participants in the CIS group linked to the diagnosing facility on the same day as diagnosis compared to 16% (RRCIS vs SOC = 9.13, 95% CI 1.65–50.40) in the SOC group, 91% within 1 week compared to 46% (RRCIS vs SOC = 2.43, 95% CI 0.70–8.41), and 94% within 1 month compared to 63% (RRCIS vs SOC = 1.48, 95% CI 0.93–2.35). By 12 months, nearly all CIS participants (96%) had linked to care compared to 77% (RRCIS vs SOC = 1.23, 95% CI 1.03–1.48) of SOC participants. Among those linking to care, the median (interquartile range [IQR]) time from diagnosis to linkage was 0 days (0–0) in the CIS group and 3 days (1–26) in the SOC group (median test p < 0.001 for CIS versus SOC). The effect of the intervention on retention in care, regardless of the timing of linkage, was more modest but statistically significant (6-month retention: 62% CIS versus 53% SOC, RRCIS vs SOC = 1.18, 95% CI 1.00–1.39; 12-month retention: 58% CIS versus 44% SOC, RRCIS vs SOC = 1.32, 95% CI 1.12–1.54).In analyses restricted to the participants initiating ART, the median (IQR) time from diagnosis to ART initiation in the CIS and SOC groups was 32 (12–135), and 63 (33–230) days, respectively, while the median (IQR) time from enrollment in HIV care to ART initiation was 32 (11–127), and 50 (15–205) days, respectively. Median time from ART eligibility to ART initiation for the CIS, CIS+, and SOC groups was 21 (9–40), and 25 (11–56) days, respectively.There was no additional benefit of adding FIs to the CIS, with 55% (RRCIS+ vs CIS = 0.96, 95% CI 0.81–1.16; aRRCIS+ vs CIS = 0.94, 95% CI 0.76–1.18) of those in the CIS+ group achieving the primary outcome; 95% (RRCIS+ vs CIS = 1.00, 95% CI 0.83–1.13) linking to HIV care within 1 month of diagnosis, regardless of retention at 12 months; and 55% (RRCIS+ vs CIS = 0.95, 95% CI 0.79–1.13) being retained in care 12 months after diagnosis, regardless of the timing of linkage to care.Intervention effect on linkage to and retention in care at any health facilityAnalyses supplementing data from electronic medical records from participating facilities with data from patient interviews and other health facilities in the study regions to examine linkage to and retention at any health facility showed similar effects of the intervention package. A total of 74% (RRCIS vs SOC = 1.47, 95% CI 1.08–2.01) of participants in the CIS group and 47% in the SOC group were found to have linked to HIV care at any health facility within 1 month of diagnosis and were retained in HIV care 12 months after diagnosis (Table 2). Adjustment for patient-level differences did not result in any change in this finding (aRRCIS vs SOC = 1.46, 95% CI 1.05–2.04). Inclusion of FIs in the CIS also showed no additional benefit for linkage to and retention at any health facility, with 73% (RRCIS+ vs CIS = 0.98, 95% CI 0.85–1.15; aRRCIS+ vs CIS = 0.96, 95% CI 0.83–1.11) of those in the CIS+ group known to have linked to and been retained in HIV care at any health facility compared to the CIS group.Intervention effect on ART eligibility and initiation, disease progression, and deathData from electronic medical records at study sites indicated that compared to patients in the SOC group, patients in the CIS group were more likely to ever have their ART eligibility assessed (100% versus 76.9%, RRCIS vs SOC = 1.29, 95% CI 1.08–1.54), be identified as ART eligible (75% versus 60%, RRCIS vs SOC = 1.24, 95% CI 1.07–1.43), and initiate ART (65% versus 54%, RRCIS vs SOC = 1.20, 95% CI 1.00–1.43) (Table 3). Very few participants were diagnosed with a new WHO stage 3/4 event at the diagnosing facility or self-reported a hospitalization in the 12 months after HIV diagnosis. Those in the CIS group had a non-significantly but modestly decreased risk compared to those in the SOC group (1% versus 3%, RRCIS vs SOC = 0.38, 95% CI 0.07–2.03), while similar results were observed between the CIS and CIS+ groups (1% versus 1%, RRCIS+ vs CIS = 0.65, 95% CI 0.12–3.64). Neither the CIS nor the CIS+ interventions had a significant effect on mortality within 12 months of diagnosis, with 6%, 5%, and 7% of participants in the CIS, CIS+, and SOC groups, respectively, known to have died during study follow-up (RRCIS vs SOC = 0.87, 95% CI 0.40–1.91; RRCIS+ vs CIS = 0.88, 95% CI 0.45–1.74). The CIS also did not have a significant impact on mortality before (3%, RRCIS vs SOC = 0.78, 95% CI 0.46–1.32) or after ART initiation (3%, RRCIS vs SOC = 0.96, 95% CI 0.26–3.48); participants in the CIS+ group were less likely to die, though non-significantly so, before initiating ART compared to those in the CIS group (1% versus 3%, RRCIS+ vs CIS = 0.34, 95% CI 0.09–1.29).10.1371/journal.pmed.1002433.t003Table 3ART determination and initiation, disease progression, and death: CIS versus SOC and CIS+ versus CIS.\xa0OutcomeCIS(N = 744)CIS+(N = 493)SOC(N = 767)RR1 (95% CI), p-valueNPercentNPercentNPercentCIS versus SOC1CIS+ versus CIS1ART eligibility assessed744100%493100%59077%1.29 (1.08–1.54)p = 0.011.00 (0.89–1.12)p = 1.00Identified as ART eligible55775%37275%46460%1.24 (1.07–1.43)p = 0.011.01 (0.85–1.19)p = 0.91Initiated ART48465%33267%41654%1.20 (1.00–1.43)p = 0.051.03 (0.88–1.22)p = 0.59New WHO stage 3/4 or hospitalization71%31%233%0.38 (0.07–2.03)p = 0.220.65 (0.12–3.64)p = 0.53Death within 12 months466%275%547%0.87 (0.40–1.91)p = 0.690.88 (0.45–1.74)p = 0.63Death before ART initiation223%51%294%0.78 (0.46–1.32)p = 0.310.34 (0.09–1.29)p = 0.09Death after ART initiation243%224%253%0.96 (0.26–3.48)p = 0.941.38 (0.62–3.07)p = 0.331RR accounts for clustering within sites using random-intercept log-Poisson regression with empirical standard error estimates.ART, antiretroviral therapy; CIS, combination intervention strategy; RR, relative risk; SOC, standard of care.DiscussionWe conducted a cluster-randomized study in Mozambique to examine the effectiveness of a multi-component approach to increase linkage to and retention in HIV care—2 critical elements of the HIV care continuum—among adults newly diagnosed with HIV. The operational model of the CIS that we evaluated addresses known structural, biomedical, and behavioral barriers across the HIV care continuum and was composed of evidence-based, practical, and scalable interventions, including CD4 testing in VCT clinics with immediate turnaround of results, accelerated ART initiation for eligible individuals, and SMS health messages and appointment reminders. An enhanced version of the CIS additionally included FIs. In the spirit of implementation science, 2 of the interventions were implemented by existing health facility staff, rather than study staff, providing information on the real-world successes and challenges associated with the CIS that can be extrapolated to a range of settings with similar implementation contexts.Our study showed that participants receiving the CIS were 1.58 times more likely to link to HIV care at their diagnosing facility within 1 month of diagnosis and be retained in care at that same facility 12 months following diagnosis, representing not only a statistically significant but also a programmatically meaningful improvement. Particularly impressive gains were observed in timely linkage to care at the diagnosing facility: 89% of CIS participants linked to care on the day of diagnosis, representing a greater than 5-fold improvement compared to the SOC, and nearly universal linkage (96%) was achieved within 1 month of diagnosis. Notably, the intervention effect was greatest in subpopulations documented to have particularly poor outcomes across the HIV care continuum, including young adults [38,39] and those with high stigma perceptions [40–42]. The intervention also had beneficial effects on other important milestones in the HIV care continuum in the 12 months following diagnosis, including the likelihood of patients having their ART eligibility assessed and initiating ART. While the intervention significantly increased retention in HIV care at both 6 and 12 months following diagnosis, retention in the CIS group remained concerningly low and far short of what is needed to end the HIV epidemic in Mozambique and other high-burden countries.We found no additional gain in effectiveness from adding FIs to the CIS. Prior studies examining the effect of FIs in enhancing outcomes across the HIV care continuum among people living with HIV have shown inconsistent results. Studies from India, Uganda, and Democratic Republic of the Congo reported reductions in time to ART initiation and improvements in retention with the provision of incentives, while in the United States, randomized trials did not show any effect of FIs on linkage to care or viral load suppression [43–47]. While 89% of participants in the current study reported that the type of FI provided and the amount of the FIs (i.e., mobile phone air-time vouchers worth approximately US$5 at 3 points in time) were adequate, it is possible that the FIs were not sufficiently optimized to affect behaviors. Indeed, as reported elsewhere, patient reactions to the FIs were surprisingly tepid, with only 21% reporting it to be the “most useful” intervention for retention in care 12 months following diagnosis [21]. Additionally, fidelity to the FI component of the intervention package was imperfect, with, for example, 86% of participants eligible to receive the first incentive actually receiving it, which may have further limited the effect of this intervention [21]. However, given the benefits of FIs in other health sectors [48–50], further research is needed to understand whether and how they may be optimized to enhance outcomes across the HIV care continuum.This study has several important strengths. It is among the first studies to evaluate the impact of a multi-component approach on 2 important HIV care and treatment indicators: timely linkage to care following an HIV diagnosis and sustained retention in care. Improving performance for these 2 elements of the HIV care continuum is critical for realizing the individual and population benefits of HIV programming in sub-Saharan Africa. Further, while studies have examined the effectiveness of multi-component intervention packages that include FIs on HIV care outcomes [51,52], this study is the first to our knowledge to use a design that permits estimation of the additional benefit of including FIs as part of such a package.Our study also had limitations. First, in alignment with recent recommendations for implementation science studies [19], we used existing electronic medical records in the HIV clinics at the study sites to ascertain outcomes at the diagnosing facility, but such records may have limited data quality. However, data quality assessments were conducted regularly during the study period and ensured at least 85% concurrence between paper-based and electronic medical records on key data elements. Second, aside from the FI, we cannot unpack the effect of individual intervention components. Third, the relevance of point-of-care CD4 count testing may change as countries adopt “treatment for all” strategies, although our results suggest that providing people living with HIV with additional information on their health status immediately following diagnosis may be important in facilitating same-day linkage to care and likely same-day ART initiation. Fourth, the CIS+ cohort was enrolled once the target sample size had been reached in the CIS cohort, thus introducing the potential for secular trends to have biased the comparison of the CIS and CIS+ packages. However, because we found no difference in the primary outcome between the CIS+ and CIS groups, secular trends would have had to have operated in the direction of reducing overall linkage and retention for this bias to result in the failure to observe an additional benefit of FIs for linkage and retention. While this is plausible, we do not have any evidence that a substantial reduction in overall linkage and retention occurred over the relatively limited time frame of the study. Finally, while the study was implemented in 2 contrasting settings within Mozambique, study facilities were located primarily in urban and semi-urban areas within the city of Maputo and Inhambane Province, which may limit generalizability. Indeed, settings with lower education and cell phone coverage than those included in our study may experience greater challenges implementing the SMS health messages and appointment reminders. Similarly, while we set broad inclusion criteria, we did exclude people who did not understand Portuguese or Xitsua, were planning on leaving the community, or were not willing to receive services at the diagnosing facility, all factors that may have reduced generalizability. Finally, due to slower-than-expected enrollment, we enrolled fewer participants in the CIS+ group than intended, which decreased our power to detect statistically significant differences in study outcomes between the CIS+ and CIS groups. However, as the proportion achieving the combined outcome in the 2 groups was extremely similar (CIS 57% versus CIS+ 55%), it is unlikely that the inability to detect significant differences was primarily due to lack of power.ConclusionMulti-component intervention strategies have been proposed to address troubling gaps in the HIV care continuum [17,18]. To our knowledge, this is amongst the first studies to rigorously evaluate such an approach. The CIS we examined, comprising 3 evidence-based, practical, and scalable interventions, holds great promise as an approach to make much needed gains in the HIV care continuum in sub-Saharan Africa, particularly in the critical first step of timely linkage to care following diagnosis.Supporting informationS1 TextStudy protocol.(PDF)Click here for additional data file.S2 TextCONSORT checklist.(DOCX)Click here for additional data file.S1 DataData file.(CSV)Click here for additional data file.S2 DataData codebook.(XLSX)Click here for additional data file.We are grateful to the study participants, study staff, and participating health facilities for their contributions to this research. We also thank Antonia Mussa, Deborah Horowitz, Margaret McNairy, and Violante Viola for their inputs during study development and launch.AbbreviationsaRRadjusted relative riskARTantiretroviral therapyCIScombination intervention strategyFIfinancial incentiveICCintraclass correlation coefficientIQRinterquartile rangeIRBinstitutional review boardRRrelative riskSMSshort message serviceSOCstandard of careVCTvoluntary counseling and testingReferences1Joint United Nations Programme on HIV/AIDS. Fact sheet July 2017. Geneva: Joint United Nations Programme on HIV/AIDS; 2017 [cited 2017 Oct 18]. Available from: http://www.unaids.org/sites/default/files/media_asset/UNAIDS_FactSheet_en.pdf.2McGrathN, GlynnJR, SaulJ, KranzerK, JahnA, MwaunguluF, et al\nWhat happens to ART-eligible patients who do not start ART? Dropout between screening and ART initiation: a cohort study in Karonga, Malawi. 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Link4Health: a cluster randomized-controlled trial evaluating the effectiveness of a combination strategy for linkage to and retention in HIV care in Swaziland. International AIDS Conference; 2016 Jul 18–22; Durban, South Africa.", 'title': 'A combination intervention strategy to improve linkage to and retention in HIV care following diagnosis in Mozambique: A cluster-randomized study.', 'date': '2017-11-15'}, '29112963': {'article_id': '29112963', 'content': "PLoS MedPLoS MedplosplosmedPLoS Medicine1549-12771549-1676Public Library of ScienceSan Francisco, CA USA29112963567537610.1371/journal.pmed.1002420PMEDICINE-D-17-02007Research ArticleBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesImmunodeficiency VirusesHIVBiology and life sciencesOrganismsVirusesRNA virusesRetrovirusesLentivirusHIVBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVBiology and Life SciencesOrganismsVirusesViral PathogensRetrovirusesLentivirusHIVBiology and Life SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesPublic and Occupational HealthPreventive MedicineVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapySocial SciencesEconomicsFinancePeople and PlacesGeographical LocationsAfricaSwazilandMedicine and Health SciencesHealth CareHealth Education and AwarenessMedicine and health sciencesEpidemiologyHIV epidemiologyMedicine and Health SciencesHealth CarePatientsMedicine and health sciencesDiagnostic medicineHIV diagnosis and managementEffectiveness of a combination strategy for linkage and retention in adult HIV care in Swaziland: The Link4Health cluster randomized trialLink4Health: A combination intervention to improve HIV carehttp://orcid.org/0000-0001-7853-633XMcNairyMargaret L.ConceptualizationData curationFormal analysisFunding acquisitionInvestigationMethodologyProject administrationSupervisionValidationWriting – original draftWriting – review & editing12*LambMatthew R.ConceptualizationData curationFormal analysisInvestigationMethodologyWriting – original draftWriting – review & editing13GachuhiAverie B.Data curationProject administrationSupervisionWriting – original draftWriting – review & editing1Nuwagaba-BiribonwohaHarrietData curationProject administrationSupervisionWriting – original draftWriting – review & editing13BurkeSeanData curationInvestigationProject administrationSupervisionWriting – review & editing1MazibukoSikhatheleConceptualizationInvestigationProject administrationWriting – review & editing4http://orcid.org/0000-0003-1155-2735OkelloVelephiConceptualizationSupervisionWriting – review & editing4http://orcid.org/0000-0003-2028-4779EhrenkranzPeterConceptualizationSupervisionWriting – original draftWriting – review & editing5http://orcid.org/0000-0002-0180-1649SahaboRubenConceptualizationProject administrationSupervisionWriting – review & editing1http://orcid.org/0000-0003-3735-9781El-SadrWafaa M.ConceptualizationFunding acquisitionMethodologyProject administrationSupervisionValidationWriting – original draftWriting – review & editing131\nICAP at Columbia University, New York, New York, United States of America2\nDepartment of Medicine, Weill Cornell Medical College, New York, New York, United States of America3\nDepartment of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, United States of America4\nMinistry of Health, Kingdom of Swaziland, Mbabane, Swaziland5\nBill and Melinda Gates Foundation, Seattle, Washington, United States of AmericaDeeksSteven G.Academic EditorSan Francisco General Hospital, UNITED STATESThe authors have declared that no competing interests exists.* E-mail: mm3780@columbia.edu71120171120171411e100242012620172992017© 2017 McNairy et al2017McNairy et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.BackgroundGaps in the HIV care continuum contribute to poor health outcomes and increase HIV transmission. A combination of interventions targeting multiple steps in the continuum is needed to achieve the full beneficial impact of HIV treatment.Methods and findingsLink4Health, a cluster-randomized controlled trial, evaluated the effectiveness of a combination intervention strategy (CIS) versus the standard of care (SOC) on the primary outcome of linkage to care within 1 month plus retention in care at 12 months after HIV-positive testing. Ten clusters of HIV clinics in Swaziland were randomized 1:1 to CIS versus SOC. The CIS included point-of-care CD4+ testing at the time of an HIV-positive test, accelerated antiretroviral therapy (ART) initiation for treatment-eligible participants, mobile phone appointment reminders, health educational packages, and noncash financial incentives. Secondary outcomes included each component of the primary outcome, mean time to linkage, assessment for ART eligibility, ART initiation and time to ART initiation, viral suppression defined as HIV-1 RNA < 1,000 copies/mL at 12 months after HIV testing among patients on ART ≥6 months, and loss to follow-up and death at 12 months after HIV testing. A total of 2,197 adults aged ≥18 years, newly tested HIV positive, were enrolled from 19 August 2013 to 21 November 2014 (1,096 CIS arm; 1,101 SOC arm) and followed for 12 months. The median participant age was 31 years (IQR 26–39), and 59% were women. In an intention-to-treat analysis, 64% (705/1,096) of participants at the CIS sites achieved the primary outcome versus 43% (477/1,101) at the SOC sites (adjusted relative risk [RR] 1.52, 95% CI 1.19–1.96, p = 0.002). Participants in the CIS arm versus the SOC arm had the following secondary outcomes: linkage to care regardless of retention at 12 months (RR 1.08, 95% CI 0.97–1.21, p = 0.13), mean time to linkage (2.5 days versus 7.5 days, p = 0.189), retention in care at 12 months regardless of time to linkage (RR 1.48, 95% CI 1.18–1.86, p = 0.002), assessment for ART eligibility (RR 1.20, 95% CI 1.07–1.34, p = 0.004), ART initiation (RR 1.16, 95% CI 0.96–1.40, p = 0.12), mean time to ART initiation from time of HIV testing (7 days versus 14 days, p < 0.001), viral suppression among those on ART for ≥6 months (RR 0.97, 95% CI 0.88–1.07, p = 0.55), loss to follow-up at 12 months after HIV testing (RR 0.56, 95% CI 0.40–0.79, p = 0.002), and death (N = 78) within 12 months of HIV testing (RR 0.80, 95% CI 0.46–1.35, p = 0.41). Limitations of this study include a small number of clusters and the inability to evaluate the incremental effectiveness of individual components of the combination strategy.ConclusionsA combination strategy inclusive of 5 evidence-based interventions aimed at multiple steps in the HIV care continuum was associated with significant increase in linkage to care plus 12-month retention. This strategy offers promise of enhanced outcomes for HIV-positive patients.Trial registrationClinicalTrials.gov NCT01904994.In a cluster-randomized trial done in Swaziland, Margaret McNairy and colleagues test a combined intervention for linking and retaining adults with HIV infection in care.Author summaryWhy was this study done?Linkage to care, retention in care, and achievement of viral load suppression on antiretroviral therapy (ART) among HIV-positive adults are necessary in order to achieve optimal health outcomes in terms of reduced morbidity and mortality and to decrease the risk of HIV transmission to others.Barriers to linkage to and retention in care are multifactorial and include both individual- and health system-level factors.We hypothesized that a multicomponent strategy using a combination of evidence-based interventions was needed to address the multiple gaps in linkage to and retention in care across the HIV care continuum.What did the researchers do and find?Ten clusters of affiliated HIV clinics in Swaziland were randomized to receive the standard of care (SOC; 1,101 participants) or a combination intervention strategy (CIS; 1,096 participants). The CIS included provision of participants with point-of-care CD4+ count testing at time of HIV testing, accelerated ART initiation among eligible patients, mobile phone appointment reminders, health educational packages, and noncash financial incentives.Participants were followed for 12 months from the time of testing HIV positive, and the primary study outcome was prompt linkage to care within 1 month of testing HIV-positive plus retention in care at 12 months after testing HIV positive. Secondary outcomes included additional steps in the HIV care continuum.We found that participants receiving care at HIV clinics randomized to the CIS study arm, as compared to the SOC study arm, were significantly more likely to achieve the primary outcome of prompt linkage to care plus 12-month retention (64% in the CIS arm versus 43% in the SOC arm, relative risk [RR] 1.52, 95% CI 1.19–1.96, p = 0.002).We also found that participants at CIS sites versus SOC sites had faster linkage to care, were more likely to be assessed for ART initiation, and had faster time to ART start. However, we did not find significant differences in viral suppression or mortality at 12-months after testing HIV positive.What do these findings mean?The Link4Health study showed that a CIS was 50% more effective than the SOC on prompt linkage to HIV care plus 12-month retention after HIV-testing and that the effect appeared to be primarily driven by enhanced retention in care.Limitations of this study include a small number of clusters and the inability to evaluate the contribution of each of the components of the strategy to the effect noted.The combination strategy used in this study could be easily adapted to other resource-limited settings and may be relevant to the challenges faced in engaging HIV-positive vulnerable and key populations.http://dx.doi.org/10.13039/100006492Division of Intramural Research, National Institute of Allergy and Infectious DiseasesRO1A1100059http://orcid.org/0000-0003-3735-9781El-SadrWafaa M.Gates FoundationOPP1145477http://orcid.org/0000-0001-7853-633XMcNairyMargaret L.This study was funded by the National Institutes of Health (NIH), NIH Award Number: RO1A1100059, and the Gates Foundation OPP1145477. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Data AvailabilityData are from the Link4Health study, which may be contacted at icap-partnerships@columbia.edu. Deidentified data are uploaded as S1 Table.Data AvailabilityData are from the Link4Health study, which may be contacted at icap-partnerships@columbia.edu. Deidentified data are uploaded as S1 Table.IntroductionAchieving the desired impact of HIV treatment, as measured by individual health outcomes and reduced transmission to others, is contingent upon completing all steps in the HIV care continuum, from identifying all individuals who are living with HIV and linking those found to be HIV positive to HIV care to retaining them in lifelong care and on antiretroviral therapy (ART) [1]. Over the past decade, the scale-up of HIV programs has been substantial, with over 18 million persons having initiated ART by the end of 2015 in low- and middle-income countries and an associated substantial decrease in HIV-related morbidity and mortality, as well as evidence of a decrease in HIV incidence in many of the most severely affected countries [2]. However, in order to achieve epidemic control, further optimization of the HIV care continuum is needed so as to achieve the Joint United Nations Programme on HIV/AIDS (UNAIDS) 90/90/90 targets, which require that 90% of individuals with HIV are aware of their diagnosis, that 90% of those aware of their HIV infection are initiated on ART, and that 90% of those on treatment achieve and maintain viral suppression [3].Findings from HIV programs indicate that linkage to and retention in HIV care currently fall far short of the desired goals [4–6]. Linkage of HIV-positive individuals to HIV care varies from less than half of individuals linking to care within 6 months of an HIV-positive test to 72% who ever linked [5,7,8]. Once linked to care, less than half of HIV-positive patients are retained in care prior to initiation of ART, with only two-thirds of ART-eligible individuals initiating ART [5,7]. Lastly, only approximately three-quarters of patients initiated on ART have been noted to be retained in care at 12 months, with retention decreasing over the ensuing follow-up years [4].Barriers to linkage to and retention in care are multifactorial and include both individual- and health system-level factors such as stigma, fear of disclosure, distance and cost of travel to clinic, attitudes of providers, and cumbersome clinic procedures with long waiting times [9,10]. Previous studies that aimed to overcome such barriers have largely focused on the assessment of 1 intervention primarily targeting a single step in the HIV care continuum [11–14]. We postulated that in order to address the multiple gaps across the care continuum, a multi-component intervention strategy is needed, with each component targeting one or more steps in the HIV care continuum.The Link4Health study evaluated the effectiveness of a combination intervention strategy (CIS) utilizing 5 evidence-based interventions that address structural, behavioral, and biomedical barriers across the continuum of care, to improve linkage to and retention in care among newly identified HIV-positive adults in Swaziland.MethodsEthicsThe study was approved by the institutional review boards at Columbia University and the Swaziland Scientific and Ethics Committee.Study designA detailed description of the study methods was previously reported [15]. In brief, Link4Health was an implementation science study using a cluster site-randomized trial design. The study unit of randomization consisted of a public secondary-level HIV clinic paired with its largest affiliated public primary-level HIV clinic. Ten study units were selected from a total of 11 existing secondary-level HIV clinics in the country, based on clinic patient volume. Study units were pair matched, first by implementing partner (matching the 2 study units from implementing partner A) and then by location (urban [4] versus rural [4]) and clinic size, based on the estimated number of adults testing HIV positive in the 2 years prior to study implementation (<50 versus >50 per month for rural study units and <100 versus >100 per month for urban study units). Matched study units were randomized by a computerized random number generator to the CIS or standard of care (SOC) study arm. A cluster design was chosen to avoid disruption of service delivery, enable better fit within the routine workings at the clinical site, and allow the clinic staff to more easily implement the study. The study staff and clinic providers at each study unit were not blinded to the assigned arm for the site.Study setting and populationSwaziland is located in Southern Africa and has the world’s highest HIV prevalence, with HIV as the leading cause of death in the country [16]. The estimated adult (age 18–49 years) HIV prevalence is 31%, and the estimated incidence is 2.4% (95% CI 2.1–2.8) [17, 18]. The country has made impressive strides in responding to the epidemic, with nearly 70% of persons estimated to be living with HIV having initiated ART as of 2015 [19]. Nevertheless, historic rates of linkage to and retention in care at 12 months after ART initiation remain suboptimal [20]. Data available from Swaziland at the time of the initiation of the study showed that among 1,105 adults who tested HIV positive at community testing venues, only 37% linked to HIV care within 12 months of HIV testing [21]. Retention among adults at 36 months after ART start was 68% in 2011 per national estimates [22].Inclusion criteria were as follows: adults aged ≥18 years, newly tested HIV positive, and willing to receive HIV care at the study unit and consent to study procedures. Exclusion criteria were as follows: planning on leaving the community during the study, prior enrollment in HIV care or initiation of ART in the past 6 months, currently on ART, reports a current pregnancy, or not able to speak English or SiSwati.Study interventionsAll adults who tested HIV positive at participating sites were informed of the study by their providers. Interested individuals were referred to a study nurse who provided further information, confirmed eligibility, and, if eligible, obtained written consent. All consenting participants provided baseline information and thereafter were managed based on the study arm to which the clinic was randomly assigned.SOCParticipants at study units randomized to the SOC arm were managed according to country guidelines. These guidelines recommend that individuals identified as HIV positive receive post-test counseling and be referred to an HIV clinic using a national referral form [21]. Thereafter, upon presentation at their first HIV clinic visit, such individuals are to present their referral form, receive a clinical assessment, and have blood drawn for a CD4+ count test as well as hematology and chemistry tests and are instructed to return in 1–2 weeks for receipt of their results. Upon return, those eligible for ART according to then prevailing national guidelines (i.e., with a CD4+ count ≤ 350 cells/mm3) are to receive the first of 3 counseling sessions. Patients who are prescribed ART are instructed to return to the clinic every month for 6 months and then every 3 months, if they are stable on treatment. Patients who are ineligible for ART are instructed to return to clinic every 3 months for follow-up. Peer counselors are encouraged to call patients within 7 days of a missed clinic appointment. All patients are prescribed cotrimoxazole prophylaxis, and condoms, and health informational materials are to be made available in the clinics.CISParticipants at clinics randomized to the CIS arm received a multicomponent strategy of 5 evidence-based interventions, targeting structural, biomedical, and behavioral barriers, which are described briefly below (Table 1) [15]. All components of the combination strategy utilized in this study were selected based on evidence of their effectiveness, feasibility, and suitability to patients in diverse healthcare settings.10.1371/journal.pmed.1002420.t001Table 1Comparison of combination intervention strategy (CIS) to standard of care (SOC) procedures.InterventionStandard of care (SOC)Combination intervention strategy (CIS)Type of interventionStep targeted in HIV care continuumPoint-of-care CD4+ count testing• Point-of-care CD4 assays available in some primary care clinics and some secondary health centers/hospitals for patients enrolled in HIV care but not at the HIV testing site• CD4+ count (Cyflow and FACS Caliber) after linkage to HIV care in the clinic or lab• Turnaround time approximately 2 weeks• Point-of-care CD4 assays at the HIV testing site at the time of HIV testing• Turnaround time immediateStructural and biomedicalLinkage, ART eligibility assessment, and ART initiationAccelerated ART initiationART initiation per national guidelines for patients with CD4+ count ≤ 350 cells/mm3 or WHO Stage III/VI• Requires 3 counseling sessions and receipt of baseline lab tests• Initiation 2 weeks to 1 month from determination of ART eligibility• Accelerated ART initiation for patients with point-of-care CD4+ count ≤ 350 cells/mm3 within 1 week from testing• Two counseling sessions (1 at the time of HIV testing and the other at the first HIV clinic visit) and collection of blood for other baseline lab tests• Initiation of ART for eligible patients prior to return of results with use of a checklistStructural and biomedicalART initiation and retentionCellular phone visit reminders• Telephone call within 7 days of missed visit for ART patients only• SMS (or voice if illiterate) visit reminders 3 days prior to each scheduled visit• SMS (or voice if illiterate) reminder within 7 days after a missed visit for all patientsBehavioralLinkage and retentionHealth education packages• Cotrimoxazole was prescribed for all patients once enrolled in HIV care• Condoms available• A health education package was provided approximately every 3 months at visits. Packages included condoms, soap, cotrimoxazole, a pill box, and pictorial education about use of materials and HIVBiomedical and behavioralRetentionNoncash financial incentive• None• Noncash financial incentive (mobile airtime) were provided for those linked to care within 1 month of testing and completion of 6- and 12-month visitsStructuralLinkage and retentionAbbreviations: ART, antiretroviral therapy; SMS, short message service.The first intervention was provision of point-of-care (POC) CD4+ count testing performed immediately after an HIV-positive test, in the same physical location as the HIV testing site, with the aim of improving linkage to care, assessment for ART eligibility, and prompt ART initiation. Several studies have reported higher linkage and ART initiation rates with POC CD4+ count testing as compared to traditional CD4+ count testing [23–26].The second intervention of accelerated ART initiation for eligible patients (CD4+ count ≤ 350 cells/mm3 or WHO stage III/IV) involved 2 rather than 3 counseling sessions and recommended ART initiation within the first week after linkage to care. Delays in ART initiation among those eligible for treatment have been shown to be associated with increased morbidity and mortality [27]. Late ART initiation is also associated with a longer period of increased infectiousness due to ongoing viral replication [28]. In this study, initiation of ART promptly rather than waiting for the return of baseline safety laboratory test results was strongly encouraged, and a checklist was made available to the providers to assist in identifying those potential participants at risk for renal insufficiency who would require waiting for the serum creatinine results prior to ART initiation.The third intervention involved use of short-message-service (SMS) appointment reminders, sent from a central server, which aimed at improving linkage to and retention in care among participants. SMS reminders were sent 3 days prior to an appointment and after a missed appointment. The message did not contain any information relating to HIV status. SMS communications have been used in HIV care and other chronic disease management to improve health communication and patient adherence [29–37].The fourth intervention was a health education package that included health information and supplies such as soap, a toothbrush, and a pill box, which also aimed to improve both linkage to and retention in care. A package of different materials and information was given every 3 months. A similar intervention has been evaluated in Uganda and was associated with high rates of cotrimoxazole use, condom use, and HIV testing of family members [38].Lastly, financial incentives of modest amount were provided that served to reimburse participants for expenses or lost wages or transport costs for clinic attendance [39]. This intervention was selected because there has been great interest in the use of financial incentives as a structural intervention to achieve positive health behaviors including retention in care [39–45]. A noncash type of financial incentive was provided in the form of a prepaid mobile phone card valued at US$8 and was given to participants upon linkage to care within 1 month of HIV testing and at completion of 6 and 12 months in follow-up care.Data collection and study measuresAll participants completed a baseline questionnaire, at the time of study enrollment, which solicited information on sociodemographic characteristics, HIV disease history, barriers to care, travel time to clinic, depression, social and family support, and HIV-related knowledge. Follow-up questionnaires were conducted at 1 and 12 months after enrollment, at the participant’s home or a prespecified location in the community, to collect information on changes in sociodemographic characteristics, self-reported linkage to care and retention, preferences about the study interventions, and vital status, if the latter was not known. Clinical data including CD4+ count, WHO Stage, date of ART initiation, ART regimen, and clinic and pharmacy visit dates were abstracted from participants’ medical charts—the data source for the primary outcome. These data were collected between 3–6 months after the participant reached the end of the study follow-up period. If the participant’s medical record was missing, he/she was assumed to have not achieved the primary outcome. Death was ascertained via medical record reviews or at the time of the 1- or 12-month interview. Viral load measurement was done using dried blood samples (DBSs) (HIV-1 RNA Abbott m2000rt system) collected at the time of the 12-month questionnaire at the participant’s home or a prespecified location [46].Study outcomesThe primary outcome was a combined outcome of linkage to HIV care within 1 month of HIV testing plus retention in care at 12 months from HIV testing among participants at the individual level. Linkage to care was defined by participant attendance of at least 1 visit to an HIV clinic with completion of an intake assessment including medical history and physical exam. Retention in care at 12 months after HIV testing was defined as no documented death and a clinic visit at the study unit within 90 days prior to the end of the study follow-up period. Participants with a missing medical record at the time of medical record abstraction were considered nonretained.Secondary endpoints included evaluation of the effectiveness of the CIS compared to the SOC with regard to the following: each component of the primary outcome described above, time to linkage, ART eligibility, ART initiation, time to ART initiation, viral suppression defined as HIV-1 RNA < 1,000 copies/mL at 12 months among patients on ART for at least 6 months, and death and loss to follow-up at 12 months after HIV testing. Death and transfer status were ascertained from medical records and through the 12-month follow-up visit questionnaire. Linkage and retention at clinics other than the assigned study unit were assessed in a sensitivity analysis using self-reported linkage and retention data from the 1- and 12-month questionnaires.Statistical analysisThe study sample size was calculated by estimating that 35% of the participants in the SOC study arm would achieve the primary outcome (assuming that 50% link to HIV care within 1 month of testing and that 70% of those linking within 1 month are retained at 12 months after testing). We estimated that approximately 2,750 adults would be eligible for study enrollment based on historic HIV testing volume and the proportion of individuals testing HIV positive at the study units in the year prior to the study start. Assuming 80% of eligible individuals would consent to enrollment, we estimated an average enrollment of 220 participants per study unit or 2,200 in total (1,110 per study arm). With this sample size and 5 study units per study arm, we then estimated the minimum difference in the primary outcome we could detect with 80% power, 2-sided alpha of 0.05, assuming an interclass correlation coefficient (ICC) of 0.05. In a post hoc analysis, we estimated the ICC of the primary outcome using the method outlined by Snijders and Bosker for binary outcome data [47].An intent-to-treat analysis compared the relative risk (RR) of achieving the primary outcome between study arms, with each having 5 clusters per arm. Within study unit clustering was accounted for using random-intercept multilevel models. For dichotomous outcomes, log-Poisson models with robust standard error were used. For continuous outcomes, random-intercept linear regression models were used. Assessment of potential confounding despite cluster randomization was performed by constructing multivariable random-intercept regression models including covariates found statistically different between treatment arms at an alpha of 0.01. Additionally, we conducted a per-protocol analysis comparing the RR of achieving the primary outcome among participants who received the full package of the CIS for the duration of study participation. Sensitivity analysis assessed any changes to the intent-to-treat analysis after including self-reported linkage and retention obtained from follow-up surveys. In post hoc analyses, assessment of the RR for achieving the primary outcome by key subgroups was done using interaction contrast ratios.ResultsStudy populationOf the 10 study units included in this study, 6 were located in urban areas, and 4 in rural areas. At study units randomized to the CIS study arm, a total of 1,234 individuals were screened for eligibility, with 1,096 (89%) enrolled in the study from 19 August 2013 to 21 November 2014 (Fig 1). At study units assigned to the SOC study arm, a total of 1,316 were screened, with 1,101 (84%) enrolled. Study refusal differed by study arm, with 23 refusals (1.9%) in the CIS arm and 114 refusals (8.7%) in the SOC arm (p < 0.001). Reasons for ineligibility are shown in Fig 1, with 111 participants ineligible in the CIS arm compared to 101 in the SOC arm.10.1371/journal.pmed.1002420.g001Fig 1Flow diagram of study enrollment.ART, antiretroviral therapy; CIS, combination intervention strategy; SOC, standard of care; SU, study unit.Among 2,197 participants included in this analysis, 1,294 (59%) were female, and the median age was 31 years (IQR 26–39), with 445 (20%) of the participants being young adults aged 18–24 years (Table 2). Forty-five percent reported no education or only primary schooling; approximately half were unemployed. Median individual weekly income was US$9 (IQR US$0–US$37). Eighty-four percent reported living in the current residence for more than 1 year, with 16% reporting travel away from home for over a 1-month duration in the past year. The median travel time from residence to HIV clinic was 30 minutes (IQR 20–50). The majority (80%) were diagnosed with HIV through a voluntary counseling and testing site, with the remainder having received HIV testing through provider-initiated testing and counseling at clinics within the study units. Over half (54%) of the participants reported that this was their first HIV test, while 89% indicated that it was their first positive HIV test.10.1371/journal.pmed.1002420.t002Table 2Participant characteristics at HIV testing (N = 2,197).CharacteristicsCIS armSOC armTotal\xa0\xa0N%N%N%\xa01,096\xa01,101\xa02,197\xa0Female\xa065760%63758%1,29459%Age (years)Median (IQR)32 (26–40)30 (25–39)31 (26–39)18–2421019%23521%44520%25–3961256%60455%1,21655%40–4915814%16615%32415%>5011611%959%21110%Missing/refused\xa0\xa010%10%EducationNone/primary47844%51947%99745%Secondary or higher61756%58153%1,19855%Missing/refused10%10%20%Weekly incomeMedian (IQR)US$9 (US$0-US$37)US$14 (US$0-US$37)US$9 (US$0-US$37)Unemployed\xa062457%53148%1,15553%Married\xa040036%40837%80837%Number of living children020619%20719%41319%1 to 364559%68062%1,32560%>324322%21419%45721%Missing/refused20%00%20%Lives alone\xa011611%16015%27613%Away from home >1 month in past year\xa017916%17015%34916%Time at current residence1 year or less16415%19217%35616%Greater than 1 year93085%90682%1,83684%Missing/refused20%30%50%Travel time to clinicMedian (IQR) time minutes30 (20–45)30 (20–60)30 (20–50)<30 minutes69063%58453%1,27458%31–60 minutes33030%32329%65330%>60 minutes626%19117%25311%Missing/refused141%30%171%Currently on TB treatment\xa081%141%221%HIV testing siteVCT93785%82074%1,75780%PITC15915%28025%43920%Missing/refused00%10%10%First HIV test\xa064259%53949%1,18154%First positive HIV test\xa096788%97889%1,94589%Household member with HIV\xa042739%34832%77535%Alcohol consumption in the last 7 daysEvery day161%182%342%Some days23521%23421%46921%Never84577%84977%1,69477%Abbreviations: CIS, combination intervention strategy; PITC, provider-initiated testing and counselling; SOC, standard of care; TB, tuberculosis; VCT, voluntary HIV counselling and testing.Primary outcomeIn the intent-to-treat analysis, 705 (64%) participants at sites randomized to the CIS study arm and 477 (43%) participants at sites randomized to the SOC study arm achieved the primary outcome of linkage to HIV care within 1 month of HIV-positive testing plus retention in HIV care at 12 months after HIV testing, for an RR of 1.48 (95% CI 1.37–1.61, p < 0.001). Accounting for clustering within study units, the RR was 1.52 (95% CI 1.19–1.96, p = 0.002) (Fig 2, Table 3). Additionally, adjusting for covariates significant in the bivariate analyses listed in Table 2 did not appreciably change the results. A total of 64 (6%) of participants in the CIS arm and 144 (13%) of participants in the SOC arm did not have a medical record and were classified as “not linked” to HIV care.10.1371/journal.pmed.1002420.g002Fig 2Proportion of participants who achieved the primary outcome of linkage to HIV care within 1 month of HIV testing plus retention in HIV care at 12 months after HIV testing by study arm (combination intervention strategy [CIS] and standard of care [SOC]).10.1371/journal.pmed.1002420.t003Table 3Primary and secondary outcomes for the combination intervention strategy (CIS) and standard of care (SOC) study arms.CIS group (N = 1,096)SOC group (N = 1,101)Relative risk (RR)N%N%RR95% CIp-ValuePrimary outcomeIntention to treat70564%47743%1.48(1.37–1.61)<0.001Intention to treat accounting for clustering170564%47743%1.52(1.19–1.96)0.002Intention to treat accounting for clustering and differences in covariates1,370564%47743%1.50(1.12–1.99)0.009Per protocol1,267269%44743%1.68(1.32–2.15)<0.001Sensitivity analysis1,476169%55751%1.41(1.13–1.74)0.004Secondary outcomesLinkageLinked to care (ever)1103294%95787%1.08(0.97–1.21)0.13Mean (SD) time from HIV testing to linkage2.5 days (19.5)7.5 days (46.6)0.189ART eligibilityAssessed for ART eligibility11,096100%92084%1.20(1.07–1.34)0.004Became ART eligible183376%72165%1.18(1.01–1.37)0.038Mean (SD) time from HIV testing to ART eligibility assessment50 (0)6.3 (35.5)<0.001ART initiation*Initiated ART (ever)1*71065%63558%1.16(0.96–1.40)0.12Median (IQR) time from testing HIV positive to ART initiation among ART eligible, days67.0 (3.0–21.0)14.0 (7.0–31.0)<0.001Retention regardless of time to linkage and ART statusRetained 12 months after HIV testing172066%49845%1.48(1.18–1.86)0.002Viral suppressionViral suppression (HIV-1 RNA < 1,000 copies/ml) among participants on ART for ≥6 months (N = 477 CIS and N = 451 SOC)1,741988%40690%0.97(0.88–1.07)0.55Deaths within 12 months of HIV testingTotal deaths1353%434%0.80(0.46–1.35)0.41Death before ART initiation1101%232%0.44(0.19–1.01)0.05Death after ART initiation1252%202%1.18(0.57–2.47)0.63Transfers within 12 months of HIV testingTotal transfers1232%262%0.88(0.44–1.77)0.71Transfers before ART initiation171%192%0.37(0.16–0.85)0.02Transfers after ART initiation1161%71%2.10(0.72–6.18)0.16Lost to follow-up within 12 months of HIV testingTotal lost to follow-up131829%53449%0.56(0.40–0.79)0.002Lost to follow-up before ART initiation124022%35732%0.60(0.40–0.89)0.014Lost to follow-up after ART initiation1787%17716%0.51(0.31–0.85)0.0131 Accounting for within-study unit clustering using random intercept log-Poisson regression models with robust standard error.2 The per-protocol analysis compared all patients in the SOC arm to those in the CIS arm self-reporting receipt of all interventions: point-of-care (POC) CD4+ count, accelerated antiretroviral therapy (ART) initiation (if eligible), health education package, short message service (SMS), and financial incentives. A total of 937 of the 1,096 patients in the CIS arm were included. Patients were excluded for the following: missing PIMA (2), ART counseling session #1 (24), ART counseling session #2 (14), first health education package (7), second health education package (12), third health education package (4), fourth health education package (2), financial incentive for linkage to care (86), second financial incentive (8), or third financial incentive (4).3 Additionally adjusting for covariates significantly different between groups at an alpha of 0.1: employment status, number of children, whether the participant lives alone, HIV testing location, family member with HIV, travel time to clinic, and whether this was the participant’s first HIV test.4 The sensitivity analysis considers participants linked to HIV care or retained in HIV care if they are recorded as linked and retained in their medical records or if they self-reported linkage or retention in the 1- and/or 12-month study questionnaire.5 All participants in the SOC arm were assessed for ART eligibility at the time of testing HIV positive. Of the SOC participants, 920/1,101 (84%) were assessed at enrollment into HIV care or clinical follow-up.6 Time to ART initiation measured from date of HIV-positive test to ART initiation among those becoming ART eligible. The p-values are Wilcoxon tests of differences between medians.7 The proportion of viral load suppression (<1,000 copies/ml) among participants who were on ART for ≥6 months with available viral loads is reported in the table. Among all participants who were on ART for ≥6 months, 85% (419/493) in the CIS arm and 89% (406/458) in the SOC arm had viral suppression.* In the CIS arm, 85% of those ART eligible initiated ART. In the SOC arm, 88% of those eligible initiated ART.The RR in the per-protocol analysis accounting for clustering for achieving the primary outcome was 1.68 (95% CI 1.32–2.15, p = 0.003) (Table 3). The RR in the sensitivity analysis, accounting for clustering, which included participants who self-reported linkage and retention in the 1- and 12-month surveys at a clinic other than 1 with their assigned study unit, was 1.41 (95% CI 1.13–1.74, p = 0.004), respectively (Table 3). Using this approach, we calculated an ICC of 0.086, similar to but slightly higher than the assumed ICC used in power and sample size estimation.The CIS strategy was delivered according to the study protocol to 937 (85%) of the 1,096 participants enrolled in study units assigned to the CIS. Reasons for not receiving all of the CIS strategy intervention components included missing POC CD4+ count testing (<1% CIS participants), missing an ART counseling session per accelerated ART procedures (3%), missing receipt of 1 healthcare bag (2%), and missing receipt of 1 financial incentive (9%). There was heterogeneity in the primary outcome across the 5 pairs of matched study units. The proportion of participants who achieved the primary outcome in study units randomized to the CIS ranged from 49% to 82%, while this ranged from 22% to 57% in the study units randomized to SOC.Secondary outcomesA similar proportion of participants linked to care anytime during the study follow-up period in both study arms: 1,032 (94%) in the CIS arm as compared to 957 (87%) in the SOC arm (RR 1.08, 95% CI 0.97–1.21, p = 0.13), with no significant differences in linkage within the same day or 1 month after testing (Table 3). The mean time to linkage to care was shorter in the CIS arm versus the SOC study arm but was not statistically different (2.5 compared to 7.5 days, p = 0.189). However, among those who ever linked to care (1,032 in the CIS study arm and 957 in the SOC study arm), significantly fewer patients (13%) in CIS sites versus SOC sites (18%) did not return for subsequent visits after the first clinic visit (p = 0.008).Assessment for ART eligibility through either a CD4+ count or WHO staging was done for all participants in the CIS arm as compared to 84% of participants in the SOC arm (RR 1.20, 95% CI 1.07–1.34, p = 0.004). The mean time to ART eligibility assessment was 0 days in the CIS study arm compared to 6.3 days in the SOC arm (p < 0.001). The median CD4+ count among 1,096 participants in the CIS arm who had POC CD4+ count testing done at the time of HIV testing was 311 cells/mm3 (IQR 159–443). Among the 907 (82%) participants in the SOC arm who linked to HIV care and had a CD4+ count done, the median CD4 count was 285 cells/mm3 (155–444) (p = 0.07).A total of 710 participants (85% of ART-eligible participants) in the CIS arm as compared to 635 (88% among ART-eligible participants) in the SOC arm initiated ART within the study follow-up period (RR 1.16, 95% CI 0.96–1.40, p = 0.12) (Table 3). The median time from HIV testing to ART initiation among eligible patients was 7.0 days (IQR 3.0–21.0) as compared to 14.0 days (IQR 7.0–13.0) in the CIS and SOC study arms, respectively (p < 0.001).Retention in care, regardless of time to linkage or ART status, at 12 months was significantly greater in participants in the CIS as compared to the SOC study arm, with an RR of 1.48 (95% CI 1.18–1.86, p = 0.002). Loss to follow-up during pre-ART care (RR = 0.60, 95% CI 0.40–0.89, p = 0.014) and after ART initiation (RR = 0.51, 95% CI 0.31–0.85, p = 0.013) was significantly lower in the CIS arm as compared to the SOC arm.For participants on ART for at least 6 months during follow-up regardless of retention status, viral load data were available for 97% (N = 477/493) of participants in the CIS arm and 98% (N = 451/458) in the SOC arm. Viral suppression among participants on ART ≥6 months with available viral loads was similar by study arm at 88% in CIS and 90% in SOC (RR 0.97, 95% CI 0.88–1.07, p = 0.55).There were 78 deaths (3.6% of the study population) that occurred during follow-up, and this did not differ by study arm (35 deaths [3%] in the CIS study arm versus 43 deaths [4%] in the SOC arm, with an RR of 0.80, 95% CI 0.46–1.35, p = 0.40) (Table 3). However, there was nonsignificantly lower mortality among participants prior to ART initiation in the CIS arm (10 deaths) compared to the SOC arm (23 deaths), with an RR of 0.44 (95% CI 0.19–1.01, p = 0.05). Fig 3 compares the CIS study arm versus the SOC study arm across the HIV care continuum from linkage to care within 1 month of testing through retention in care at 12 months after testing HIV positive.10.1371/journal.pmed.1002420.g003Fig 3HIV care continuum comparing the combination intervention strategy (CIS) study arm versus the standard of care (SOC) study arm.In post hoc analyses, we examined achievement of the primary outcome between study arms by key subgroups. The effect of the CIS, as compared to the SOC, was consistent across all prespecified subgroups, including by age, sex, income, employment, marital status, travel away from home in the past year, travel time to clinic, past HIV testing history, household members with HIV, and type of clinic (Fig 4, S1 Table).10.1371/journal.pmed.1002420.g004Fig 4Primary outcome by subgroups of participants.USD, US dollars; yrs, years.DiscussionIn this cluster-randomized study, a novel combination strategy, inclusive of 5 evidence-based interventions, was 50% more effective than the SOC in enhancing linkage to care plus retention in care among HIV-positive individuals. The robustness of this outcome is supported by the consistent findings in the per-protocol analysis, in sensitivity analyses, and across subgroups of participants. In addition, the combination strategy was associated with improvements across multiple steps of the care continuum, with an increased proportion of participants who were assessed for ART eligibility, decreased time to ART eligibility assessment, decreased time to ART initiation, increased retention at 12 months after HIV testing regardless of time to linkage and ART status, and decreased mortality among participants prior to ART initiation. However, high rates of viral suppression were similar among ART patients by study arm.In our study, the effect noted on the primary outcome appeared to be largely driven by enhanced retention rather than by the linkage-to-care component. This finding may be due to the high proportion of participants in both study arms who linked to care within 1 month of HIV testing in both arms of the study (87% in the SOC arm and 92% in the CIS arm), and thus, our sample size was insufficient to show a difference between the arms. The high proportion of participant linkage was likely influenced by a national campaign to improve linkage that was implemented during the study period [21].The combination strategy significantly reduced loss to follow-up among participants regardless of whether they were in pre-ART care or on treatment. Loss to follow-up, in both study arms, was higher among pre-ART participants, as compared to participants who had initiated ART. This is consistent with findings from other studies, including those from a large study of 390,603 HIV-positive adults in Kenya, Mozambique, Rwanda, and Tanzania, in which 34.8% of all patients who had not initiated ART were lost from care at 12 months, compared to 5.8% among patients on ART [6]. While the pre-ART care phase should largely be minimized with the release of the recent WHO guidelines that recommend offering ART to all HIV-positive individuals irrespective of CD4+ count or WHO disease stage, evidence suggests that retention in care and on ART remains a challenge even in the context of “treatment for all” [48]. For example, while adoption of Option B+, which entails initiation of ART for all HIV-positive pregnant women, has been associated with an increase in the number of pregnant women on ART, loss to follow-up has remained a challenge. Among 21,939 HIV-infected pregnant women who started ART as per Option B+ in Malawi, 17% were lost to follow-up at 6 months after treatment start, with a 5-fold higher loss to follow-up compared to those who initiated ART at a more advanced stage of HIV disease [49]. Thus, the findings from our study remain relevant even though the study was conducted at a time when a CD4+ count threshold was recommended for ART initiation.In this study, viral suppression was high among all participants on ART for a minimum of 6 months, irrespective of study arm. This confirms the potency of the first-line regimen, consisting of tenofovir, lamivudine, and efavirenz or nevirapine, and suggests that participants were highly adherent to their medications. These findings build upon those from the Population-based HIV Impact Assessment Project surveys that were conducted recently in Malawi, Zambia, Zimbabwe, and Swaziland, which included nationally representative samples of individuals in which 87% of HIV-positive adults who reported being on ART were virally suppressed (HIV-1 RNA < 1,000 copies/ml) [50,51]. Findings from this project survey in Swaziland showed that among adults who were aware of their HIV-positive status and who indicated being on ART, 92% had a suppressed viral load [52]. The finding of similarly high proportions of viral suppression among participants in both arms of our study suggests that the sample size was insufficient to detect a difference. In addition, it is important to note that the interventions used in this study were not designed with a focus specifically on enhancing medication adherence and viral suppression. Design of future combination strategies may prioritize the use of interventions that focus specifically on enhancing adherence to ART, such as the use of financial incentives to improve viral suppression [53].Every effort was made to ascertain accurate loss to follow-up and mortality outcomes in our study. It should be noted that reporting of accurate loss to follow-up and mortality outcomes by HIV programs has been a controversial topic. This is due to the fact that when tracing was done for individuals reported as lost to follow-up by HIV programs, a substantial proportion were found to have either died or transferred care to another health facility [54]. We feel confident that it is unlikely that such misclassification occurred in our study as home tracing was conducted for all study participants to ascertain their outcomes at the end of the 12-month follow-up period. While the study was not powered to detect a difference between the study arms in terms of mortality, the combination strategy appeared to have a meaningful—albeit not statistically significant—effect, with as much as 50% lower mortality noted among pre-ART patients. This may be due to better retention in care among participants in the intervention arm. Poor retention in care has been demonstrated to be associated with increased mortality, likely due to missed clinic visits that deprive patients of clinical and laboratory assessments for diagnosis of early complications and delay prompt initiation of ART [55].We observed substantial heterogeneity in the primary outcome across clinics in both the CIS and SOC study arms. This may reflect clinic-level differences such as clinic size and location. For example, the CIS study unit with the lowest achievement of the study’s primary outcome was the largest clinic in urban Swaziland. It is possible that individuals who test HIV positive at such a large clinic may seek ongoing care at clinics closer to their homes. Other reasons could be differences in patient-level factors, such as sex, age, and immunological status, which warrant further analyses.To date, most intervention studies to address gaps in the HIV care continuum have focused on 1 step in the continuum, largely that of ART initiation. The Rapid Initiation of Treatment trial showed that single-visit ART initiation that included POC CD4+ count testing was associated with significantly higher ART initiation (97%) compared to the standard of care (72%) [56]. The START-ART trial was a stepped-wedge cluster-randomized trial of 20 clinics in Uganda that evaluated an intervention aimed at improving ART initiation among eligible patients; this intervention was associated with a higher proportion of patients initiating ART (80%) within 14 days after determination of ART eligibility compared to 38% in the control group [13]. Finally, the Same Day ART Initiation Study in Haiti, which evaluated the effect of same-day ART initiation on the day of HIV diagnosis among asymptomatic HIV-positive adults with CD4+ count ≤ 500 cells/uL and WHO stage I or II disease, noted that a higher proportion (53%) of participants randomized to same-day ART initiation were retained in care at 12 months with viral suppression compared to those in the standard of care arm (44%) [14].Our study had several strengths, including the use of a pragmatic approach consistent with implementation science design. Specifically, it utilized broad eligibility criteria, was conducted within established health facilities, tested feasible interventions that were delivered primarily by available staff rather than research staff, and assessed the primary outcome largely through routinely available data. In addition, the study included the majority of clinics in Swaziland and involved cluster-randomized design rather than randomization of individual participants, which allowed for ease of implementation and avoided disruption of services within the clinics. The study also uniquely assessed the effect of the delivery of multiple interventions packaged in 1 strategy aimed at multiple steps in the HIV care continuum. Thus, implementation of the study strategy has the potential to achieve not only prompt ART initiation but also better retention in care and on ART, consequently enhancing individual and society benefits from the “treat all” approach.The primary limitations of this study included a limited number of clusters, although it was inclusive of all the available clusters in the country. At the time of study initiation, there were only 11 secondary health facilities offering HIV services in Swaziland, and we selected 10 of these for participation in this study. Consequently, it is possible that the cluster randomization did not evenly distribute all determinants of linkage and retention other than the study interventions between treatment arms. While it is encouraging that analyses adjusting for individual-level differences between treatment arms did not appreciably change the results, we cannot definitively rule out residual confounding as a potential explanation of the findings. In addition, the design focused on evaluation of a package of interventions as 1 strategy and, thus, it did not allow for evaluation of the effectiveness of individual components of the combination approach. Another limitation was use of self-reported linkage and retention at other clinics to ascertain undocumented transfers to other clinics outside of the study unit.ConclusionsThe Link4Health study demonstrated that a combination strategy of evidence-based interventions, aimed at gaps in various steps of the HIV care continuum, was highly effective in enhancing linkage of HIV-positive individuals to care plus increasing their retention in care and on ART. The study also showed that once participants initiated ART, viral load suppression was high irrespective of the study arm. Cost effectiveness and qualitative analyses are ongoing in order to inform decision makers considering adoption of this strategy. Our findings offer an effective strategy that can advance the quality of HIV programs in Swaziland and that can be adapted to other similar contexts.Supporting informationS1 TextConsolidated Standards of Reporting Trials (CONSORT) statement.(DOCX)Click here for additional data file.S1 DataLink4Health deidentified dataset.(XLSX)Click here for additional data file.S1 TablePrimary outcome by prespecified participant subgroup.(DOCX)Click here for additional data file.AbbreviationsARTantiretroviral therapyCIScombination intervention strategyCONSORTConsolidated Standards of Reporting TrialsDBSdried blood sampleICCinterclass correlation coefficientPITCprovider-initiated testing and counsellingPOCpoint of careRRrelative riskSMSshort message serviceSOCstandard of careSUstudy unitTBtuberculosisUNAIDSJoint United Nations Programme on HIV/AIDSVCTvoluntary HIV counselling and testingReferences1McNairyML, El-SadrWM. The HIV care continuum: no partial credit given. 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J Acquir Immune Defic Syndr. 2011;58(3):e54–9. doi: 10.1097/QAI.0b013e3182303921 .2185735626LarsonBA, SchnippelK, NdibongoB, XuluT, BrennanA, LongL, et al\nRapid point-of-care CD4 testing at mobile HIV testing sites to increase linkage to care: an evaluation of a pilot program in South Africa. J Acquir Immune Defic Syndr. 2012;61(2):e13–7. doi: 10.1097/QAI.0b013e31825eec60 ; PubMed Central PMCID: PMC3458178.2265965027LahuertaM, UeF, HoffmanS, ElulB, KulkarniSG, WuY, et al\nThe problem of late ART initiation in Sub-Saharan Africa: a transient aspect of scale-up or a long-term phenomenon?\nJ Health Care Poor Underserved. 2013;24(1):359–83. doi: 10.1353/hpu.2013.0014 ; PubMed Central PMCID: PMC3655523.2337773928CohenMS, ChenYQ, McCauleyM, GambleT, HosseinipourMC, KumarasamyN, et al\nPrevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365(6):493–505. Epub 2011/07/20. doi: 10.1056/NEJMoa1105243 ; PubMed Central PMCID: PMC3200068.2176710329ChangL, KagaayiJ, NakigoziG, PackerAH, SerwaddaD, QuinnTC, et al\nResponding to the human resource crisis: peer health workers, mobile phones, and HIV care in Rakai, Uganda. AIDS Patient Care STDS. 2008;22(3):173–4. doi: 10.1089/apc.2007.0234 PubMed Central PMCID 2674572 1829075030DownerSR, MearJG, Da CostaAC, SethuramanK. SMS text messaging improves outpatient attendance. Aust Health Rev. 8\n2006;30(3):389–96. .1687909831FjeldsoeBS, MarshallAL, MillerYD. Behavior change interventions delivered by mobile telephone short-message service. Am J Prev Med. 2\n2009;36(2):165–73. doi: 10.1016/j.amepre.2008.09.040 .1913590732HabererJE, KiwanukaJ, NanseraD, WilsonIB, BangsbergDR. Challenges in using mobile phones for collection of antiretroviral therapy adherence data in a resource-limited setting. AIDS Behav. Dec\n2010;14(6):1294–301. doi: 10.1007/s10461-010-9720-1 .2053260533LesterRT, RitvoP, MillsEJ, KaririA, KaranjaS, ChungMH, et al\nEffects of a mobile phone short message service on antiretroviral treatment adherence in Kenya (WelTel Kenya1): a randomised trial. Lancet. 11\n27\n2010;376(9755):1838–45. doi: 10.1016/S0140-6736(10)61997-6 .2107107434LiewSM, TongSF, LeeVK, NgCJ, LeongKC, TengCL. Text messaging reminders to reduce non-attendance in chronic disease follow-up: a clinical trial. Br J Gen Pract. 12\n2009;59(569):916–20. doi: 10.3399/bjgp09X472250 .1971254435Mukund BahadurKC, MurrayPJ. Cell phone short messaging service (SMS) for HIV/AIDS in South Africa: a literature review. Stud Health Technol Inform. 2010;160(Pt 1):530–5. .2084174336Pop-ElechesC, ThirumurthyH, HabyarimanaJP, ZivinJG, GoldsteinMP, de WalqueD, et al\nMobile phone technologies improve adherence to antiretroviral treatment in a resource-limited setting: a randomized controlled trial of text message reminders. AIDS. Mar 27\n2011;25(6):825–34. doi: 10.1097/QAD.0b013e32834380c1 .2125263237ShetA, de CostaA. India calling: harnessing the promise of mobile phones for HIV healthcare. Trop Med Int Health. 2011;16(2):214–6. doi: 10.1111/j.1365-3156.2010.02678.x .2137121438ColindresP, MerminJ, EzatiE, KambabaziS, BuyungoP, SekabembeL, et al\nUtilization of a basic care and prevention package by HIV-infected persons in Uganda. AIDS Care. 2008;20(2):139–45. Epub 2007/09/27. doi: 10.1080/09540120701506804 .1789619639GiuffridaA, TorgersonDJ. Should we pay the patient? Review of financial incentives to enhance patient compliance. BMJ. 1997;315(7110):703–7. Epub 1997/10/07. ; PubMed Central PMCID: PMC2127496.931475440VolppKG, JohnLK, TroxelAB, NortonL, FassbenderJ, LoewensteinG. Financial incentive-based approaches for weight loss: a randomized trial. JAMA. 2008;300(22):2631–7. Epub 2008/12/11. doi: 10.1001/jama.2008.804 .1906638341VolppKG, LoewensteinG, TroxelAB, DoshiJ, PriceM, LaskinM, et al\nA test of financial incentives to improve warfarin adherence. BMC Health Serv Res. 2008;8:272 Epub 2008/12/24. doi: 10.1186/1472-6963-8-272 ; PubMed Central PMCID: PMC2635367.1910278442VolppKG, TroxelAB, PaulyMV, GlickHA, PuigA, AschDA, et al\nA randomized, controlled trial of financial incentives for smoking cessation. N Engl J Med. 2009;360(7):699–709. Epub 2009/02/14. doi: 10.1056/NEJMsa0806819 .1921368343CharnessG, GneezyU. Incentives to exercise. Econometrica. 2009;77(3):909–31.44MarcusAC, KaplanCP, CraneLA, BerekJS, BernsteinG, GunningJE, et al\nReducing loss-to-follow-up among women with abnormal Pap smears. Results from a randomized trial testing an intensive follow-up protocol and economic incentives. Med Care. 1998;36(3):397–410. Epub 1998/04/01. .952096345MalotteCK, RhodesF, MaisKE. Tuberculosis screening and compliance with return for skin test reading among active drug users. Am J Public Health. 1998;88(5):792–6. Epub 1998/05/20. ; PubMed Central PMCID: PMC1508952.958574746WHO. Technical and Operational Considerations for Implementing HIV Viral Load Testing. Geneva: WHO, 2014.47SnijdersTA, BoskerRJ. Multilevel analysis: An introduction to basic and advanced mulitlevel modeling. Thousand Oaks, California: Sage; 1999.48WHO. Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV. Geneva: WHO, 2015 9\n2015.49TenthaniL, HaasAD, TweyaH, JahnA, van OosterhoutJJ, ChimbwandiraF, et al\nRetention in care under universal antiretroviral therapy for HIV-infected pregnant and breastfeeding women ('Option B+') in Malawi. AIDS. 2014;28(4):589–98. doi: 10.1097/QAD.0000000000000143 ; PubMed Central PMCID: PMC4009400.2446899950Columbia University. The Population HIV Impact Assessment (PHIA) Project. Accessed May 31 2017 at: www.phia.icap.columbia.edu.51Justman J. Real Progress in the HIV Epidemic: PHIA Findings from Zimbabwe, Malawi, and Zambia. Oral Abstract. Conference of Retroviruses and Opportunistic Infections February 13–15, 2017; Seattle, WA2017.52Nkambule R, Nuwagaba-Biribownwoha H, Mnisi Z, Ao T, Duong Y, Patel H, et al. Substantial progress in confronting the HIV epidemic in Swaziland: first evidence of national impact. Abstract 204LB. International AIDS Society 2017; July 24, 2017; Paris, France 2017.53El-SadrWM, DonnellD, BeauchampG, HallHI, TorianLV, ZingmanB, et al\nFinancial Incentives for Linkage to Care and Viral Suppression Among HIV-Positive Patients: A Randomized Clinical Trial (HPTN 065). JAMA. 2017;177(8):1083–92. doi: 10.1001/jamainternmed.2017.2158 .2862870254GengEH, GliddenDV, BwanaMB, MusinguziN, EmenyonuN, MuyindikeW, et al\nRetention in care and connection to care among HIV-infected patients on antiretroviral therapy in Africa: estimation via a sampling-based approach. PLoS ONE. 2011;6(7):e21797\ndoi: 10.1371/journal.pone.0021797 ; PubMed Central PMCID: PMC3144217.2181826555GiordanoTP, GiffordAL, WhiteACJr., Suarez-AlmazorME, RabeneckL, HartmanC, et al\nRetention in care: a challenge to survival with HIV infection. Clin Infect Dis. 2007;44(11):1493–9. Epub 2007/05/08. doi: 10.1086/516778 .1747994856RosenS, MaskewM, FoxMP, NyoniC, MongwenyanaC, MaleteG, et al\nInitiating Antiretroviral Therapy for HIV at a Patient's First Clinic Visit: The RapIT Randomized Controlled Trial. PLoS Med. 2016;13(5):e1002015\ndoi: 10.1371/journal.pmed.1002015 .27163694", 'title': 'Effectiveness of a combination strategy for linkage and retention in adult HIV care in Swaziland: The Link4Health cluster randomized trial.', 'date': '2017-11-08'}, '28542080': {'article_id': '28542080', 'content': 'Lack of accessible laboratory infrastructure limits HIV antiretroviral therapy (ART) initiation, monitoring, and retention in many resource-limited settings. Point-of-care testing (POCT) is advocated as a mechanism to overcome these limitations. We executed a pragmatic, prospective, randomized, controlled trial comparing the impact of POCT vs. standard of care (SOC) on treatment initiation and retention in care.\nSelected POC technologies were embedded at 3 primary health clinics in South Africa. Confirmed HIV-positive participants were randomized to either SOC or POC: SOC participants were venesected and specimens referred to the laboratory with patient follow-up as per algorithm (∼3 visits); POC participants had phlebotomy and POCT immediately on-site using Pima CD4 to assess ART eligibility followed by hematology, chemistry, and tuberculosis screening with the goal of receiving same-day adherence counseling and treatment initiation. Participant outcomes measured at recruitment 6 and 12 months after initiation.\nFour hundred thirty-two of 717 treatment eligible participants enrolled between May 2012 and September 2013: 198 (56.7%) SOC; 234 (63.6%) POC. Mean age was 37.4 years; 60.5% were female. Significantly more participants were initiated using POC [adjusted prevalence ratio (aPR) 0.83; 95% confidence interval (CI): 0.74 to 0.93; P < 0.0001], the median time to initiation was 1 day for POC and 26.5 days for SOC. The proportion of patients in care and on ART was similar for both arms at 6 months (47 vs. 50%) (aPR 0.96; 95% CI: 0.79 to 1.16) and 12 months (32 vs. 32%) (aPR 1.05; 95% CI: 0.80 to 1.38), with similar mortality rates. Loss to follow-up at 12 months was higher for POC (36% vs. 51%) (aPR 0.82; 95% CI: 0.65 to 1.04).\nAdoption of POCT accelerated ART initiation but once on treatment, there was unexpectedly higher loss to follow-up on POC and no improvement in outcomes at 12 months over SOC.', 'title': 'Multidisciplinary Point-of-Care Testing in South African Primary Health Care Clinics Accelerates HIV ART Initiation but Does Not Alter Retention in Care.', 'date': '2017-05-26'}}
| 0.142857
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Public Health, Epidemiology & Health Systems
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20
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Is retention in care at 12 months higher, lower, or the same when comparing rapid ART to standard initiation?
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higher
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low
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yes
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['28742880', '29509839', '27163694', '29136001', '29112963', '28542080']
| 31,206,168
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{'28742880': {'article_id': '28742880', 'content': 'PLoS MedPLoS MedplosplosmedPLoS Medicine1549-12771549-1676Public Library of ScienceSan Francisco, CA USA28742880552652610.1371/journal.pmed.1002357PMEDICINE-D-17-00266Research ArticleBiology and Life SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesPublic and Occupational HealthPreventive MedicineVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesImmunodeficiency VirusesHIVBiology and 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acquisitionInvestigationMethodologySupervisionWriting – original draftWriting – review & editing12*DorvilNancyInvestigationMethodologyProject administrationSupervisionWriting – review & editing1DévieuxJessy G.ConceptualizationFunding acquisitionInvestigationMethodologySupervisionWriting – original draftWriting – review & editing3http://orcid.org/0000-0002-9689-5413Hedt-GauthierBethany L.ConceptualizationFormal analysisFunding acquisitionMethodologySoftwareSupervisionValidationVisualizationWriting – review & editing4RiviereCynthiaInvestigationMethodologyProject administrationSupervisionWriting – review & editing1FaustinMikerlyneInvestigationMethodologyProject administrationSupervisionWriting – review & editing1LavoileKerlyneInvestigationMethodologyProject administrationSupervisionWriting – review & editing1PerodinChristianFormal analysisInvestigationMethodologySoftwareValidationVisualizationWriting – review & editing1ApollonAlexandraConceptualizationInvestigationMethodologyProject administrationSupervisionWriting – review & editing1DuvergerLimatheInvestigationMethodologyProject administrationSupervisionWriting – review & editing1McNairyMargaret L.MethodologyWriting – review & editing56HennesseyKelly A.Formal analysisMethodologySoftwareValidationVisualizationWriting – review & editing1SouroutzidisAriadneFormal analysisMethodologySoftwareValidationVisualizationWriting – review & editing7CremieuxPierre-YvesFormal analysisMethodologySoftwareValidationVisualizationWriting – review & editing7SeverePatriceConceptualizationFunding acquisitionInvestigationMethodologyProject administrationSupervisionWriting – review & editing1PapeJean W.ConceptualizationFunding acquisitionInvestigationMethodologyProject administrationSupervisionWriting – review & editing151\nHaitian Study Group for Kaposi’s Sarcoma and Opportunistic Infections (GHESKIO), Port-au-Prince, Haiti2\nDivision of Global Health Equity, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America3\nAIDS Prevention Program, Florida International University, Miami, Florida, United States of America4\nDepartment of Global Health and Social Medicine, Harvard Medical School, Harvard University, Boston, Massachusetts, United States of America5\nCenter for Global Health, Department of Medicine, Weill Cornell Medical College, Cornell University, New York, New York, United States of America6\nDivision of General Internal Medicine, Department of Medicine, Weill Cornell Medical College, Cornell University, New York, New York, United States of America7\nAnalysis Group, Boston, Massachusetts, United States of AmericaGengElvin H.Academic EditorUniversity of California, San Francisco, UNITED STATESThe authors have declared that no competing interests exist.* E-mail: skoenig@bwh.harvard.edu257201772017147e100235724120171662017© 2017 Koenig et al2017Koenig et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThe science of rapid start—From the when to the how of antiretroviral initiation\nBackgroundAttrition during the period from HIV testing to antiretroviral therapy (ART) initiation is high worldwide. We assessed whether same-day HIV testing and ART initiation improves retention and virologic suppression.Methods and findingsWe conducted an unblinded, randomized trial of standard ART initiation versus same-day HIV testing and ART initiation among eligible adults ≥18 years old with World Health Organization Stage 1 or 2 disease and CD4 count ≤500 cells/mm3. The study was conducted among outpatients at the Haitian Group for the Study of Kaposi’s Sarcoma and Opportunistic infections (GHESKIO) Clinic in Port-au-Prince, Haiti. Participants were randomly assigned (1:1) to standard ART initiation or same-day HIV testing and ART initiation. The standard group initiated ART 3 weeks after HIV testing, and the same-day group initiated ART on the day of testing. The primary study endpoint was retention in care 12 months after HIV testing with HIV-1 RNA <50 copies/ml. We assessed the impact of treatment arm with a modified intention-to-treat analysis, using multivariable logistic regression controlling for potential confounders. Between August 2013 and October 2015, 762 participants were enrolled; 59 participants transferred to other clinics during the study period, and were excluded as per protocol, leaving 356 in the standard and 347 in the same-day ART groups. In the standard ART group, 156 (44%) participants were retained in care with 12-month HIV-1 RNA <50 copies, and 184 (52%) had <1,000 copies/ml; 20 participants (6%) died. In the same-day ART group, 184 (53%) participants were retained with HIV-1 RNA <50 copies/ml, and 212 (61%) had <1,000 copies/ml; 10 (3%) participants died. The unadjusted risk ratio (RR) of being retained at 12 months with HIV-1 RNA <50 copies/ml was 1.21 (95% CI: 1.04, 1.38; p = 0.015) for the same-day ART group compared to the standard ART group, and the unadjusted RR for being retained with HIV-1 RNA <1,000 copies was 1.18 (95% CI: 1.04, 1.31; p = 0.012). The main limitation of this study is that it was conducted at a single urban clinic, and the generalizability to other settings is uncertain.ConclusionsSame-day HIV testing and ART initiation is feasible and beneficial in this setting, as it improves retention in care with virologic suppression among patients with early clinical HIV disease.Trial registrationThis study is registered with ClinicalTrials.gov number NCT01900080In a randomized unblinded trial in Port-au-Prince, Haiti, Serena Koenig and colleagues investigate whether initiating ART on the day of HIV diagnosis improved retention in care and viral suppression.Author summaryWhy was this study done?Multiple visits for counseling, laboratory testing, and other procedures to prepare patients for initiation of antiretroviral therapy (ART) are burdensome and contribute to the high rate of attrition during the period from HIV testing to ART initiation.The World Health Organization (WHO) recently changed their guidelines to recommend ART for all persons living with HIV, facilitating ART initiation.This study was conducted to determine if ART initiation on the day of HIV diagnosis could improve treatment initiation rates, retention in care, and HIV viral suppression for patients with asymptomatic or minimally symptomatic HIV disease.What did the researchers do and find?We randomly assigned patients who presented for HIV testing at a clinic in Port-au-Prince, Haiti to standard ART initiation or same-day HIV testing and ART initiation (356 in the standard and 347 in the same-day groups).The standard group had 3 weekly visits with a social worker and physician and then started ART 21 days after the date of HIV diagnosis; the same-day ART group initiated ART on the day of HIV diagnosis.All participants in the same-day ART group and 92% of participants in the standard group initiated ART.At 12 months after HIV testing, a higher proportion of participants in the same-day ART group were retained in care (80% versus 72%), and a higher proportion were retained in care with viral load <50 copies/ml (53% versus 44%) and viral load <1,000 copies/ml (61% versus 52%).What do these findings mean?This study demonstrates that it is feasible to initiate ART on the day of HIV diagnosis for patients with early HIV clinical disease and that same-day treatment leads to increased ART uptake, retention in care, and viral suppression.Though same-day ART initiation improves outcomes, retention in care and viral suppression remain suboptimal, so further interventions to maximize long-term outcomes will be essential.The study is limited by being conducted at 1 clinic in urban Haiti. Further study will be necessary to determine if this strategy will be effective in other settings.http://dx.doi.org/10.13039/100000060National Institute of Allergy and Infectious DiseasesR01AI104344http://orcid.org/0000-0001-7464-275XKoenigSerena P.This project was supported by the National Institute of Allergy and Infectious Diseases, grant number R01AI104344. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Data AvailabilityWe have included the anonymized dataset as a Supporting Information file (S1 Data).Data AvailabilityWe have included the anonymized dataset as a Supporting Information file (S1 Data).IntroductionThe Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 targets state that 90% of HIV-infected persons know their status, 90% initiate antiretroviral therapy (ART), and 90% achieve virologic suppression by the year 2020 to curb the AIDS epidemic [1]. In 2015, the World Health Organization (WHO) updated their guidelines to recommend ART for all persons living with HIV based on evidence that earlier treatment improves outcomes and decreases transmission [2–4]. To achieve these goals, patients must be promptly linked to HIV services, initiated on ART, and retained in lifelong care [5].Attrition rates are particularly high during the period from HIV testing to ART initiation, with one-quarter to one-third of patients lost in the process of starting ART [6–9]. Even if many of these patients re-engage in care at a later date, they will return with more advanced disease. Though there are many factors that contribute to pretreatment attrition, the current standard of care in most settings, which requires multiple sequential visits for HIV testing and counseling, laboratory testing, and adherence counseling prior to ART initiation, creates barriers to treatment initiation. As of June 2016, WHO guidelines note inadequate evidence to support a recommendation of same-day HIV testing and ART initiation [2]. However, the availability of point-of-care tests, the fact that CD4 cell counts are no longer necessary prior to ART initiation, and the provision of same-day counseling can accelerate treatment initiation, potentially reducing attrition [10–12]. We conducted a randomized trial in Haiti to determine whether same-day HIV testing and ART initiation, as compared with standard ART initiation, improves retention in care with viral suppression.MethodsStudy design and settingWe conducted an unblinded, randomized controlled trial of standard ART initiation versus same-day HIV testing and ART initiation among HIV-infected adults at the Haitian Group for the Study of Kaposi’s Sarcoma and Opportunistic infections (GHESKIO) in Port-au-Prince, Haiti. Haiti is the poorest country in the Western Hemisphere, with adult HIV prevalence of 1.7% [13,14]. GHESKIO is a Haitian nongovernmental organization and the largest provider of HIV care in the Caribbean, treating up to 700 patients per day for HIV and/or tuberculosis (TB). All care is provided free of charge. The study was approved by the institutional review boards at Partners Healthcare, GHESKIO, Weill Cornell Medical College, and Florida International University. See supporting information files S1 Text for the study protocol and S2 Text for the CONSORT checklist.ParticipantsParticipants were recruited from the HIV voluntary counseling and testing center at GHESKIO from August 2013 to October 2015. They received HIV testing and posttest counseling; those with a positive HIV test were referred for same-day physician evaluation, CD4 count (FACS Count, Becton-Dickinson, Franklin Lakes, New Jersey), WHO staging, and chest radiograph. Patients were eligible for study inclusion if they were infected with HIV-1, ≥18 years of age, and had WHO Stage 1 or 2 disease and CD4 count ≤500 cells/mm3. Initially, enrollment was limited to patients with CD4 count ≤350 cells/mm3, but in February 2014, the cutoff was increased to ≤500 cells/mm3 in response to revised WHO and Haitian guidelines [15]. Patients were excluded if they were already aware of their HIV diagnosis, had received ART previously, were pregnant or breastfeeding, lived outside of the greater Port-au-Prince metropolitan area, planned to transfer care during the study period, or failed to demonstrate preparedness on an ART readiness survey, which was administered by a social worker prior to study enrollment. The survey includes a 5-point scale, with respondents ranking their preparedness from “not at all ready” to “completely ready” in response to 7 questions. Study inclusion required a response of “somewhat ready” or “completely ready” for all 7 questions (S3 Text) [16].Randomization and maskingAfter the patients had provided written informed consent, the study team performed a screening evaluation for study exclusion criteria, and eligible participants were enrolled and randomized on the day of HIV testing. Participants were randomly assigned with the use of a computer-generated random-number list to either standard ART or same-day ART initiation in a 1:1 ratio, with allocation concealment. The randomization sequence was generated by a computer in the GHESKIO data management unit by a data manager who had no other involvement in study procedures. Participants were enrolled in the study and assigned to groups by a study physician. Participants, site personnel, and study statisticians were not masked to group assignment.ProceduresAfter randomization, the standard group participants received ART initiation procedures that mirror national guidelines. Participants were referred to return on Day 7 for baseline laboratory tests (creatinine, alanine aminotransferase, aspartate aminotransferase, complete blood count, purified protein derivative [PPD]), physician evaluation, and counseling with a social worker. On Day 10, they received interpretation of PPD results, and on Days 14 and 21, they were seen by a physician and social worker for additional counseling, test results, and ongoing evaluations for opportunistic infections. Participants started ART on Day 21 and had an additional social worker and physician visit at Week 5 (Fig 1). The ART regimen was the same as that for nonstudy patients at GHESKIO. First-line therapy included a single combination tablet including tenofovir disoproxil fumarate, lamivudine, and efavirenz.10.1371/journal.pmed.1002357.g001Fig 1Study interventions for the standard ART and same-day ART groups.The same-day ART group had identical laboratory tests as the standard ART group, a 30-minute counseling session with a social worker, and physician evaluation, and then initiated the same ART regimen as the standard ART group. They returned on Day 3 for physician and social worker visits and receipt of baseline laboratory test results; those with creatinine clearance <50 mL/minute as calculated by the Cockcroft-Gault equation were switched from tenofovir to zidovudine or abacavir. They returned on Days 10 and 17 for additional physician and social worker visits and on Day 24 for a physician visit. The same number of scheduled physician visits and counseling sessions were provided to each group so that the only difference in care was in the schedule of visits during the first 5 weeks of the study and the timing of ART initiation.All care was delivered by GHESKIO clinic staff, and the same providers (physicians, nurses, social workers, pharmacists, and field workers) cared for both groups. A counseling manual was followed with an outline for the social workers to follow at each scheduled counseling visit; these were identical between groups, except for the timing of ART initiation, and each session took about 30 minutes. All counseling was provided for individual patients, rather than for groups. The counseling sessions were audiotaped and systematically evaluated for quality control purposes. If a participant in either group missed a study visit that included a scheduled social worker counseling session, the counseling was provided at the next visit.Participants in both groups had monthly physician visits throughout the follow-up period and received the same package of services provided to all HIV-infected patients at GHESKIO, including prophylactic treatment with trimethoprim-sulfamethoxazole and isoniazid. Field workers phoned patients who missed a visit and attempted a home visit for those not reachable by phone. Participants received a transportation subsidy of 100 Haitian gourdes (US$1.70) per visit.OutcomesThe primary endpoint was retention in care with HIV-1 RNA <50 copies/ml at 12 months after HIV testing. Retention was defined as attending the 12-month visit (1 clinic visit between 12 and 15 months after HIV testing). Lost to follow-up (LTFU) was defined as failure to attend the 12-month visit. Deaths were ascertained by review of medical records or report from family members. A National Institutes of Health Division of AIDS Expedited Adverse Event Form was filled out within 48 hours after the study team became aware of any death. Transfers were ascertained by confirmation that the participant was receiving care at a different site. Secondary outcomes include survival, ART initiation, retention in care with HIV-1 RNA <1,000 copies/ml at 12 months after HIV testing, adherence as measured by pharmacy refill records and self-report, and cost and cost-effectiveness of standard and same-day ART; the adherence and cost-effectiveness evaluations will be reported in separate manuscripts.Statistical analysisDemographic, clinical, and laboratory data from the electronic medical record and study forms were de-identified, entered into an Excel spreadsheet, and exported into Stata v14 software (StataCorp, 2011, College Station, Texas) for analysis. After study completion, all participants who were LTFU were recontacted to determine their vital status.The study was powered to detect a 10% absolute difference in the rate of retention with virologic suppression between the 2 groups at 12 months after enrollment (65% in the standard and 75% in the same-day ART group). At the α = 0.05 significance level, we estimated that we would need to enroll 349 participants per group (698 in total) to achieve 80% power to detect this difference. Because patients who transferred during the study period were excluded, we increased the total sample size to 762 participants. For all analyses, a modified intention-to-treat approach was used, in which all patients were analyzed according to their assignment group, excluding patients who transferred to another facility during the follow-up period, according to protocol.Baseline characteristics were summarized using simple frequencies and proportions and medians with interquartile ranges (IQRs) stratified by treatment arm. Among participants who died, baseline CD4 count was compared using the Wilcoxon rank-sum test. We compared the proportion of participants who were retained in care with HIV-1 RNA <50 copies/ml (primary endpoint), retained with HIV-1 RNA <1,000 copies/ml, retained regardless of HIV-1 RNA, initiated ART, and died (secondary endpoints) at 12 months after enrollment using a chi-square test. We conducted multivariable logistic regression including all covariates listed in Table 1 to control for any residual confounding. We present unadjusted and adjusted risk ratios (RR) with 95% confidence intervals. Because of the change in enrollment criteria mid-study, we conducted a sensitivity analysis that included only the participants who met the original enrollment criteria of CD4 count ≤350 cells/mm3. In response to a reviewer’s request, we also plotted retention in care, regardless of viral load, for both groups and compared the distributions with the log-rank test. The study is registered with ClinicalTrials.gov number NCT01900080.10.1371/journal.pmed.1002357.t001Table 1Baseline characteristics of study participants by group.CharacteristicStandard Group (n = 356)Same-Day ART Group (n = 347)Age (years)—Median (IQR)37 (30, 45)37 (29, 46)Female sex—no. (%)181 (51)166 (48)Education—no. (%)\xa0\xa0\xa0\xa0No school90 (25)93 (27)\xa0\xa0\xa0\xa0Primary school110 (31)111 (32)\xa0\xa0\xa0\xa0Secondary school or more156 (44)143 (41)Income—no. (%)\xa0\xa0\xa0\xa0No income92 (26)90 (26)\xa0\xa0\xa0\xa0>$0 to $1/day176 (49)159 (46)\xa0\xa0\xa0\xa0>$1 to $2/day67 (19)76 (22)\xa0\xa0\xa0\xa0>$2/day21 (6)22 (6)Marital status—no. (%)\xa0\xa0\xa0\xa0Single71 (20)71 (20)\xa0\xa0\xa0\xa0Currently married/living with partner222 (62)211 (61)\xa0\xa0\xa0\xa0Formerly married63 (18)65 (19)WHO Stage—no. (%)\xa0\xa0\xa0\xa0WHO Stage 1117 (33)101 (29)\xa0\xa0\xa0\xa0WHO Stage 2239 (67)246 (71)CD4 count (cells/mm3)—Median (IQR)247 (150, 349)249 (143, 336)Body mass index—Median (IQR)*21.6 (19.7, 23.9)20.9 (19.3, 23.5)* Body mass index differed significantly between the 2 groups (p = 0.025).ART, antiretroviral therapy; IQR, interquartile range, WHO, World Health Organization.ResultsA total of 821 patients were screened, and 762 were enrolled in the study and underwent randomization (Fig 2). After randomization, 59 participants (28 in the standard ART and 31 in same-day ART group) transferred to another clinic and were excluded from all analyses, as per protocol. The median age was 37 years old (IQR: 30–45 years), 347 (49%) were women, and the median CD4 count was 248 cells/mm3 (IQR: 148, 345).10.1371/journal.pmed.1002357.g002Fig 2Screening, randomization, and follow-up.Of the 356 participants in the standard group, 256 (72%) were retained in care, 20 (6%) died, and 80 (23%) were LTFU (Table 2). Among the 256 participants retained in the standard ART group, 156 (61% of retained and 44% overall) had HIV-1 RNA <50 copies/ml. Of the 347 participants in the same-day ART group, 277 (80%) were retained in care, 10 (3%) died, and 60 (17%) were LTFU. Among the 277 participants retained in the same-day ART group, 184 (66% of retained and 53% overall) had HIV-1 RNA <50 copies/ml. The unadjusted RR of being retained in care at 12 months and achieving HIV-1 RNA <50 copies/ml was 1.21 (95% CI: 1.04, 1.38; p = 0.015) for the same-day ART group compared to the standard group (Table 3); the adjusted RR for this comparison was 1.24 (95% CI: 1.06, 1.41; p = 0.008).10.1371/journal.pmed.1002357.t002Table 2Study outcomes by group.OutcomeStandard ART Group (n = 356)Same-Day ART Group (n = 347)Unadjusted Risk Difference (95% CI)p-valuePrimary OutcomeRetained in care at 12 months with VL <50 copies/ml156 (43.8%)184 (53.0%)9.2% (1.8%, 16.6%)0.015†Secondary OutcomesRetained in care at 12 months with VL <1,000 copies/ml184 (51.7%)212 (61.1%)9.4% (2.1%, 16.7%)0.012‡Retained in care at 12 months, regardless of VL results256 (71.9%)277 (79.8%)7.9% (1.6%, 14.2%)0.014††Died20 (5.6%)10 (2.9%)Lost to follow-up80 (22.5%)60 (17.3%)† p-value comparing the proportion of all patients who were retained in care with viral load <50 copies/ml between the 2 arms.‡ p-value comparing the proportion of all patients who were retained in care with viral load <1,000 copies/ml between the 2 arms.†† p-value comparing the proportion of all patients who were retained in care between the 2 arms.ART, antiretroviral therapy; VL, viral load.10.1371/journal.pmed.1002357.t003Table 3Unadjusted and adjusted risk ratios of study outcomes.UnadjustedAdjusted for All Baseline Co-variatesRR95% CIp-valueRR95% CIp-valueRetained in care with viral load <50 copies/mlStandard ART Group1.01.0Same-Day ART Group1.21(1.04, 1.38)0.0151.24(1.06, 1.41)0.008Retained in care with viral load <1,000 copies/mlStandard ART Group1.01.0Same-Day ART Group1.18(1.04, 1.31)0.0121.20(1.05, 1.33)0.008Mortality during study periodStandard ART Group1.01.0Same-Day ART Group0.51(0.24, 1.08)0.0730.43(0.19, 0.94)0.033ART, antiretroviral therapy; RR, risk ratio.In the standard ART group, 184 (72% of retained and 52% overall) participants who were retained in care had HIV-1 RNA <1,000 copies/ml. In the same-day ART group, 212 (77% of retained and 61% overall) participants who were retained in care had HIV-1 RNA <1,000 copies/ml. The unadjusted RR of being retained in care at 12 months and achieving HIV-1 RNA <1,000 copies/ml was 1.18 (95% CI: 1.04, 1.31; p = 0.012) for the same-day ART group compared to the standard ART group (Table 3); the adjusted RR for this comparison was 1.20 (95% CI: 1.05, 1.33; p = 0.008). In the sensitivity analysis that included only participants who met the original enrollment criteria (CD4 count ≤350 cells/mm3), the adjusted RR of being retained in care at 12 months and achieving HIV-1 RNA <50 copies/ml was 1.19 (95% CI: 0.99, 1.38; p = 0.060), and the adjusted RR of being retained in care at 12 months and achieving HIV-1 RNA < 1,000 copies/ml was 1.18 (95% CI: 1.01, 1.34; p = 0.035).Vital status at the end of the study was known for 328 (92%) participants in the standard ART group and 329 (95%) in the same-day ART group. The unadjusted RR for mortality was 0.51 (95% CI: 0.24, 1.08; p = 0.073) for the same-day group compared to the standard group; the adjusted RR for this comparison was 0.43 (95% CI: 0.19, 0.94; p = 0.033). In the sensitivity analysis that included only participants with CD4 count ≤350 cells/mm3, the adjusted RR for mortality was 0.41 (95% CI: 0.18, 0.93; p = 0.033). Among the participants who died, the median baseline CD4 count was 100 cells/mm3 (IQR: 45, 192) in the standard and 207 cells/mm3 (IQR: 112, 291) in the same-day ART group (p = 0.078). Eight of 20 (40%) deaths in the standard ART group occurred in participants who were LTFU prior to ART, 8 (40%) deaths occurred in those LTFU after starting ART, and 4 (20%) occurred while in care; the causes of death for those in care were stroke, trauma, and cancer in 3, and the fourth had pain and died after seeing a traditional healer. Three of the 10 (30%) deaths in the same-day ART group occurred in participants who were LTFU after starting ART; among the 7 (70%) participants who died while in care, 1 of each died of stroke, pneumonia, malaria, renal failure, and sudden death, and 2 died of gastroenteritis. No deaths for those in care were attributed to immune reconstitution syndrome or an opportunistic infection that was missed at ART initiation. In Fig 3, the Kaplan-Meier curve plots the retention in care, regardless of viral load, for both groups. The log-rank test comparing the curves between the standard and same-day ART group indicates a significant difference (p = 0.028).10.1371/journal.pmed.1002357.g003Fig 3Retention in care by study group.In the same-day ART group, 344 of 347 (99%) participants started ART on the day of HIV testing, and the remaining 3 patients started ART within the subsequent week. During the Day 3 follow-up visit, 13 patients (4%) in the same-day ART group had adjustments in their ART regimens (replacement of tenofovir with zidovudine or abacavir) because they had creatinine clearance <50 mL/minute on baseline testing. In the standard group, 281 (79%) participants initiated ART by Day 28, the end of the time window for the 3-week ART initiation visit. Thirty-six (10%) standard group participants initiated ART from Day 29 to Day 90, and 12 (3%) initiated ART after Day 90 due to late or missed visits. Twenty-seven (8%) standard group participants never started ART during the study period because they were LTFU or died prior to initiating treatment. Isoniazid prophylaxis was initiated for 337 (95%) participants in the standard group and 340 (98%) in the same-day group. Eight cases of TB were diagnosed during the first 3 months after ART initiation; 6 of these occurred in the standard group and 2 in the same-day ART group.DiscussionThe results of this randomized controlled trial show that among HIV-infected adults with early WHO Stage disease and CD4 count ≤500 cells/mm3, same-day HIV testing and ART initiation, as compared to standard care, improves retention in care with virologic suppression and, in the multivariable analysis, decreases mortality. These results are important given recent WHO 2016 guidelines stating the lack of evidence in support of same-day ART initiation.Our findings suggest that ART initiation as soon as possible after HIV testing may be beneficial for clinically stable patients. In resource-poor settings with fragile delivery systems, such as Haiti, the provision of immediate support by care providers at the time of HIV diagnosis can have both structural and individual impact. In addition to making treatment initiation logistically easier for patients, we believe that same-day counseling and ART initiation increase the sense of hope, optimism, and overall connectedness to the healthcare system for patients, which have been shown to be important for retention [17–20].Our findings are consistent with the results of the RapIT study, a randomized trial that included participants in South Africa with WHO Stage 3 or 4 disease or CD4 count ≤350 cells/mm3 [11]. Participants in the standard group in that study generally started ART at the sixth visit, and 72% of participants in the rapid group started ART on the day of study enrollment. Rapid ART initiation resulted in a 17% improvement in retention and 13% improvement in viral suppression. A stepped-wedge cluster-randomized trial in Uganda found an increase in ART initiation within 2 weeks after eligibility by implementing a multicomponent intervention to streamline ART initiation that included training healthcare workers, providing point-of-care CD4 count testing platforms, eliminating mandatory multiple preinitiation sessions, and giving feedback to facilities on their ART initiation rates [21]. A weighted proportion of 80% in the intervention group had started ART within 2 weeks after eligibility compared with 38% in the control group. A cohort study of same-day ART initiation in pregnant women in South Africa also found high rates of treatment initiation, with 91% initiating ART on the day of referral to the service [22]. In the intervention group of the Sustainable East Africa Research on Community Health (SEARCH) HIV test-and-treat study, a cluster-randomized controlled trial conducted in Kenya and Uganda, HIV-infected patients who were identified through community testing were referred to HIV care upon diagnosis and then offered immediate ART initiation; retention was high (89%) among patients newly linking to care [23].At ART initiation, it is critical that patients are ready to start lifelong therapy, that TB screening is conducted, and that renal function is evaluated to avoid the use of tenofovir in patients with renal insufficiency. In this study, ART readiness was remarkably high, with over 99% of patients screened for the study reporting they were ready to start lifelong ART. This is a particularly significant and timely finding for the provision of recommended universal ART because the majority of people living with HIV have early clinical disease, and there has been prior concern that healthier patients may be less willing to accept lifelong therapy [4]. Most patients with early clinical disease do not have TB symptoms (cough, fever, night sweats, or weight loss), so they do not require further work up to exclude TB, according to WHO guidelines [2]. With the exclusion of patients with a baseline chest x-ray that was suspicious for TB, we found that less than 1% of participants in the same-day ART group had TB that was missed at the time of ART initiation. We found that 4% of participants in the same-day ART group had creatinine clearance <50 mL/minute; ART regimens were adjusted on Day 3 for these patients.Both groups in our study received high-level care, with multiple counseling and physician visits in the first month, followed by monthly physician visits. At the time the study was started, this was the standard of care in Haiti. However, this standard has shifted over the past few years towards decreased frequency of visits and nonphysician providers [2,24–27]. We believe that same-day ART can be provided with fewer follow-up visits if proper counseling is provided during the early period after ART initiation. However, clinic-level procedures play a major role in the effectiveness of accelerated ART initiation strategies, as illustrated in Malawi, where among nearly 22,000 pregnant women who started ART for mother-to-child prevention, LTFU rates ranged from 0% to 58% between facilities and were highest among women who initiated ART on the day of HIV testing at large clinics [28].Though lower than anticipated, retention in both groups in our study was higher than reports of standard ART initiation from other resource-poor settings. Two studies from South Africa found that approximately one-third of patients remained in care from HIV testing through 12 months of ART, and systematic reviews of African studies have found high rates of pre-ART attrition [6,8,29,30]. In Haiti, data on pre-ART outcomes are limited, but 12-month retention after ART initiation is 73% nationwide [31]. We attribute the higher retention in our study in large part to faster ART initiation, even in the standard group, compared to many other HIV programs. We surmise that retention would have been lower in the standard group if there had been longer delays in ART initiation [5,11,30].The rates of retention with viral suppression in our study are lower than those reported from clinical trial cohorts, including at GHESKIO. In the GHESKIO Clinical Trials Unit, with a median monthly average of 483 subjects participating in NIH-funded clinical trials, retention is 97%. We attribute the lower retention and viral suppression rates in our study to 2 major reasons. First, nearly all patients meeting WHO stage and CD4 criteria were enrolled in the study on the day of HIV testing, including those with substantial barriers to retention in care and adherence. In contrast, over one-third of patients are generally lost to care prior to ART initiation or enrollment in clinical trials [6,8,29,30]. Second, the care that was provided in this study was similar to that received by nonstudy patients at GHESKIO, with the aim of producing findings that could be reproduced in other resource-poor settings. In order to achieve the UNAIDS 90-90-90 targets, it will be important to evaluate reasons for attrition and implement new strategies to improve retention in care. One approach that has been successful in a cohort of nonresearch patients at GHESKIO has been expedited follow-up care, with fewer visits of shorter duration for clinically stable patients [32]. Streamlined care has also been associated with high rates of retention in the SEARCH study, which is described above [23].Our study was conducted in a large urban clinic, which may limit the generalizability of our findings. In addition, though our study included patients with early clinical disease, the CD4 counts in our population were lower than would be expected with the provision of universal ART. It is possible that patients with higher CD4 counts may experience less benefit from same-day ART. It is also noteworthy that we conducted a chest x-ray prior to enrollment; if same-day ART is provided without a chest x-ray, it is possible that TB cases will be missed. Our study was not blinded. All participants in both groups received the same number of visits and the same retention plan, but we cannot exclude the possibility that awareness of study group impacted provider behavior.In conclusion, in a population of asymptomatic or minimally symptomatic HIV-infected patients, same-day HIV testing and ART initiation decreased mortality and improved the rate of retention in care with virologic suppression compared with standard ART initiation. Furthermore, human and material resources provided to each group were similar, so same-day ART is not expected to increase treatment costs. The new WHO recommendations to provide ART to all HIV-infected patients should facilitate same-day test and treat.Supporting informationS1 TextStudy protocol.(DOCX)Click here for additional data file.S2 TextCONSORT checklist.(DOC)Click here for additional data file.S3 TextHIV medication readiness scale.(PDF)Click here for additional data file.S1 DataAnonymized dataset.(XLSX)Click here for additional data file.Presented in part at the 21st International AIDS Conference, Durban, South Africa, July 18 to 22, 2016. We thank all of the patients who participated in this study and all of the GHESKIO staff who cared for them. We thank Drs. Paul Farmer, Daniel Fitzgerald, Martin Hirsch, Warren Johnson, Daniel Kuritzkes, and Paul Sax for expert advice on study design and Kaya Hedt and Anshul Saxena for manuscript formatting and preparation. We also thank Drs. Carlos del Rio, Kenneth Mayer, and Larry Moulton for serving on the data safety monitoring board and providing oversight of the study.AbbreviationsARTantiretroviral therapyGHESKIOHaitian Group for the Study of Kaposi’s Sarcoma and Opportunistic infectionsIQRinterquartile rangeLTFUlost to follow-upPPDpurified protein derivativeRRrisk ratioSEARCHSustainable East Africa Research on Community HealthUNAIDSThe Joint United Nations Programme on HIV/AIDSWHOWorld Health OrganizationReferences1UNAIDS Fast-Track, Ending the AIDS Epidemic by 2030. Accessed May 24, 2017 at: http://www.unaids.org/en/resources/campaigns/World-AIDS-Day-Report-2014.2Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection. Recommendations for a Public Health Approach. Second Edition, World Health Organization, 2016. 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Conference on Retroviruses and Opportunistic Infections (CROI), Boston, MA, USA, 2016.', 'title': 'Same-day HIV testing with initiation of antiretroviral therapy versus standard care for persons living with HIV: A randomized unblinded trial.', 'date': '2017-07-26'}, '29509839': {'article_id': '29509839', 'content': 'Home-based HIV testing is a frequently used strategy to increase awareness of HIV status in sub-Saharan Africa. However, with referral to health facilities, less than half of those who test HIV positive link to care and initiate antiretroviral therapy (ART).\nTo determine whether offering same-day home-based ART to patients with HIV improves linkage to care and viral suppression in a rural, high-prevalence setting in sub-Saharan Africa.\nOpen-label, 2-group, randomized clinical trial (February 22, 2016-September 17, 2017), involving 6 health care facilities in northern Lesotho. During home-based HIV testing in 6655 households from 60 rural villages and 17 urban areas, 278 individuals aged 18 years or older who tested HIV positive and were ART naive from 268 households consented and enrolled. Individuals from the same household were randomized into the same group.\nParticipants were randomly assigned to be offered same-day home-based ART initiation (n\u2009=\u2009138) and subsequent follow-up intervals of 1.5, 3, 6, 9, and 12 months after treatment initiation at the health facility or to receive usual care (n\u2009=\u2009140) with referral to the nearest health facility for preparatory counseling followed by ART initiation and monthly follow-up visits thereafter.\nPrimary end points were rates of linkage to care within 3 months (presenting at the health facility within 90 days after the home visit) and viral suppression at 12 months, defined as a viral load of less than 100 copies/mL from 11 through 14 months after enrollment.\nAmong 278 randomized individuals (median age, 39 years [interquartile range, 28.0-52.0]; 180 women [65.7%]), 274 (98.6%) were included in the analysis (137 in the same-day group and 137 in the usual care group). In the same-day group, 134 (97.8%) indicated readiness to start ART that day and 2 (1.5%) within the next few days and were given a 1-month supply of ART. At 3 months, 68.6% (94) in same-day group vs 43.1% (59) in usual care group had linked to care (absolute difference, 25.6%; 95% CI, 13.8% to 36.3%; P\u2009<\u2009.001). At 12 months, 50.4% (69) in the same-day group vs 34.3% (47) in usual care group achieved viral suppression (absolute difference, 16.0%; 4.4%-27.2%; P\u2009=\u2009.007). Two deaths (1.5%) were reported in the same-day group, none in usual care group.\nAmong adults in rural Lesotho, a setting of high HIV prevalence, offering same-day home-based ART initiation to individuals who tested positive during home-based HIV testing, compared with usual care and standard clinic referral, significantly increased linkage to care at 3 months and HIV viral suppression at 12 months. These findings support the practice of offering same-day ART initiation during home-based HIV testing.\nclinicaltrials.gov Identifier: NCT02692027.', 'title': 'Effect of Offering Same-Day ART vs Usual Health Facility Referral During Home-Based HIV Testing on Linkage to Care and Viral Suppression Among Adults With HIV in Lesotho: The CASCADE Randomized Clinical Trial.', 'date': '2018-03-07'}, '27163694': {'article_id': '27163694', 'content': 'PLoS MedPLoS MedplosplosmedPLoS Medicine1549-12771549-1676Public Library of ScienceSan Francisco, CA USA27163694486268110.1371/journal.pmed.1002015PMEDICINE-D-15-03455Research ArticleBiology and Life SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesPublic and Occupational HealthPreventive MedicineVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesImmunodeficiency VirusesHIVBiology and life sciencesOrganismsVirusesRNA virusesRetrovirusesLentivirusHIVBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVBiology and Life SciencesOrganismsVirusesViral PathogensRetrovirusesLentivirusHIVPeople and placesGeographical locationsAfricaSouth AfricaBiology and Life SciencesAnatomyBody FluidsBloodBlood CountsMedicine and Health SciencesAnatomyBody FluidsBloodBlood CountsBiology and Life SciencesPhysiologyBody FluidsBloodBlood CountsMedicine and Health SciencesPhysiologyBody FluidsBloodBlood CountsMedicine and Health SciencesHematologyBloodBlood CountsMedicine and Health SciencesHealth CareHealth Care ProvidersNursesPeople and PlacesPopulation GroupingsProfessionsNursesBiology and Life SciencesMicrobiologyVirologyViral Transmission and InfectionViral LoadMedicine and Health SciencesInfectious DiseasesBacterial DiseasesTuberculosisMedicine and Health SciencesTropical DiseasesTuberculosisMedicine and Health SciencesPharmaceuticsDrug TherapyInitiating Antiretroviral Therapy for HIV at a Patient’s First Clinic Visit: The RapIT Randomized Controlled TrialSingle-Visit ART InitiationRosenSydney\n1\n\n2\n*MaskewMhairi\n2\nFoxMatthew P.\n2\n\n3\nNyoniCynthia\n2\nMongwenyanaConstance\n2\nhttp://orcid.org/0000-0003-1473-880XMaleteGiven\n2\nSanneIan\n2\nhttp://orcid.org/0000-0001-5800-1960BokabaDorah\n4\nSaulsCeleste\n2\nhttp://orcid.org/0000-0002-1180-8764RohrJulia\n1\nLongLawrence\n2\n\n1\nDepartment of Global Health, Boston University School of Public Health, Boston, Massachusetts, United States of America\n\n2\nHealth Economics and Epidemiology Research Office, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa\n\n3\nDepartment of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, United States of America\n\n4\nHealth Department, City of Johannesburg, Johannesburg, South Africa\nBinagwahoAgnesAcademic Editor\nRwanda Ministry of Health, RWANDA\nThe authors have declared that no competing interests exist.Conceived and designed the experiments: SR LL MM IS MPF. Performed the experiments: CN CM DB CS JR. Analyzed the data: MM GM SR. Wrote the first draft of the manuscript: SR MM. Contributed to the writing of the manuscript: SR MM LL MPF. Enrolled patients: CN. Agree with the manuscript’s results and conclusions: SR MM LL MPF CN CM GM IS DB CS JR. All authors have read, and confirm that they meet, ICMJE criteria for authorship.* E-mail: sbrosen@bu.edu105201652016135e1002015171120152232016© 2016 Rosen et al2016Rosen et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.BackgroundHigh rates of patient attrition from care between HIV testing and antiretroviral therapy (ART) initiation have been documented in sub-Saharan Africa, contributing to persistently low CD4 cell counts at treatment initiation. One reason for this is that starting ART in many countries is a lengthy and burdensome process, imposing long waits and multiple clinic visits on patients. We estimated the effect on uptake of ART and viral suppression of an accelerated initiation algorithm that allowed treatment-eligible patients to be dispensed their first supply of antiretroviral medications on the day of their first HIV-related clinic visit.Methods and FindingsRapIT (Rapid Initiation of Treatment) was an unblinded randomized controlled trial of single-visit ART initiation in two public sector clinics in South Africa, a primary health clinic (PHC) and a hospital-based HIV clinic. Adult (≥18 y old), non-pregnant patients receiving a positive HIV test or first treatment-eligible CD4 count were randomized to standard or rapid initiation. Patients in the rapid-initiation arm of the study (“rapid arm”) received a point-of-care (POC) CD4 count if needed; those who were ART-eligible received a POC tuberculosis (TB) test if symptomatic, POC blood tests, physical exam, education, counseling, and antiretroviral (ARV) dispensing. Patients in the standard-initiation arm of the study (“standard arm”) followed standard clinic procedures (three to five additional clinic visits over 2–4 wk prior to ARV dispensing). Follow up was by record review only. The primary outcome was viral suppression, defined as initiated, retained in care, and suppressed (≤400 copies/ml) within 10 mo of study enrollment. Secondary outcomes included initiation of ART ≤90 d of study enrollment, retention in care, time to ART initiation, patient-level predictors of primary outcomes, prevalence of TB symptoms, and the feasibility and acceptability of the intervention. A survival analysis was conducted comparing attrition from care after ART initiation between the groups among those who initiated within 90 d. Three hundred and seventy-seven patients were enrolled in the study between May 8, 2013 and August 29, 2014 (median CD4 count 210 cells/mm3). In the rapid arm, 119/187 patients (64%) initiated treatment and were virally suppressed at 10 mo, compared to 96/190 (51%) in the standard arm (relative risk [RR] 1.26 [1.05–1.50]). In the rapid arm 182/187 (97%) initiated ART ≤90 d, compared to 136/190 (72%) in the standard arm (RR 1.36, 95% confidence interval [CI], 1.24–1.49). Among 318 patients who did initiate ART within 90 d, the hazard of attrition within the first 10 mo did not differ between the treatment arms (hazard ratio [HR] 1.06; 95% CI 0.61–1.84). The study was limited by the small number of sites and small sample size, and the generalizability of the results to other settings and to non-research conditions is uncertain.ConclusionsOffering single-visit ART initiation to adult patients in South Africa increased uptake of ART by 36% and viral suppression by 26%. This intervention should be considered for adoption in the public sector in Africa.Trial RegistrationClinicalTrials.gov NCT01710397, and South African National Clinical Trials Register DOH-27-0213-4177.In the RapIT randomized controlled trial, Sydney Rosen and colleagues investigate whether accelerated initiation of antiretroviral therapy can improve viral suppression for HIV patients in South Africa.Author SummaryWhy Was This Study Done?One of the most persistent operational challenges facing antiretroviral therapy (ART) programs for HIV/AIDS in sub-Saharan Africa is late presentation of patients for care and high rates of attrition from care between HIV testing and ART initiation.One reason for this is that starting ART in many countries is a lengthy and burdensome process, imposing long waits and multiple clinic visits on patients; in South Africa, the country with the world’s largest HIV treatment program, patients must typically make five or six clinic visits, starting with an HIV test, before they receive medications.There have not yet been any controlled evaluations of an integrated, rapid HIV treatment initiation algorithm that allows patients to initiate ART in a single clinic visit, so the RapIT trial was done to find out if “same-day initiation” of ART would increase the number of patients starting treatment and improve overall health outcomes, compared to current practices.What Did the Researchers Do and Find?We randomly assigned 377 adult patients at two public clinics in Johannesburg, South Africa, who had provided consent to participate in the study to one of two groups.Patients in the group assigned to receive rapid treatment initiation were offered the chance to start treatment on the same day as their first clinic visit, using rapid, point-of-care laboratory tests and an accelerated sequence of other steps, including a physical exam, education, and counseling.Patients in the group assigned to receive standard treatment initiation followed the standard schedule for treatment initiation used by the clinics, which usually required three to five additional clinic visits over a 2–4 wk period.After the study enrollment visit, patients were followed up by reviewing their regular clinic medical records, to determine how many did start treatment and how many were still in care and had good outcomes, as indicated by a suppressed viral load, 10 mo later.We found that 97% of patients in the rapid initiation group had started ART by 90 d after study enrollment—three-quarters of them on the same day—compared to 72% of patients in the standard initiation group.By 10 mo after study enrollment, 64% of patients in the rapid group had good outcomes compared to 51% in the standard group.Rapid initiation group patients spent roughly two and a half hours in the clinic to complete all the steps required before they got their medications.What Do These Findings Mean?The RapIT (Rapid Initiation of Treatment) trial showed that it is possible to initiate nearly all eligible patients on HIV therapy, and to do so in a much shorter time interval than previously required.By showing that offering the opportunity to start treatment on the spot, without delay, overcomes many barriers patients would otherwise face, this study demonstrates that same-day ART initiation is an effective strategy for improving health outcomes.More patients in the rapid initiation group dropped out of care after starting treatment than in the standard initiation group; although the rapid initiation group still had better health outcomes overall, adherence support after starting treatment remains essential.The findings of this study are limited because the study took place in only two clinics in one part of South Africa and was carried out by study staff, not by regular clinic staff.Based on this study’s results, consideration could be given to accelerating the process of ART initiation in many different settings and for different types of patients.http://dx.doi.org/10.13039/100000060National Institute of Allergy and Infectious Diseases1U01AI100015RosenSydneyFunding for this study was provided by the U.S. National Institutes of Health (National Institute of Allergy and Infectious Diseases) under the terms of grant 1U01AI100015 to Boston University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Data AvailabilityData will be made publicly available in the Dryad repository (http://www.datadryad.org/) after the protocol has been closed (anticipated closure June 2018). Until then, data will remain under the supervision of the University of the Witwatersrand Human Research Ethics Committee (HREC). Requests should be sent to the HREC Research Administrator at: https://www.wits.ac.za/research/about-our-research/ethics-and-research-integrity/human-research-ethics-committee-medical/.Data AvailabilityData will be made publicly available in the Dryad repository (http://www.datadryad.org/) after the protocol has been closed (anticipated closure June 2018). Until then, data will remain under the supervision of the University of the Witwatersrand Human Research Ethics Committee (HREC). Requests should be sent to the HREC Research Administrator at: https://www.wits.ac.za/research/about-our-research/ethics-and-research-integrity/human-research-ethics-committee-medical/.IntroductionOne of the most persistent operational challenges facing antiretroviral therapy (ART) programs for HIV/AIDS in sub-Saharan Africa is late presentation of patients for care and high rates of attrition from care between HIV testing and ART initiation, with baseline median CD4 cell counts remaining well below 200 cells/mm3 in the region despite steadily rising eligibility thresholds [1]. Even among those who have been diagnosed and found to be treatment-eligible, loss to care before starting ART has consistently been estimated at a third to a quarter of patients [2,3]. While many of those who drop out of care prior to ART initiation will make their way back at a later time, they will almost certainly have lower CD4 counts and more symptoms of illness than when they first tested positive. Some will be very sick or die before treatment can be started, and those who do eventually start will have a poorer prognosis on treatment than if they had begun treatment earlier [4,5]. Offering ART to all who test positive regardless of CD4 count, as is now recommended by the World Health Organization [6], will make little difference if those who test positive fail to initiate treatment.There are likely many causes of loss to care before treatment initiation, but one reason observed is that starting ART in many countries is a lengthy and burdensome process, requiring long waits and multiple clinic visits [7,8]. In South Africa, the country with the world’s largest HIV treatment program [9], the process typically includes an HIV test (visit 1), determination of treatment eligibility (visit 2), adherence education and counseling and baseline blood tests (visits 3, 4, and 5), and physical examination and dispensing of antiretrovirals (ARVs) (visit 6). The proliferation of visits has three main causes. First, clinic receipt of printed test results from centralized laboratories typically takes several days, if not longer. Second, a belief remains that to ensure adherence, patients must participate in multiple preparatory educational and counseling sessions [2,10,11]. And third, clinics have had little motivation to accelerate the initiation process for patients who are not critically ill, as standard performance indicators do not include the proportion of eligible patients who actually initiate ART, nor the time required to do so.If patients are deterred from starting treatment by the complexity of the process, then one strategy for reducing loss of patients prior to ART initiation and encouraging earlier treatment initiation may be to shorten the time period, reduce the number of visits, and simplify the steps required before medications are dispensed. This strategy depends critically on two factors: a clinic’s willingness and ability to adjust its schedules and procedures to compress and accelerate the required steps, and the availability of rapid, point-of care (POC) laboratory assays that eliminate delays in receiving whatever lab results are required for initiation. There have not yet been any rigorous, controlled evaluations of an integrated, rapid HIV treatment initiation algorithm incorporating procedural changes and POC tests for adult, non-pregnant patients. We therefore conducted a randomized controlled trial of rapid ART initiation that allowed patients in public sector clinics in Johannesburg, South Africa to have treatment eligibility determined, all treatment preparation steps performed, and ARV medications dispensed on the day of their first HIV-related clinic visit.MethodsRapIT (Rapid Initiation of Treatment) was an unblinded, individually randomized, controlled trial of a service delivery intervention. It was approved by the Institutional Review Board of Boston University Medical Campus (H-31880) and the Human Research Ethics Committee (Medical) of the University of the Witwatersrand (M120843) and is registered with ClinicalTrials.gov, number NCT01710397.Study Sites, Infrastructure, and StaffingRapIT was conducted at two public sector outpatient clinics. Site 1 is a primary health clinic serving an urban informal settlement population on the edge of Johannesburg. Site 2 is a large, hospital-based HIV clinic serving an urban formal and informal population within Johannesburg. Both sites follow South African national treatment guidelines for ART initiation, ARV regimens, and monitoring [12]. During the period of study enrollment, May 8, 2013–August 29, 2014, the prevailing threshold for ART eligibility was a CD4 count ≤ 350 cells/mm3 or a WHO Stage 3/4 clinical condition. Requirements for care prior to initiating ART are not standardized in South Africa [13], but both sites generally required four to five clinic visits between HIV testing and dispensing the first month’s supply of ARVs.At each site, a small clinic room with security bars, running water, and basic furnishings was designated for study equipment and supplies, POC instruments, and files. As all the POC instruments were designed as desktop devices, no separate laboratory was needed. An outdoor booth for safe collection of sputum samples from tuberculosis (TB) suspects was constructed at Site 1 and made available for both study arms; existing facilities for this purpose were used at Site 2. Clinical procedures were performed by study nurses with the same level of clinical certification as existing primary health care nurses at the sites. Non-clinical procedures (consent, questionnaire, education, counseling, patient flow management) were implemented by study assistants with qualifications comparable to those of experienced lay counselors at the sites. All study staff received study and instrument-specific training. A small stipend (R1000/month, equivalent to US$86 at the exchange rate at the time of the study) was paid to clinic lay counselors at Site 1 and a messenger at Site 2 who assisted by referring potential study participants to the study assistant.Study PopulationThe study enrolled adult (≥18 y old), non-pregnant patients who presented to have an HIV test, provide a blood sample for a CD4 count if already known to be HIV-infected, or receive the results of the patient’s first treatment-eligible CD4 count. During pre-screening and screening, patients who had previously been found to be eligible for ART, were already on ART or reported receiving it in the past 12 mo, indicated that they intended to seek HIV care during the next 12 mo at a different clinic, were judged by clinic or study staff to be physically or emotionally unable to provide consent or participate in all study procedures, or did not meet other study inclusion criteria were excluded. Potential participants whose visit purpose was to have an HIV test were enrolled; those found post-enrollment not to be eligible for ART were subsequently withdrawn upon determination of ineligibility. Potential participants whose visit purpose was to receive a CD4 count result and were not eligible for treatment on the basis of that CD4 count were not enrolled.Participants were individually randomized 1:1 to either rapid treatment initiation or standard-of-care treatment initiation, using block randomization in blocks of 6. Sealed, opaque envelopes containing the allocations were prepared by the local principal investigator and numbered sequentially. The envelopes were kept in sequential, numbered order at the study sites. After obtaining written informed consent, the study assistant opened the next sequentially numbered envelope to reveal the allocation.Study Design and ProceduresProcedures for each study arm are illustrated in Fig 1. Standard-of-care treatment initiation followed existing procedures at the sites as closely as possible. Study staff interaction with participants was limited to screening for study eligibility, obtaining written informed consent, administering a questionnaire, and referring patients to clinic staff for either a blood draw for a CD4 count or a next visit appointment if the patient already had results of a CD4 count in hand. After referral, patients in the standard-initiation arm of the study were followed passively, through medical record review, and had no further interaction with the study. Standard-of-care procedures for ART initiation at both study sites included a CD4 count to determine eligibility, TB symptom screening followed by a TB test and TB treatment initiation if required, pre-initiation blood tests (hemoglobin, creatinine, and alanine aminotransferase (ALT)), group and individual counseling and education sessions, and a physical examination. All samples for laboratory tests were sent to centralized public sector laboratories, requiring patients to make separate clinic visits to provide biological samples and to receive results. Once ART eligibility was determined, initiation typically required three to four more clinic visits over a period of 2–4 wk. Patients who were very ill or found to have low CD4 counts could be “fast-tracked,” with the schedule shown in Fig 1 completed in as little as one week.10.1371/journal.pmed.1002015.g001Fig 1Standard initiation of treatment and rapid initiation procedures and visit schedule.For patients randomized to rapid initiation, all the same procedures were performed, but the use of a compressed and accelerated schedule and rapid laboratory instruments at point of care allowed them all to be completed in a single visit (Box 1). Patients offered rapid initiation typically completed each step in order, with little or no waiting time in between unless a TB test was required, which entailed a wait to process the sample. Patients who enrolled in the study too late in the day for all steps to be completed before the clinic closed were asked to return the next day to finish study procedures. Patients who were randomized to rapid initiation but did not have time to participate on the day of enrollment or wished to delay for other reasons were given up to 30 d to return and be initiated under rapid procedures. Those returning beyond 30 d were offered standard initiation by the clinic.Box 1. Rapid Initiation ProceduresCD4 countPatients who enrolled in the study and did not already have CD4 count results from a test performed within the previous 6 mo were given a rapid CD4 count using the Alere Pima CD4 Test (http://alerehiv.com/hiv-monitoring/alere-pima-cd4/) with venous blood draw. This test, previously evaluated in several studies in Africa [14–18], provides a CD4 count result from a capillary or venous blood sample in 20 min. Following the test, patients with a CD4 count ≤ 350 cells mm3 or evident physical symptoms or complaints that suggested a Stage 3 or 4 condition continued with study procedures. Those not eligible for ART were withdrawn from the study at this point and referred to the clinic for standard pre-ART monitoring.TB symptom screen and testWhile awaiting CD4 count results, a TB symptom screen was administered using South Africa’s four-question screening tool. All patients who reported symptoms were then asked to provide a sputum sample, which was immediately processed using the Cepheid Xpert MTB/RIF test (http://www.cepheid.com/us/cepheid-solutions/clinical-ivd-tests/critical-infectious-diseases/xpert-mtb-rif). This is the technology currently used for TB diagnosis in the public sector throughout South Africa, but it is located in centralized laboratories rather than at point of care [19]. It generates a TB diagnosis in 90 min [20]. Two sputum samples were run simultaneously to increase the reliability of results. Any patient who received a positive Xpert test was escorted to the clinic TB nurse to initiate TB treatment, which under national guidelines required a delay of at least 2 wk before ART could be initiated. Patients initiated on TB treatment were asked to return 2 wk later to complete rapid ART initiation on a second visit.Baseline testsOnce eligibility for ART was established, pre-initiation blood tests (hemoglobin, creatinine, and ALT) were run on a point-of-care Reflotron Plus instrument (Roche, http://www.roche-diagnostics.co.in/Products/Pages/ReflotronPlusDry.aspx)[14] using the same blood sample dawn for the CD4 count. This instrument takes approximately 2 min to complete each test. A standard clinic urine dipstick pregnancy test was also conducted for female patients of child-bearing age.Physical examA standard physical examination was conducted by the study nurse to identify any specific conditions or concerns prior to initiating ART. Initiation was delayed in patients found to have conditions that required referral to a hospital or consultation with the clinic’s doctor.Education sessionA condensed version of HIV/ART/adherence education was developed using the study clinics’ materials and provided to study participants. It was delivered in a one-on-one session by the study counselor in approximately 20 min.Counseling sessionAfter completing all tests, physical examination, and education session, each patient met individually with the study nurse, who reviewed results with the patient and provided an opportunity for the patient to ask any remaining questions and confirm that she or he was indeed ready for treatment initiation.Dispensing of ARVsThe study nurses, like other qualified nurses in South Africa, were authorized to write prescriptions for ARVs, which could then be filled directly by the nurse from study room stock (Site 1) or at the on-site clinic pharmacy (Site 2). Study patients at Site 2 were served at the pharmacy immediately, rather than being required to wait in pharmacy queues to fill prescriptions. Once the initial 4 wk supply of ARVs was dispensed, study interaction with rapid group patients ceased. Patients were asked to return to the clinic for monitoring and prescription refill by clinic staff in 1 mo, consistent with routine practice.After the enrollment visit, or completion of rapid initiation procedures for patients in the rapid-initiation arm of the study (“rapid arm”) who delayed initiation but returned to complete it within 30 d, the study team had no further contact with study patients. Patients who started ART in either arm received standard-of care treatment management from the clinic, which called for monitoring visits and medication refills at 1, 2, 3, 6, and 12 mo after initiation, with a routine viral load test at the 6 mo visit.Outcomes and DataThe primary, protocol-defined outcome for the study was viral suppression (≤400 copies/ml) within 10 mo of study enrollment, a time period selected to capture the 6 mo routine monitoring visit called for by national guidelines. Ten months was selected as the endpoint to allow patients to take up to 3 mo to initiate ART and to be up to 1 mo late for the 6 mo routine visit. Because the study sites occasionally omitted the 6 mo viral load and performed the test only at 12 mo, we considered a patient with a suppressed viral load test result any time from 3 to 12 mo after study enrollment to have achieved viral suppression. In this analysis, missing viral load test results were regarded as failures; only patients with recorded, suppressed viral load results were defined as virally suppressed. To account for the possibility that viral load results could be missing due to clinic oversight in not ordering the test, rather than patient default, and to investigate the possibility that rapid initiation merely shifts attrition from before to after treatment initiation, we also report the secondary outcome of retention in care at 10 mo after study enrollment, with retention defined as any HIV-related clinic visit in months 5–10 after study enrollment, regardless of viral load.Although viral suppression was the primary outcome assessed, the pathway by which the study aimed to increase suppression was reduction of attrition between HIV testing and treatment initiation. We therefore report initiation of treatment within 90 d of study enrollment as a secondary outcome, with initiation defined as being dispensed a first month’s supply of ARVs. We also report uptake of treatment within 180 d, as a CD4 count result is considered to be valid under South African guidelines for 6 mo—after that, a patient must have a new CD4 count to establish eligibility for ART. Finally, we report the distribution of time (d) to treatment initiation in each group.Other secondary outcomes evaluated in the study included the feasibility of the intervention, as indicated by the ability of both study sites to implement the accelerated algorithm; acceptability of the intervention, as measured by the proportion of patients offered rapid initiation who accepted it; patient-level predictors of the primary outcome; and, in the rapid arm, the prevalence of TB symptoms and confirmed TB disease and ART initiation among patients with TB.After the enrollment visit, all data collection for both groups was by passive medical record review. Both study sites routinely utilized an electronic medical record system called TherapyEdge-HIV, into which patient data were entered retrospectively by data clerks from paper files (Site 1) or by a combination of clinicians in real time and data clerks from paper files (Site 2)[21]. This record system improved the completeness of the follow-up dataset used in the study. In instances of incomplete follow-up data—for example, if the database reported a clinic visit 6 mo after ART initiation but contained no viral load test result—study staff searched the clinics’ paper files and registers and the online data portal of the National Health Laboratory Service to determine if any additional information existed but had not been recorded in the clinics’ databases. The study team had no further contact with study participants after the enrollment visit so as not to have any influence on retention in care, a study outcome.Data AnalysisWe designed the study to detect a 20% difference in viral suppression rates between the arms at 10 mo after study enrollment. With an α of 0.05, power of 90%, 1:1 randomization, and an uncorrected Fisher’s exact test, we estimated that we would need to enroll at least 124 HIV positive ART-eligible participants per group (248 total). We increased this to a maximum of 200 per group (400 total) to allow for stratification by site, sex, or age.Characteristics at study enrollment of all randomized participants who met ART initiation and study inclusion criteria were summarized using simple proportions and medians with interquartile ranges (IQR) stratified by treatment arm. For the remaining analyses, we excluded patients who were found after randomization not to be eligible for ART or not to meet study inclusion criteria. We compared the proportions of patients achieving each dichotomized study outcome and present crude risk ratios (RR) and risk differences (RD) with 95% confidence intervals (CI) stratified by group. Baseline predictors of outcomes that appeared imbalanced by treatment arm were also adjusted for using log-linear regression models to estimate adjusted risk ratios (aRR). We estimated time to treatment initiation in days using a cumulative incidence curve. To investigate whether attrition after initiation of ART differed between the study arms, we performed a survival analysis comparing attrition from care after ART initiation among those who initiated within 90 d between the groups. Person-time accrued from ART initiation date to the earliest of loss to follow up, transfer, or 10 mo of follow up, and hazard ratios of attrition from care were estimated with Cox proportional hazards models. A stratified analysis was performed to detect effect measure modification by site or patient-level factors. Finally, to confirm that no imbalance was created by excluding patients after randomization for reasons other than ineligibility for ART or evidence of a previous eligible CD4 count, we conducted sensitivity analysis incorporating the excluded patients and assigning each a negative outcome.ResultsBetween May 8, 2013, and August 29, 2014, 603 patients were screened for study eligibility and 463 provided written informed consent and were enrolled in the study (Fig 2). Of the 140 screened but excluded prior to randomization, 109 did not meet study eligibility criteria, including 43 who resided outside study clinic catchment areas or intended to seek further care elsewhere; 24 who were determined by the study assistant to be too ill for consent and study procedures; 16 who were not eligible on the basis of a prior CD4 count, were ineligible for ART, or were already on ART; 12 who were determined by the study assistant to be too emotionally upset to provide consent; 9 who did not speak any of the languages spoken by the study team; 3 who were found to be pregnant; and 2 who were excluded for other reasons. An additional 31 patients refused participation; of these, 18 were in a hurry and did not have time for study procedures, six did not wish to participate in the study, five stated that they would prefer standard care, and two were not willing to initiate therapy. Follow-up ended 10 mo after the last patient was enrolled (June 28, 2015).10.1371/journal.pmed.1002015.g002Fig 2Study enrollment and randomization.Characteristics of patients in each study arm at time of enrollment are reported in Table 1. There were no important differences between the study arms in the variables shown. Just over half the participants were female and the median age was 35 y. The median CD4 count was less than 200 cells/mm3. Age, sex, and CD4 count characteristics of the study sample were similar to those of the overall non-pregnant patient populations initiating ART at the study clinics in 2014.10.1371/journal.pmed.1002015.t001Table 1Baseline characteristics of study sample (n = 463).VariableStandard armRapid arm\nn (randomized participants)229234Enrollment site (n)\xa0\xa0\xa0\xa0Site 1 (primary health clinic)124126\xa0\xa0\xa0\xa0Site 2 (hospital-based HIV clinic)105108Age (median, IQR)35.8 (29.5–41.6)34.2 (29.0–40.1)Sex (% female)132 (58%)129 (55%)CD4 count (cells/mm3) (median, IQR)195 (103–322)224 (128–327)Purpose of clinic visit (%)\xa0\xa0\xa0\xa0Have HIV test (diagnosed today)100 (44%)90 (38%)\xa0\xa0\xa0\xa0Provide blood sample for CD4 count8 (4%)10 (4%)\xa0\xa0\xa0\xa0Receive first CD4 count results109 (47%)112 (48%)\xa0\xa0\xa0\xa0Other11 (5%)22 (10%)Reason for treatment eligibility (%)\xa0\xa0\xa0\xa0CD4 count below threshold182 (79%)183 (78%)\xa0\xa0\xa0\xa0Clinical condition Stage 3 or 43 (1%)4 (2%)\xa0\xa0\xa0\xa0Excluded (not eligible for treatment or study)44 (20%)47 (20%)Household composition\xa0\xa0\xa0\xa0Live alone (% yes)36 (16%)41 (18%)\xa0\xa0\xa0\xa0# other persons in house (median, IQR)2 (1–4)2 (1–3)Household type (%)\xa0\xa0\xa0\xa0Formal house or flat146 (63%)165 (71%)\xa0\xa0\xa0\xa0Informal dwelling or shack83 (37%)69 (29%)Travel time to clinic (minutes) (median, IQR)18 (9–24)15 (9–27)Employment status (%)\xa0\xa0\xa0\xa0Employed formally68 (30%)90 (38%)\xa0\xa0\xa0\xa0Work informally62 (27%)54 (23%)\xa0\xa0\xa0\xa0Unemployed, seeking work91 (40%)84 (36%)\xa0\xa0\xa0\xa0Unemployed, not seeking work8 (3%)6 (3%)Marital status (%)\xa0\xa0\xa0\xa0Married or long-term partner173 (76%)157 (67%)\xa0\xa0\xa0\xa0Single, no long-term partner41 (18%)57 (24%)\xa0\xa0\xa0\xa0Other (widowed, divorced)15 (6%)20 (9%)Reasons for excluding patients during the study screening process are reported in Fig 2. The 603 patients screened represent a subset of those pre-screened by clinic counselors and then referred to the study assistant for screening. While pre-screening data, which were collected by the counselors and not by study staff, are of uncertain quality, they do provide some indication of the proportion of all patients presenting at clinics who could be eligible for rapid initiation. At Site 1, for which the pre-screening data are more complete, a total of 2,636 patients presenting at the clinic’s HIV counseling and testing service were pre-screened. More than half of these were HIV-negative (1,468/2,636, 56%) or known to have CD4 counts above the eligibility threshold or already on ART (114/2,636, 4%). Of the remaining 1,054, 325 (31%) were referred for study screening. Another 293/1,054 (28%) were judged by the counselors not to meet study protocol eligibility criteria (age, residence location, language, not first CD4 count) but would likely have been eligible for the intervention if it were offered as routine care. A fifth (225/1,054, 21%) were regarded by the counselors as too sick for study participation (not necessarily for ART initiation) and were referred to a clinic doctor or nurse for immediate care; it is not clear if they would have been eligible for the intervention or not. The remainder (20%) included patients who refused study participation (36/1,054, 3%) or refused any further care (12/1,054, 1%), were deemed too upset or emotionally distressed to participate (25/1,054, 2%), were referred directly to the clinic’s HIV or TB nurse rather than the study assistant (75/1,054, 7%), or were in a hurry or had no reason stated (63/1,254, 6%).Among 463 patients screened and found eligible for study participation, 234 patients were randomized to rapid initiation and 229 to standard initiation (Fig 2). Upon completion of a CD4 count, which occurred after randomization for those who did not already have one in hand, 37 patients in each group were determined not to be eligible for ART under South African guidelines and were excluded from further data collection and from the analysis. An additional 12 patients were excluded after randomization, for reasons indicated in Fig 2. One hundred and ninety patients in the standard group and 187 in the rapid group (n = 377 total) were offered full study procedures and are included in the analysis below, with sensitivity analysis incorporating the six who were excluded after randomization for a reason other than ineligibility for ART or evidence of a prior eligible CD4 count.The protocol-defined primary outcome for the study was viral suppression within 10 mo of study enrollment. As presented in Table 2, viral suppression by 10 mo was 64% (119/187) in the rapid arm and 51% (96/190) in the standard arm, indicating a risk difference of 13% (3%–33%) and a crude relative risk of 1.26 (1.05–1.50).10.1371/journal.pmed.1002015.t002Table 2ART initiation, 10-mo retention in care, and 10-mo viral suppression.OutcomeStandard arm(%)n = 190Rapid arm(%)n = 187Crude risk difference(95% CI)Crude relative risk(95% CI)Initiated ≤ 90 d and suppressed by 10 mo (primary outcome)96 (51%)119 (64%)13% (3%–23%)1.26 (1.05–1.50)\xa0\xa0\xa0\xa0Of those\nnot\ninitiated ≤ 90 d and suppressed by 10 mo\n\n94 (49%)\n\n68 (36%)\n\n\xa0\xa0\xa0\xa0\xa0\xa0Not initiated\n\n54 (28%)\n\n5 (3%)\n\n\xa0\xa0\xa0\xa0\xa0\xa0Initiated but not suppressed\n\n40 (21%)\n\n63 (34%)\n\n\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0Of those initiated but not suppressed:\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0Retained, unsuppressed viral load test reported\n\n11 (6%)\n\n17 (9%)\n\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0Retained, no viral load test reported\n\n14 (7%)\n\n16 (9%)\n\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0Transferred to another clinic\n\n1 (1%)\n\n6 (3%)\n\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0Died\n\n3 (2%)\n\n0 (0%)\n\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0Lost to follow-up\n\n11 (6%)\n\n24 (13%)\nInitiated ≤ 90 d136 (72%)182 (97%)25% (19%–33%)1.36 (1.24–1.49)Initiated ≤ 90 d and retained at 10 mo (secondary outcome)121 (64%)151 (81%)17% (5%–23%)1.27 (1.12–1.44)\xa0\xa0\xa0\xa0Of those not initiated ≤ 90 d and retained at 10 mo:\n69 (36%)\n\n36 (19%)\n\xa0\xa0\xa0\xa0\xa0\xa0Initiated but not retained\n\n15 (8%)\n\n31 (17%)\n\xa0\xa0\xa0\xa0\xa0\xa0Not initiated\n\n54 (28%)\n\n5 (3%)\nBy 90 d after study enrollment, 97% (182/187) of participants in the rapid arm and 72% (136/190) of participants in the standard arm had initiated ART, equating to a risk difference of 25% (95% CI 19%–33%) and a crude relative risk of 1.36 (1.24–1.49) (Table 2). In adjusted analysis (S1 Table), neither age, sex, nor baseline CD4 count affected these values. By 180 d, one additional patient in the rapid arm and two in the standard arm had initiated, leaving four patients in the rapid arm and 52 in the standard arm who did not initiate within the period of validity of their CD4 count results. In the rapid arm, all four were referred to a clinic nurse or doctor for clinical confirmation of TB and did not return for ART initiation. In the standard arm, 73% (38/52) of the patients who did not initiate within 180 d made no further visits to the site after the visit in which they were enrolled in the study.\nFig 3 shows the cumulative incidence of treatment initiation in each study arm over the 180 d following enrollment. In the rapid arm, 72% (135/187) of patients started ART on the same day as study enrollment, an additional 7% (13/187) on the next day, and 96% (179/187) within 1 mo. In the standard arm, 58% of patients initiated within one month. The median (IQR) time to initiation in the standard arm for the subset who did initiate within 90 d (n = 136) was 17 (11–26) d. For rapid arm patients who did not initiate on the same day (n = 48), the reasons for delay were the need for clinical confirmation of TB or a Stage 3 or 4 condition or for TB treatment (25/48, 52%), insufficient time to complete all steps on the same day (6/48, 13%), patient preferences (5/48, 10%), lack of electricity in the clinic (2/48, 4%), and unknown reasons (10/48, 21%). Time to treatment initiation in the standard arm was shorter for patients who already had CD4 count results available upon study enrollment (median days 16, [IQR 11–22]) compared to those who enrolled in the study at the time of having an HIV test (22 [IQR 10–35]); the median for both types of patients in the rapid arm was 0 d (i.e., same-day initiation).10.1371/journal.pmed.1002015.g003Fig 3Time to ART initiation, by study arm.Cumulative incidence of ART initiation in each study arm, by number of days since study enrollment.All patients in the rapid arm had the opportunity to initiate treatment on the day of study enrollment (same-day initiation) unless one of the reasons for delay listed above pertained to them. To explore whether a delay in initiation was associated with different post-initiation outcomes, we compared patients who did initiate on the same day to those who delayed for any reason. There were no differences in either the primary outcome of viral suppression or the secondary outcome of retention in care between these two groups of patients (S3 Table). Because this analysis was limited to rapid arm patients, however, it is not a randomized comparison and should be interpreted with caution.Retention in care, defined as making a clinic visit between months 5 and 10 after study enrollment, was 81% (151/187) in the rapid arm and 64% (121/190) in the standard arm, for a risk difference of 17% (5%–23%) and a crude relative risk of 1.27 (1.12–1.44). Table 2 also indicates that 86% (31/36) of patients in the rapid arm who were not retained were lost from care after ART initiation, compared to just 22% (15/69) in the standard arm; the fall-off in the standard arm, in contrast, was mainly among those who never initiated (54/69, 78%). Although there was less loss to follow-up after initiation in the standard arm (15/190, 8% versus 31/187, 17%), this was more than offset by the higher pre-initiation loss in the standard arm (54/190, 28% versus 5/187, 3%), resulting in an overall increase in retention of 17%. Among the patients lost to care after initiation (15 in the standard arm and 31 in the rapid arm), a large majority of patients who initiated ART but were not retained in care either never came back after their initiation visit (40% of patients in the standard arm (6/15) and 45% in the rapid arm (14/31)) or came back just once (47% (7/15) and 35% (11/31), respectively), suggesting that most of these patients were never “established” on ART.To explore further the rate of loss to care, we estimated attrition from care within the first 10 mo after initiation among the subsample of 318 patients who did initiate ART within 90 d. In the standard arm, during 1,250 mo of total person-time, 22/136 (16%) dropped out of care after ART initiation, for an attrition rate of 1.8 per 100 person-months. In the rapid arm, during 1,626 mo of total person-time, 30/182 (16%) dropped out of care, for a rate of 1.8 per 100 person-months. The hazard of attrition within the first 10 mo after ART initiation among those who initiated within 90 d did not differ between the treatment arms (HR 1.06; 95% CI 0.61–1.84). We note that this result is subject to selection bias and confounding, however, due to the exclusion of those who did not start treatment within 90 d.In pooled analysis of both study arms, none of the variables presented in Table 1 predicted any of the outcomes reported above, with three exceptions (S2 Table). A slightly higher proportion of patients with baseline CD4 counts below 100 cells/mm3 initiated ART, but this difference did not persist through retention or viral suppression at 10 mo. As might be expected, patients who enrolled in the study at the time of receiving their CD4 count results (thus their second HIV-related clinic visit overall), rather than at the time of having an HIV test, were slightly more likely to achieve all three outcomes, though only for retention in care was this difference statistically significant. Finally, patients who reported being employed at the time of study enrollment, while no more likely to initiate ART, had significantly better retention in care and viral suppression than did those who reported being unemployed.In stratified analysis (S4 Table) we observed non-significant differences in effect sizes for the primary outcome (viral suppression at 10 mo) by sex, age group, and study site. A larger effect was seen among men aged <35 y (risk difference [95% CI] 34% [12%–55%]), while little effect was seen among men or women ≥35 (5% [-9%–19%]). The effect size was also greater at the primary health clinic (21% [8%–34%]), while little effect was seen at the hospital-based HIV clinic (2% [-12%–17%]). As noted, these differences were not statistically significant, and the study was not powered to detect differences among subgroups.In the rapid arm, for which TB diagnostic data were available, 29/187 patients (16%) presented with TB symptoms and were tested for TB using Xpert MTB/RIF. Four patients (17% of those with symptoms and 2% of all rapid arm patients) had a confirmed TB diagnosis. All four initiated ART within the 90-d outcome defined above, with a range of 11–54 d between study enrollment and ART initiation.The results of the sensitivity analysis incorporating the six patients who were excluded after randomization for reasons other than ART eligibility or prior CD4 count, and assigning each a negative outcome, did not differ substantively from the findings presented above, with a relative risk of viral suppression by 10 mo of 1.22 [1.02–1.46].Rapid initiation, using the procedures described above and as implemented by the study, appeared acceptable to patients at the time it was offered and feasible to implement at both study sites. We were not able to assess acceptability after patients received the intervention, as the study had no post-initiation interaction with those enrolled, and thus can surmise acceptability only on the basis of acceptance of the intervention. The study refusal rate was very low (31/603, 5%); nearly four out of five (148/187, 79%) patients offered the intervention accepted initiation on the same day or the next day, and rapid arm patients consistently expressed appreciation for the opportunity to start immediately.All steps in the rapid initiation process were completed on the same day as study enrollment for 72% (135/187) of those in the rapid arm, demonstrating the feasibility of the intervention, at least within the context of the study. From provision of informed consent (study enrollment) to dispensing of the first supply of ARV medications, rapid initiation took a median of 2.4 (IQR 2.1–2.8) hours for those who initiated on the same day as study enrollment. This interval was shorter for patients who already had CD4 count results in hand at study enrollment (median 2.25 hours). It was longer (median 4.5 hours) for those who required a TB test and did initiate ART on the same day, but 15/20 patients requiring TB tests did not initiate on the same day. The only obstacle encountered in implementing rapid procedures was fairly frequent power outages, a common occurrence in South Africa, at Site 1, which did not have a generator for backup power supply. Most rapid instrument tests could not be performed during power outages. The rapid test instruments otherwise performed well throughout the study, and no major delays or problems arose in the acceleration of clinic procedures.DiscussionIn this randomized controlled trial, we evaluated the effectiveness of an accelerated ART initiation algorithm that combined compressed and accelerated clinic procedures with point-of-care laboratory testing technologies that allowed eligible patients to initiate ART in a single clinic visit. This intervention increased the proportion of patients eligible for ART at study enrollment who initiated ART within 90 d by 25%, to 97% of all eligible patients and 100% of patients who were not delayed for TB treatment. By 10 mo after study enrollment, the intervention increased viral suppression among all treatment-eligible patients by 13% and retention in care by 17%. It was feasible and appeared acceptable at both study sites.The trial demonstrated that it is possible to initiate nearly all eligible patients on ART, and to do so in a much shorter time interval than previously required. The net benefit for overall viral suppression was clinically meaningful and may underestimate the true benefits of the intervention. Both the study sites were relatively well-managed, public sector clinics, resulting in a higher rate of ART initiation in the standard arm (72%) than is found elsewhere in the country, for example in rural KwaZulu Natal Province where the rate was 59% [2]. In addition, we observed a larger effect at Site 1, the primary health clinic, than at Site 2, the hospital-based HIV clinic. Primary health clinics, which have fewer resources than hospital-based clinics but treat 85% of HIV patients in South Africa, may struggle more with loss to follow-up before treatment initiation than do hospital-based clinics, creating a greater opportunity for a service delivery intervention like RapIT to be effective. The potential for reaching younger men, who have been among the least likely to access ART under standard care [22], is another important potential benefit of rapid initiation. Additional research is needed to explore further the non-significant differences in effect that we observed in our study.The patients who likely benefited most from RapIT were those who would not otherwise have initiated treatment at all, or who would have waited until they were sick enough to compromise their prognosis on treatment. In the standard arm, most patients who did not start treatment did not return to the study clinics for even one more visit, underscoring the importance of taking full advantage of the first visit to get as many patients started on treatment as possible. For those who would have initiated treatment, just not as soon, there is some evidence that even relatively short delays may be harmful. A recent modeling exercise using South African data estimated that compared to immediate initiation, a delay in initiating ART of 70 d would lead to a 34% increase in 12-mo mortality [22]. Delaying treatment initiation thus both deters some patients from starting at all and jeopardizes outcomes for those who do start.We hypothesize that the delays and multiple visits patients must endure before starting ART directly deter treatment initiation. Patients who cannot afford transport fare for multiple visits, have childcare obligations at home, or risk job or wage loss if they miss too many days of work may be directly deterred from returning. Others may simply grow impatient or lose their courage or motivation, particularly if they are asymptomatic when diagnosed. These patients are likely to drift away and only return when their CD4 counts are lower and symptoms have started, or to die before treatment can be started. Our results suggest that offering the opportunity to start treatment on the spot, without delay, overcomes these barriers, without risking poorer outcomes later on.Among patients who did initiate ART, post-initiation loss to care was higher in the rapid arm than the standard arm. This difference disappeared in the survival analysis, which controlled for number of months on ART but does not reflect the benefits of randomization. We speculate that some patients who did not want or were not ready for treatment chose to accept immediate initiation simply because it was offered or they wanted to participate in the study. For these patients, attrition from care was simply shifted from before ART initiation to after. While the intervention was successful in increasing the overall proportion of treatment-eligible patients with successful outcomes (viral suppression and/or retention in care), the rate of post-initiation attrition is a reminder that early retention in care and adherence support once patients start treatment remain high priorities for further research and intervention.Other studies have gauged the impact on treatment uptake of a single POC technology [23] or changes in service delivery [24], but we found only one prior report of a “single-visit initiation” intervention that was similar, to some degree, to RapIT. That study enrolled pregnant women initiating ART for prevention of mother-to-child transmission in South Africa and found very high uptake of ART among women offered rapid initiation, but it did not have a comparison arm to allow an effect to be estimated [25]. A study in Tanzania and Zambia compared the effect of community support on a two-visit algorithm and reported 99% uptake of ART in both study arms [26]. Taken together, these studies imply that accelerating ART initiation is effective in a wide range of settings.Nothing in the rapid initiation procedures used in this study differed fundamentally from existing clinic procedures. The intervention was delivered by study nurses and counselors with the same qualifications as existing clinic staff, though with study-specific training and supervision. The intervention imposed no major burdens on site management, though managerial acquiescence to the study and operational flexibility were needed to adjust the schedule and content of patient visits, staff responsibilities, and record keeping to allow for rapid initiation [27]. The main technical training required was in the use of the POC test instruments, which also required a secure location within the clinic, temperature control, and electricity.Although South Africa has better clinic infrastructure than do many other countries in the region, the RapIT intervention does not require anything that most urban and many rural clinics cannot provide. We speculate that the RapIT intervention would be feasible and potentially even more effective in other high HIV prevalence areas, where patients travel farther to reach clinics and results from centralized laboratories take even longer to return. As the new WHO guidelines are adopted, moreover, laboratory test results may not be required prior to ART initiation for patients who are asymptomatic, reducing the need for POC technology.The generalizability of our results is limited in several ways. The study was conducted in only two clinics in one province of one country. The trial intervention was delivered by study staff; it is uncertain if clinic staff delivering the same intervention will achieve the same outcomes (and whether their outcomes will be better or worse than those observed in the trial). As is typical in individually randomized trials of service delivery interventions, the possibility exists that quality of care in the standard arm was improved by the presence of the study, as clinic staff providing care for the standard arm may have been motivated by the study to make treatment initiation more efficient. If this occurred, the effect reported here would understate the true improvement in ART initiation that could be expected under routine implementation. As with many studies in which retention in care is an endpoint, we do not know the true outcomes of study patients who were not retained nor whether rapid arm patients who were not retained and who agreed to start treatment solely due to the presence of the study, and would otherwise not have done so, are at increased risk of developing ARV resistance. Finally, as reported above, rapid initiation under the study algorithm took 2–3 hours to complete, making same-day initiation impractical for patients who arrive late in the day (and for clinics with large numbers of such patients).We also do not know how clinic and patient characteristics will affect the net cost and cost-effectiveness of the intervention. Most of the changes introduced in the RapIT intervention entailed only adjustments in schedules and staff time, and we speculate that these will not result in a major net change to service delivery costs. The POC instruments used in the trial require an up-front investment, but it may be possible to initiate ART in a single visit without any POC instruments if there is no CD4 count threshold for initiation, patients with TB symptoms are identified and managed separately, and ARV regimen adjustments are routinely made at the first refill visit, rather than before initiation. Costs saved by patients, who must make just one clinic visit rather than four or five, should also be taken into account.The RapIT intervention as designed and implemented showed clinically meaningful improvements in ART uptake and viral suppression, providing “proof of principle” for a single-visit treatment initiation algorithm. Follow-on studies are needed to evaluate effectiveness and cost-effectiveness in routine practice in a variety of settings, and variations on the algorithm could also be considered. The RapIT trial has demonstrated that accelerating ART initiation can be effective and feasible in this setting and appeared acceptable to patients to whom it was offered; the next challenge will be adapting it to the range of settings and conditions found in clinics throughout Africa.Supporting InformationS1 TableStudy outcomes adjusted for baseline CD4 count, age, and sex.(DOCX)Click here for additional data file.S2 TableCrude patient-level predictors of treatment uptake, viral suppression, and retention in care.(DOCX)Click here for additional data file.S3 TableStudy outcomes stratified by immediate versus delayed initiation (rapid arm patients initiating ≤90 d only).(DOCX)Click here for additional data file.S4 TableAbsolute and relative effect measure modification of primary outcome (initiated ≤90 d and suppressed by 10 mo).(DOCX)Click here for additional data file.S1 TextResearch protocol.(PDF)Click here for additional data file.S2 TextCONSORT statement.(PDF)Click here for additional data file.AbbreviationsALTalanine aminotransferaseaRRadjusted risk ratioARTantiretroviral therapyARVantiretroviralIQRinterquartile rangeCIconfidence intervalHRhazard ratioPHCprimary health clinicPOCpoint-of-careRapITRapid Initiation of TreatmentRDrisk differenceRRrelative riskTBtuberculosisReferences1\nSiednerMJ, NgCK, Bassett IV, KatzIT, BangsbergDR, TsaiAC. 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BMJ Open. 2012; 2:e000195\n10.1136/bmjopen-2011-000195\n25\nBlackS, ZulligerR, MyerL, MarcusR, JenekerS, HonsBA, et al\nSafety, feasibility and efficacy of a rapid ART initiation in pregnancy pilot programme in Cape Town, South Africa. S Afr Med J. 2013; 103:557–562. 10.7196/SAMJ.6565\n2388573926\nMfinangaS, ChandaD, KivuyoSL, GuinnessL, BottomleyC, SimmsV, et al\nCryptococcal meningitis screening and community-based early adherence support in people with advanced HIV infection starting antiretroviral therapy in Tanzania and Zambia: an open-label, randomised controlled trial. Lancet. 2015; 385:2173–2182. 10.1016/S0140-6736(15)60164-7\n2576569827\nClouseK, Page-ShippL, DanseyH, MoatlhodiB, ScottL, BassettJ, et al\nImplementation of Xpert MTB/RIF for routine point-of-care diagnosis of tuberculosis at the primary care level. S Afr Med J. 2012; 102:805–807. 10.7196/SAMJ.5851\n23034211', 'title': "Initiating Antiretroviral Therapy for HIV at a Patient's First Clinic Visit: The RapIT Randomized Controlled Trial.", 'date': '2016-05-11'}, '29136001': {'article_id': '29136001', 'content': "PLoS MedPLoS MedplosplosmedPLoS Medicine1549-12771549-1676Public Library of ScienceSan Francisco, CA USA29136001568543710.1371/journal.pmed.1002433PMEDICINE-D-17-02016Research ArticleMedicine and health sciencesDiagnostic medicineHIV diagnosis and managementBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesImmunodeficiency VirusesHIVBiology and life sciencesOrganismsVirusesRNA virusesRetrovirusesLentivirusHIVBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVBiology and Life SciencesOrganismsVirusesViral PathogensRetrovirusesLentivirusHIVBiology and Life SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesPublic and Occupational HealthPreventive MedicineVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyResearch and Analysis MethodsDatabase and Informatics MethodsHealth InformaticsElectronic Medical RecordsMedicine and health sciencesEpidemiologyHIV epidemiologyResearch and Analysis MethodsResearch DesignSurvey ResearchQuestionnairesMedicine and Health SciencesDiagnostic MedicineClinical Laboratory SciencesClinical LaboratoriesPeople and PlacesGeographical LocationsAfricaMozambiqueA combination intervention strategy to improve linkage to and retention in HIV care following diagnosis in Mozambique: A cluster-randomized studyA combination intervention strategy to improve HIV care in Mozambiquehttp://orcid.org/0000-0001-6101-3073ElulBatyaConceptualizationFunding acquisitionMethodologyProject administrationSupervisionWriting – original draftWriting – review & editing12*LambMatthew R.ConceptualizationData curationFormal analysisFunding acquisitionMethodologyWriting – original draftWriting – review & editing12http://orcid.org/0000-0002-9748-9273LahuertaMariaMethodologyProject administrationSupervisionWriting – original draftWriting – review & editing12AbacassamoFatimaInvestigationProject administrationWriting – review & editing3AhouaLaurenceConceptualizationFunding acquisitionInvestigationMethodologyProject administrationWriting – review & editing1http://orcid.org/0000-0001-7915-8553KujawskiStephanie A.Data curationFormal analysisWriting – review & editing2TomoMariaMethodologyProject administrationWriting – review & editing3JaniIleshMethodologyWriting – review & editing41\nICAP at Columbia University, Mailman School of Public Health, Columbia University, New York, New York, United States of America2\nDepartment of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, United States of America3\nCenter for Collaboration in Health, Maputo, Mozambique4\nInstituto Nacional de Saúde, Maputo, MozambiqueLewinSharon R.Academic EditorUniversity of Melbourne, AUSTRALIAI have read the journal's policy and the authors of this manuscript have the following competing interests: FA and MT were employees of the Center for Collaboration in Health which was providing technical support to the study health facilities at the time of the study.* E-mail: be2124@columbia.edu141120171120171411e100243396201710102017© 2017 Elul et al2017Elul et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.BackgroundConcerning gaps in the HIV care continuum compromise individual and population health. We evaluated a combination intervention strategy (CIS) targeting prevalent barriers to timely linkage and sustained retention in HIV care in Mozambique.Methods and findingsIn this cluster-randomized trial, 10 primary health facilities in the city of Maputo and Inhambane Province were randomly assigned to provide the CIS or the standard of care (SOC). The CIS included point-of-care CD4 testing at the time of diagnosis, accelerated ART initiation, and short message service (SMS) health messages and appointment reminders. A pre–post intervention 2-sample design was nested within the CIS arm to assess the effectiveness of CIS+, an enhanced version of the CIS that additionally included conditional non-cash financial incentives for linkage and retention. The primary outcome was a combined outcome of linkage to care within 1 month and retention at 12 months after diagnosis. From April 22, 2013, to June 30, 2015, we enrolled 2,004 out of 5,327 adults ≥18 years of age diagnosed with HIV in the voluntary counseling and testing clinics of participating health facilities: 744 (37%) in the CIS group, 493 (25%) in the CIS+ group, and 767 (38%) in the SOC group. Fifty-seven percent of the CIS group achieved the primary outcome versus 35% in the SOC group (relative risk [RR]CIS vs SOC = 1.58, 95% CI 1.05–2.39). Eighty-nine percent of the CIS group linked to care on the day of diagnosis versus 16% of the SOC group (RRCIS vs SOC = 9.13, 95% CI 1.65–50.40). There was no significant benefit of adding financial incentives to the CIS in terms of the combined outcome (55% of the CIS+ group achieved the primary outcome, RRCIS+ vs CIS = 0.96, 95% CI 0.81–1.16). Key limitations include the use of existing medical records to assess outcomes, the inability to isolate the effect of each component of the CIS, non-concurrent enrollment of the CIS+ group, and exclusion of many patients newly diagnosed with HIV.ConclusionsThe CIS showed promise for making much needed gains in the HIV care continuum in our study, particularly in the critical first step of timely linkage to care following diagnosis.Trial registrationClinicalTrials.gov NCT01930084In a cluster-randomized trial done in Mozambique, Batya Elul and colleagues study a combined intervention for linkage to and retention of people with HIV in care.Author summaryWhy was this study done?In sub-Saharan Africa, HIV testing, care, and treatment programs have been widely scaled up over the past decade, but suboptimal outcomes across the HIV care continuum—particularly with regards to timely linkage to and sustained retention in care—compromise their effectiveness.Patients experience multiple barriers to linkage to and retention in HIV care including health system barriers, structural barriers, and behavioral barriers, yet prior studies have largely evaluated individual interventions targeting a single barrier to care.Our study was designed specifically to examine the effectiveness of a combination intervention strategy (CIS) composed of several scalable evidence-based interventions targeting the multiple and prevalent health system, structural and behavioral barriers that patients face across the HIV continuum.What did the researchers do and find?We randomly assigned 10 primary health facilities in the city of Maputo and Inhambane Province in Mozambique to provide the standard of care (SOC) or the CIS, which included point-of-care CD4 testing at the time of diagnosis, accelerated ART initiation, and short message service (SMS) health messages and appointment reminders. A pre–post intervention 2-sample design was nested within the intervention arm to assess the effectiveness of CIS+, an enhanced version of the CIS that additionally included conditional non-cash financial incentives for linkage and retention.We enrolled 2,004 adults diagnosed with HIV in the voluntary counseling and testing clinics of participating health facilities, and compared the proportion who achieved a combined outcome of linkage to HIV care within 1 month of diagnosis and retention in care at 12 months across the 3 study groups.We found an increased likelihood of achieving the combined outcome in the CIS group compared to the SOC group, driven primarily by very large increases in same-day linkage, but no difference between the CIS+ and CIS groups.What do these findings mean?The CIS may help improve outcomes across the HIV care continuum in high-burden settings, particularly in the critical first step of timely linkage to care following diagnosis.Further research is needed to understand whether financial incentives can be optimized in this setting, given their effectiveness in enhancing other health outcomes.http://dx.doi.org/10.13039/100000200United States Agency for International DevelopmentAID-OAA-A-12-00027http://orcid.org/0000-0001-6101-3073ElulBatyahttp://dx.doi.org/10.13039/100000060National Institute of Allergy and Infectious DiseasesT32 AI114398http://orcid.org/0000-0001-7915-8553KujawskiStephanieThis study was funded by the United States Agency for International Development (USAID), USAID Award Number: AID-OAA-A-12-00027 and the National Institute of Allergy & Infectious Diseases of the National Institutes of Health, T32 AI114398 (SAK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Data AvailabilityAll relevant data are within the paper and its Supporting Information files.Data AvailabilityAll relevant data are within the paper and its Supporting Information files.IntroductionAlthough the extraordinary scale-up of HIV testing, care, and treatment programs in sub-Saharan Africa over the past decade has resulted in more than 19 million persons accessing antiretroviral therapy (ART) [1], the effectiveness of these programs has been significantly hindered by high levels of attrition across the HIV care continuum. Observational studies and systematic reviews have repeatedly reported disturbing gaps in care as patients move from HIV testing clinics to HIV care clinics (i.e., linkage to care) and that patient dropout among those enrolled in HIV care is far too common, both before and after ART initiation (i.e., retention in care) [2–7]. Indeed, available data suggest that less than 1/3 of individuals who are diagnosed with HIV are successfully linked to and remain engaged in HIV care 12 months later [4,8].Barriers to timely linkage to and sustained retention in HIV care have been well documented, and include health system barriers (e.g., multiple HIV clinic visits for counseling and clinical and laboratory assessments prior to ART initiation), structural barriers (e.g., transport costs and distances, work and childcare constraints), and behavioral barriers (e.g., forgetting appointments, lack of understanding of required care) [9–14]. Prior studies have overwhelmingly evaluated individual interventions targeting a single barrier at a single point in the HIV care continuum such as mobile phone short message service (SMS) messaging to augment linkage to care following diagnosis, or point-of-care CD4 testing to enhance retention among patients enrolled in HIV care [15,16]. However, it is increasingly recognized that multi-component approaches composed of several practical, evidence-based interventions that simultaneously target the multiple and recurrent barriers that patients face as they navigate across the HIV care continuum are needed to maximize individual and population health [17,18]. Further, implementation science research that evaluates proposed multi-component approaches in real-world settings is needed to assess not only effectiveness, but also implementation outcomes including reach, adoption, and sustainability [19]. To this end, we designed a combination intervention strategy (CIS) composed of several scalable evidence-based interventions targeting prevalent health system, structural, and behavioral barriers across the HIV care continuum, and determined its effect on a combined outcome of linkage to and retention in HIV care among adults newly diagnosed with HIV in Mozambique, while also collecting information on its implementation and potential for broader scale-up [20]. Data regarding intervention feasibility and patient acceptability have been published [21], and thus we present here the effectiveness results. Because the interventions included in the CIS are expected to be implemented at the facility level, as opposed to targeted at specific individuals, should they be scaled up, we evaluated effectiveness using a cluster design, which best mirrors this implementation approach.MethodsA detailed description of the study protocol has been published [22].Ethics statementEthical approval was provided by Mozambique’s National Committee for Bioethics for Health and Columbia University’s institutional review board (IRB) (protocol AAAL1354). Informed written consent was obtained from all participants.Study designBetween April 22, 2013, and June 30, 2016, we conducted a 2-arm cluster-randomized study (effectiveness–implementation hybrid design, Type 1) [20] in health facilities in Maputo and Inhambane Province in Mozambique in order to assess the effectiveness of the CIS. Additionally, a pre–post intervention 2-sample design was nested within the intervention arm to assess the additional effectiveness of an enhanced version of the CIS, referred to as CIS+. Consequently, the standard of care (SOC) arm enrolled 1 cohort of patients, while the intervention arm enrolled 2 sequential cohorts of patients (CIS and CIS+). CIS+ participants were enrolled after CIS enrollment was completed at each facility randomized to the intervention arm.Study settingThe city of Maputo, the nation’s capital, has an area of 300 km2 and an estimated population of 1,225,868 [23], with an HIV prevalence of 16.9% among those aged 15 to 59 years [24]. The Maputo City Health Network has a total of 37 health facilities, 32 of which offered comprehensive HIV care and treatment services at the time of study implementation [25]. In contrast, Inhambane is a rural province, with an estimated 1,475,318 people spread across 68,615 km2 [23]. HIV prevalence among adults aged 15 to 59 years is 14.1% [24]. The ratio of doctors to population (5.96/100,000) is one of the lowest in the country [26]. Of the 135 health facilities in the province, 76 offered HIV care and treatment services when our study was initiated [25]. Suboptimal health facility infrastructure, long distances to facilities, and weak referral systems in the province are all believed to compromise health service uptake [26].RandomizationPrimary health facilities providing HIV testing, care, and treatment services and operated by the Ministry of Health with technical support from the Center for Collaboration in Health, a local PEPFAR implementing partner, were the unit of randomization. We focused on primary health facilities, rather than larger provincial hospitals, to reflect the increasingly decentralized nature of HIV service delivery in Mozambique. Ten facilities in Maputo (N = 4) and Inhambane Province (N = 6) were selected from the 66 primary health facilities receiving technical support from the Center for Collaboration in Health in those regions. Participating facilities were purposely chosen because they had the highest volume of adults testing HIV positive and enrolling in HIV care in the year prior to study start and thus were expected to have sufficient participants for appropriate power. Facilities were matched into pairs by region (Maputo or Inhambane), level of urbanicity (urban versus rural), and average number of patients testing HIV positive in voluntary counseling and testing (VCT) in the year prior to study initiation (high versus low), resulting in 5 matched pairs. Matched pairs were randomized by one of the authors (MRL) using a computerized random number generator to either the CIS arm or the SOC arm using matched-pair randomization. Sequences were concealed until interventions were assigned. The study was non-blinded.Study populationParticipants were enrolled in the SOC group beginning on April 22, 2013, and in the CIS group beginning on April 25, 2013. The last patient was enrolled in the SOC group on November 20, 2014, and the last patient in the CIS group was enrolled on February 11, 2015. Enrollment in the CIS+ group began after each clinic randomized to the intervention arm completed CIS enrollment, and ran from June 16, 2014, through June 30, 2015. All participants were followed for 12 months, with the last patient completing follow-up on June 30, 2016.Broad inclusion criteria were used to reflect as accurately as possible the population of adults newly diagnosed with HIV in VCT clinics at the participating health facilities. We focused on individuals newly diagnosed in VCT clinics, as opposed to those diagnosed in antenatal clinics and tuberculosis clinics, because the latter groups of patients typically follow a modified clinic flow. All adults testing HIV positive in the VCT clinics within the participating health facilities were informed of the study by HIV testing counselors following diagnosis, and those who were interested were referred to study staff for further information, eligibility screening, and consent procedures. Patients were excluded if they were less than 18 years of age, were pregnant, planned to move from their community of residence in the next 12 months, had enrolled in HIV care or initiated ART in the past 6 months, did not understand Portuguese or Xitsua, or were incapable of providing informed consent. Study participants agreed to be referred to HIV care and treatment services at the same facility where they were diagnosed (referred to as the “diagnosing facility”); to complete a baseline, 1-month, and 12-month interview; to be traced at their homes if they could not be reached by phone for follow-up interviews; to provide contact information for a family member or friend who could provide information on their vital status if they could not be located for a follow-up interview; and, if they enrolled in HIV care and treatment services at the diagnosing facility, to have their clinical data abstracted from the facility’s existing electronic medical records.Study interventionsStandard of careParticipants at health facilities randomized to receive the SOC were managed as per prevailing Ministry of Health guidelines [27]. Individuals diagnosed with HIV received post-test counseling in the VCT clinic and were referred verbally to HIV services, typically in the diagnosing facility. Patients presenting to the facility receptionist to schedule a clinical consultation for HIV care were referred to the laboratory for CD4 cell count, chemistry, and hematology testing, and provided with an appointment 2–4 weeks later to allow sufficient time for the laboratory results to be received. ART eligibility was determined at that first clinical consultation based on CD4 cell count ≤ 350 cells/mm3 and/or WHO stage 3/4. Those found to be eligible for ART received at least 1 individual counseling session before initiating treatment. For ART-eligible patients, the time interval between enrollment in HIV care and ART initiation was estimated at 1–2 months at the time the study started. Participants initiating ART were requested to return every 2 weeks for the first month, at 2 months, at 6 months, and every 6 months thereafter. ART-ineligible patients were instructed to return at 6 months for repeat clinical evaluation and laboratory testing.Combination intervention strategyAt facilities randomized to the intervention arm, we introduced 4 evidence-based interventions that simplified the clinic flow and encouraged linkage to and retention in care. These interventions targeted several known health system, structural, and behavioral barriers across the HIV care continuum, and were adapted for the on-the-ground realities—including practice norms, physical space, and available staffing—at the health facilities. First, we introduced Pima (Inverness Medical Innovations) CD4 assay machines in the VCT clinics to enable HIV testing counselors to provide real-time, point-of-care CD4 test results immediately following diagnosis, and thus addressed a health system barrier by reducing the number of visits required for CD4 testing. We also hypothesized that receipt of additional information on one’s health at the time of diagnosis would advance patient understanding of the need for care, a documented behavioral barrier [10,28]. All patients regardless of CD4 count were provided with a paper-based referral to on-site HIV services that included their CD4 count, and were instructed to present for their first clinical consultation within 1 week. Second, to address additional health system barriers, patients with Pima CD4 cell count ≤ 350 cells/mm3 were provided with accelerated ART initiation, with the ultimate goal of decreasing the HIV morbidity and mortality that contributes to significant attrition among ART-eligible patients [4]. These individuals received an individual ART preparatory counseling session in the VCT clinic immediately following CD4 testing, on the day of diagnosis. Facility receptionists were instructed to expedite appointments for these patients when they presented to schedule their clinical consultations. Although the patients were directed to the laboratory to have their blood drawn for baseline laboratory tests required by national ART guidelines, clinicians were encouraged to initiate ART at the first clinical visit rather than await the results of the laboratory tests unless the patient presented with comorbid conditions. Patients who initiated ART received a 2-week supply and followed the visit schedule dictated by national guidelines, similar to the SOC procedures. Once baseline laboratory results were available, they were reviewed by clinic staff, and if abnormalities were noted, the participant was contacted to return to the clinic. Third, participants received health messages and appointment reminders via SMS messaging to address behavioral barriers associated with deferring care engagement and forgetting appointments. The messages were sent from the central study office to the participant’s phone or to a friend or relative’s phone per participant preference, and did not refer to HIV or a specific health facility or reveal any personal information. The health messages encouraged participants to care for their health, and were sent weekly for 1 month following diagnosis and then monthly (e.g., “Hi. Your health is the most important thing. Please remember to come to the health center for health services.”). Appointment reminders were sent only to participants who linked to care at the diagnosing facility, and were sent 3–7 days before each scheduled clinic visit (e.g., “Hi. Your health is the most important thing. We expect to see you at your upcoming appointment scheduled for the day ___.”). Participants were not asked to confirm receipt or reply to the messages. Finally, patients in the CIS+ cohort received the CIS interventions plus a series of non-cash financial incentives (FIs) in the form of prepaid cellular air-time cards to offset structural barriers associated with the direct and indirect costs of coming to the health facility to receive HIV care. Air-time cards rather than cash were selected as the incentive based on discussion with the Ministry of Health. Each card was valued at approximately US$5 and was provided conditionally upon the following achievements: linkage to care within 1 month of diagnosis, retention in care 6 months after diagnosis, and retention in care 12 months after diagnosis, for a total of approximately US$15. Participants who completed each achievement received the card when presenting for routine services. Participants without cellular phones could opt to give them to a family member, sell them for cash, or trade them for other goods. Both the point-of-care CD4 testing and accelerated ART initiation interventions were provided by health facility staff to all individuals diagnosed with HIV in the VCT clinic regardless of whether they were enrolled in the study, while the SMS messages and FIs were provided by study staff and only to study participants.Data collection and outcomesSite assessmentsData on the configuration of HIV services at the 10 participating study sites were collected at the beginning and at the end of the study using a standardized site assessment form. The purpose of the site assessments was to identify important similarities and differences between participating health facilities, as well as to better understand how services at the site could impact study implementation.Baseline interviewParticipants completed closed-ended questionnaires administered by trained research assistants at the time of study enrollment. The questionnaire took about 30 minutes to complete, and gathered information on sociodemographic characteristics, social and family support, mental health, alcohol use, HIV testing history, HIV knowledge and beliefs, and anticipated stigma and barriers to care. Anticipated stigma was assessed through 6 items adapted from the 12-item anticipated HIV stigma index developed by Earnshaw and Chaudoir [29]. Stigma scores were summed, then dichotomized into 2 groups: highest (>75th percentile) versus lower anticipated stigma. Mental health was assessed via a 7-question evaluation based on the Kessler 10-item scale for psychological distress [30]. Mental health scores were summed, then dichotomized into 2 groups: highest (<75th percentile) versus lower level of distress. Perceived availability of social support was assessed with 4 questions adapted from a 9-item scale by Wortman and colleagues [31]. Social support scores were summed, then dichotomized into 2 groups: higher (>50th percentile) versus lower social support. Questions assessing HIV-related knowledge and attitudes were based on those used by one of the authors in a previous study [32]. HIV knowledge scores were summed, then dichotomized into 2 groups: higher (>50th percentile) versus lower knowledge. Baseline interview data were double-entered into a study database, and a computer program identified discrepant double-entered results for correction against the paper-based forms.Patient tracing and follow-up interviewsOne and 12 months after enrollment, up until June 30, 2016, trained research assistants contacted participants by phone to ascertain their vital status and HIV care status, and to administer follow-up questionnaires. If the participant could not be contacted by phone after 3 attempts, research assistants visited the participant’s home up to 3 times. Participants who were located completed closed-ended interviews that gathered updated information on key domains from the baseline questionnaire, as well as self-reported information on linkage to (1- and 12-month questionnaires) and retention in HIV care (12-month questionnaire only), reasons for linkage/non-linkage (1- and 12-month questionnaires) and retention/non-retention (12-month questionnaire only), ART status, hospitalizations, and anticipated stigma. In cases where the participant could not be located, research assistants contacted a friend or family member as specified by the participant at study enrollment. Research assistants did not refer to HIV or the health facility during contact tracing but rather attempted to determine whether the participant was alive or dead. For those whose vital status could not be determined through contact tracing, research assistants searched existing electronic medical records at other primary health facilities supported by the Center for Collaboration in Health in the same district to assess whether patients had enrolled in HIV care at another facility, and reviewed death registers at the municipal and provincial levels to ascertain their vital status. Similar data entry and reconciliation procedures to those used for the baseline interview data were used for the tracing and follow-up data.Abstraction of clinical data for patients linking to HIV care at the diagnosing facilityAs part of routine clinical practice for HIV patients, clinicians documented patient information at every clinic visit on national HIV care forms, and trained data clerks entered those data into an Access-based electronic medical record. In its role as a PEPFAR implementing partner supporting the study sites, the Center for Collaboration in Health assessed the completeness and accuracy of these electronic data every 4 months and initiated targeted interventions to enhance data quality if there was greater than 15% disagreement on key data elements between the electronic and paper-based systems. During the study period, research assistants reviewed the electronic medical records to identify study participants who had linked to care at their diagnosing facility. For those located, we extracted the complete electronic medical record, capturing information on visit dates, vital status, transfer status, ART status, laboratory test results, and opportunistic infections.OutcomesThe primary outcome was a combined outcome of linkage to HIV care within 1 month of diagnosis plus retention in care 12 months after diagnosis measured at the individual level. We used a combined outcome to reflect the fact that improvements are needed across the HIV care continuum in order to maximize individual and population health. Linkage to care was defined by at least 1 clinical consultation for HIV that included assessment of the patient’s medical history and a physical exam. Retention in care was defined by a clinic visit in the 90 days prior to the end of the 12-month study follow-up period, with no documentation that the patient had transferred to another facility or had died. We assessed the combined outcome from the perspective of the diagnosing health facility using data from the electronic medical records maintained by the HIV clinics. All study participants were included in these analyses, including those who did not complete follow-up interviews. Participants whose electronic medical records were not located were considered not to have achieved the combined outcome for this analysis. As a secondary approach, we evaluated the combined outcome from the perspective of the Mozambican health program by supplementing data from the electronic medical records with patient reports of linkage to and retention in care at HIV clinics at different health facilities (obtained during follow-up interviews) and information obtained from electronic medical records at other health facilities. In these analyses, participants whose self-reported linkage and retention status suggested they were linked to and/or retained at a health facility other than their diagnosing clinic were considered to have achieved the respective linkage/retention outcomes. Participants who either did not complete follow-up interviews or did not self-report linkage to or retention at another clinic maintained their initial outcome designation. All study participants were included in these analyses.Secondary outcomes included linkage to care at several predefined time points, ART eligibility assessment (defined as receipt of WHO staging and/or CD4 cell count), ART initiation, disease progression (defined as a new WHO stage 3/4 condition or hospitalization noted in the electronic medical records or self-reported during follow-up interviews), retention in care 6 and 12 months after diagnosis regardless of the timing of linkage, and death.Statistical analysisThe trial was designed and powered to measure outcomes at the individual level, with outcomes assessed within each cluster (5 clusters per arm). In our initial power calculations, we anticipated that an average of 200 patients per clinic (in the CIS and SOC arms) would be eligible for enrollment based on historical data on the annual number of adults testing positive in the VCT clinics at the participating health facilities. With 5 facilities per study arm, an average of 200 patients per facility, an intraclass correlation coefficient (ICC) of 0.05, and an alpha of 0.05 and assuming that 35% of participants in the SOC arm would achieve the primary outcome, we estimated that the study would have 80% power to detect as statistically significant 55% of participants in the CIS group achieving the primary outcome, and greater than 80% power to detect as statistically significant 75% of participants in the CIS+ group achieving the primary outcome. Because enrollment proceeded slower than originally planned, at study midpoint we assessed the implications for power if each health facility enrolled an average of 150 participants rather than 200. Our calculations revealed minimal change in power with this reduction in the number of participants per health facility. Calculations were performed using PASS 8.0 software for 2 independent proportions in a cluster randomization study design and a 2-sided Farrington and Manning Likelihood Score Test [33]. Our power estimations and statistical analyses did not take into account the pair matching prior to randomization but rather followed recommendations from Diehr et al. [34] to break matches in statistical analyses of clustered studies when the number of pairs is between 3 and 9.An intent-to-treat analysis determined the relative risk (RR) of achieving study outcomes between the CIS and SOC groups, and between the CIS+ and CIS groups. For analyses of the primary outcome, we used random-intercept multilevel log-Poisson models to account for clustering within health facilities with an empirical variance adjustment for small numbers of sampling units described by Morel et al. [35]. We also assessed whether the primary outcome differed after adjustment for patient-level factors by constructing propensity scores that estimated the probability of inclusion in the CIS, CIS+, and SOC groups by age, sex, region, education, income, employment status, marital status, religion, prior year history of being away from home for more than 1 month, travel time to clinic, tuberculosis status, past hospitalizations, diagnosis history, and whether another family member was known to be living with HIV. The propensity score was included as a covariate in the multivariable log-Poisson models (adjusted analyses). In post hoc analyses, we further estimated the likelihood of key subgroups achieving the primary outcome using interaction contrast ratios. The subgroups assessed included subgroups based on baseline age, sex, region of health facility, employment status, marital status, whether the participant was away from home for more than 1 month in the year prior to study enrollment, travel time to clinic, whether a household member was known to be HIV positive, and dichotomous variables based on scales for self-reported anticipated stigma, HIV knowledge, mental health, and perceived social support as described earlier. For analyses of secondary outcomes, log-Poisson models were used for dichotomous outcomes, and t tests and 2-way median tests as appropriate for continuous outcomes, adjusting for clustering but not for patient-level differences.ResultsHealth facility characteristicsAs noted above, 10 primary health facilities participated in the study, 4 in Maputo and 6 in Inhambane. At study start, the 5 health facilities randomized to the intervention arm reported that they had experienced disruptions of 3 or more days in VCT services in the prior 12 months, while only 1 facility randomized to the SOC arm reported experiencing a similar disruption. By study end, no facilities—whether in the intervention or SOC arm—had experienced such disruptions. Throughout the study, only intervention sites conducted point-of-care CD4 testing using Pima machines in the VCT clinic. Two SOC sites reported that they had Pima machines available in their laboratories but only used them to monitor CD4 counts after patients had enrolled in HIV care. None of the SOC sites used SMS messaging for health messages or appointment reminders on a routine basis for all patients, but 2 sites sent SMS appointment reminders for patients participating in community ART groups [36]. Though the 2013 national HIV treatment guidelines stipulate that 1 ART preparatory counseling session is required for ART-eligible patients, all the facilities participating in the study typically conducted 2 to 3 sessions prior to ART initiation, with a slight reduction in the number of sessions observed between study start and end.Enrollment and participant characteristicsFig 1 shows the enrollment, exclusion, and flow of the patients by study group. During the study period, 5,327 adults ≥18 years of age were diagnosed with HIV in the VCT clinics at the 10 study facilities. A total of 265 of those individuals were not referred to the study staff for further information on the study because they informed the HIV testing counselor that they were not interested in the study, were already receiving HIV services, or were not willing to be referred to the diagnosing health facility. Among the 5,062 who were referred to the study staff for further information, 3,058 did not meet study eligibility criteria. The main reasons for exclusion were inability to provide informed consent due to distress following diagnosis (19%), inability to understand Portuguese or Xitsua (12%), and refusal to be referred to the diagnosing health facility for HIV services (10%).10.1371/journal.pmed.1002433.g001Fig 1Flow chart for study participation.CIS, combination intervention strategy; SOC, standard of care; VCT, voluntary counseling and testing.A total of 2,004 adults ≥18 years of age enrolled in the study at the 10 health facilities: 744 (37%) in the CIS group, 493 (25%) in the CIS+ group, and 767 (38%) in the SOC group. The majority of participants were female (64%), and the median age of participants was 34 years of age, with no meaningful differences observed by study group (Table 1). More than half of the participants (53%) were living with a partner at the time of diagnosis, and 65% of participants had a primary or lower level of education. Most participants (74%) were employed, and 43% had a monthly income of less than 1,500 meticais (approximately US$50). One-quarter (27%) reported that another household member was living with HIV. While no serious adverse events were reported during the study period, there was 1 unanticipated event of a female participant reporting intimate partner violence. The Mozambican National Committee for Bioethics for Health and the Columbia University IRB were informed of this event, and the participant asked to remain in the study but to conduct all study interviews at the facility (i.e., no follow-up phone calls).10.1371/journal.pmed.1002433.t001Table 1Participant characteristics at study enrollment in the 3 study groups (N = 2,004).CharacteristicTotalN = 2,004CISN = 744CIS+N = 493SOCN = 767p-ValueRegionMaputo1,077 (54%)396 (53%)275 (56%)406 (53%)0.58Inhambane927 (46%)348 (47%)218 (44%)361 (47%)Sex0.50Female1,292 (64%)490 (66%)319 (65%)483 (63%)Male712 (36%)254 (34%)174 (35%)284 (37%)Age (years)34.2 (9.6)34.9 (9.8)33.8 (9.9)33.8 (9.3)0.04518–24265 (13%)90 (12%)70 (14%)105 (14%)0.1225–391,233 (62%)440 (59%)301 (61%)492 (64%)40–49348 (17%)148 (2%)87 (18%)113 (15%)50+158 (8%)66 (9%)35 (7%)57 (7%)Marital status<0.001Married/partner and living together1,068 (53%)376 (51%)255 (52%)437 (57%)Married/partner, but not living together222 (11%)101 (14%)86 (17%)35 (5%)Single713 (36%)266 (36%)152 (31%)295 (38%)Missing/refused1 (0%)1 (0%)0 (0%)0 (0%)Education0.003None164 (8%)59 (8%)33 (7%)72 (9%)Primary1,149 (57%)442 (59%)256 (52%)451 (59%)Secondary471 (24%)164 (22%)130 (26%)177 (23%)Above secondary219 (11%)78 (1%)74 (15%)67 (9%)Missing/refused1 (0%)1 (0%)0 (0%)0 (9%)Employment0.46Employed1,473 (74%)537 (72%)361 (73%)575 (75%)Unemployed531 (26%)207 (28%)132 (27%)192 (25%)Monthly income<0.001≤1,500 meticais871 (43%)342 (46%)165 (33%)364 (47%)>1,500 meticais936 (47%)343 (46%)271 (55%)322 (42%)Missing/refused197 (1%)59 (8%)57 (12%)81 (11%)Another household member has HIV0.28Yes550 (27%)187 (25%)144 (29%)219 (29%)No913 (46%)361 (49%)219 (44%)333 (43%)Don’t know539 (27%)196 (26%)130 (26%)213 (28%)Missing/refused2 (0%)0 (0%)0 (0%)2 (0%)Data given as N (percent).CIS, combination intervention strategy; SOC, standard of care.Intervention effect on linkage to and retention in HIV care at the diagnosing facilityAs shown in Table 2, the CIS was associated with statistically significant improvements in the combined outcome of linkage to care within 1 month of diagnosis and retention in care 12 months following diagnosis when compared to the SOC. Analyses using data from electronic medical records to examine linkage to and retention at the diagnosing health facility showed that 57% of participants in the CIS group achieved the primary outcome versus 35% of those in the SOC group (RRCIS vs SOC = 1.58, 95% CI 1.05–2.39). Post hoc calculation of the ICC for the primary outcome according to the methods of Snijders and Bosker for binary outcome data [37] estimated an ICC of 0.066, similar to but slightly higher than the assumed ICC of 0.05 used in power and sample size estimation. These results were robust to adjustment for patient-level differences (adjusted RR [aRR]CIS vs SOC = 1.55, 95% CI 1.07–2.25). As shown in Fig 2, the greatest intervention effects were observed among young adults age 18–24 years (RRCIS vs SOC = 2.39, 95% CI 1.51–3.80, p-value for interaction between age and treatment arm = 0.07), those in Maputo (RRCIS vs SOC = 2.31, 95% CI 1.90–2.79, p-value for interaction between region and treatment arm < 0.0001), those who did not report that another household member was living with HIV (RRCIS vs SOC = 1.81: 95% CI 1.52–2.16, p-value for interaction between household member with HIV and treatment arm = 0.11), and those reporting high levels of anticipated stigma at enrollment (RRCIS vs SOC = 1.95, 95% CI 1.53–2.49, p-value for interaction between stigma and treatment arm = 0.10).10.1371/journal.pmed.1002433.g002Fig 2Relative risk of the CIS compared to the SOC on the primary outcome at the diagnosing health facility by patient characteristics.a Fifteen patients with missing information were excluded from this estimate. A description of the variables examined and categories used are provided in the Methods section.10.1371/journal.pmed.1002433.t002Table 2Linkage to and retention in HIV care: CIS versus SOC and CIS+ versus CIS.CategoryOutcomeCISN = 744CIS+N = 493SOCN = 767RR1 (95% CI), p-ValueaRR2 (95% CI), p-ValueNPercentNPercentNPercentCIS versus SOCCIS+ versus CISCIS versus SOCCIS+ versus CISPrimary outcomeAt diagnosing facilityLinked to care within 1 month of diagnosis and retained 12 months after diagnosis42557%27355%26835%1.58 (1.05–2.39)p = 0.030.96 (0.81–1.16)p = 0.661.55 (1.07–2.25)p = 0.040.94 (0.76–1.18)p = 0.52At any health facilityLinked to care within 1 month of diagnosis and retained 12 months after diagnosis54774%36073%36347%1.47 (1.08–2.01)p = 0.020.98 (0.85–1.15)p = 0.911.46 (1.05–2.04)p = 0.030.96 (0.83–1.11)p = 0.52Secondary outcomesLinkage at diagnosing facilitySame day as HIV test65989%45793%12016%9.13 (1.65–50.40)p = 0.021.04 (0.92–1.20)p = 0.38N/AWithin 1 week of HIV test67891%46194%34946%2.43 (0.70–8.41)p = 0.141.03 (0.91–1.16)p = 0.59N/AWithin 1 month of HIV test70394%46795%48263%1.48 (0.93–2.35)p = 0.091.00 (0.89–1.13)p = 0.96N/AWithin 12 months of HIV test71696%46795%59277%1.23 (1.03–1.48)p = 0.030.98 (0.87–1.11)p = 0,74N/ARetention at diagnosing facility6 months after diagnosis46262%32265%40553%1.18 (1.00–1.39)p = 0.061.05 (0.88–1.26)p = 0.48N/A12 months after diagnosis43558%27355%34144%1.32 (1.12–1.54)p = 0.0040.95 (0.79–1.13)p = 0.45N/A1RR accounts for clustering within sites using random-intercept log-Poisson regression with empirical standard error estimates.2aRR adjusts for patient-level differences using propensity scores.aRR, adjusted relative risk; CIS, combination intervention strategy; N/A, not applicable; RR, relative risk; SOC, standard of care.Eighty-nine percent of participants in the CIS group linked to the diagnosing facility on the same day as diagnosis compared to 16% (RRCIS vs SOC = 9.13, 95% CI 1.65–50.40) in the SOC group, 91% within 1 week compared to 46% (RRCIS vs SOC = 2.43, 95% CI 0.70–8.41), and 94% within 1 month compared to 63% (RRCIS vs SOC = 1.48, 95% CI 0.93–2.35). By 12 months, nearly all CIS participants (96%) had linked to care compared to 77% (RRCIS vs SOC = 1.23, 95% CI 1.03–1.48) of SOC participants. Among those linking to care, the median (interquartile range [IQR]) time from diagnosis to linkage was 0 days (0–0) in the CIS group and 3 days (1–26) in the SOC group (median test p < 0.001 for CIS versus SOC). The effect of the intervention on retention in care, regardless of the timing of linkage, was more modest but statistically significant (6-month retention: 62% CIS versus 53% SOC, RRCIS vs SOC = 1.18, 95% CI 1.00–1.39; 12-month retention: 58% CIS versus 44% SOC, RRCIS vs SOC = 1.32, 95% CI 1.12–1.54).In analyses restricted to the participants initiating ART, the median (IQR) time from diagnosis to ART initiation in the CIS and SOC groups was 32 (12–135), and 63 (33–230) days, respectively, while the median (IQR) time from enrollment in HIV care to ART initiation was 32 (11–127), and 50 (15–205) days, respectively. Median time from ART eligibility to ART initiation for the CIS, CIS+, and SOC groups was 21 (9–40), and 25 (11–56) days, respectively.There was no additional benefit of adding FIs to the CIS, with 55% (RRCIS+ vs CIS = 0.96, 95% CI 0.81–1.16; aRRCIS+ vs CIS = 0.94, 95% CI 0.76–1.18) of those in the CIS+ group achieving the primary outcome; 95% (RRCIS+ vs CIS = 1.00, 95% CI 0.83–1.13) linking to HIV care within 1 month of diagnosis, regardless of retention at 12 months; and 55% (RRCIS+ vs CIS = 0.95, 95% CI 0.79–1.13) being retained in care 12 months after diagnosis, regardless of the timing of linkage to care.Intervention effect on linkage to and retention in care at any health facilityAnalyses supplementing data from electronic medical records from participating facilities with data from patient interviews and other health facilities in the study regions to examine linkage to and retention at any health facility showed similar effects of the intervention package. A total of 74% (RRCIS vs SOC = 1.47, 95% CI 1.08–2.01) of participants in the CIS group and 47% in the SOC group were found to have linked to HIV care at any health facility within 1 month of diagnosis and were retained in HIV care 12 months after diagnosis (Table 2). Adjustment for patient-level differences did not result in any change in this finding (aRRCIS vs SOC = 1.46, 95% CI 1.05–2.04). Inclusion of FIs in the CIS also showed no additional benefit for linkage to and retention at any health facility, with 73% (RRCIS+ vs CIS = 0.98, 95% CI 0.85–1.15; aRRCIS+ vs CIS = 0.96, 95% CI 0.83–1.11) of those in the CIS+ group known to have linked to and been retained in HIV care at any health facility compared to the CIS group.Intervention effect on ART eligibility and initiation, disease progression, and deathData from electronic medical records at study sites indicated that compared to patients in the SOC group, patients in the CIS group were more likely to ever have their ART eligibility assessed (100% versus 76.9%, RRCIS vs SOC = 1.29, 95% CI 1.08–1.54), be identified as ART eligible (75% versus 60%, RRCIS vs SOC = 1.24, 95% CI 1.07–1.43), and initiate ART (65% versus 54%, RRCIS vs SOC = 1.20, 95% CI 1.00–1.43) (Table 3). Very few participants were diagnosed with a new WHO stage 3/4 event at the diagnosing facility or self-reported a hospitalization in the 12 months after HIV diagnosis. Those in the CIS group had a non-significantly but modestly decreased risk compared to those in the SOC group (1% versus 3%, RRCIS vs SOC = 0.38, 95% CI 0.07–2.03), while similar results were observed between the CIS and CIS+ groups (1% versus 1%, RRCIS+ vs CIS = 0.65, 95% CI 0.12–3.64). Neither the CIS nor the CIS+ interventions had a significant effect on mortality within 12 months of diagnosis, with 6%, 5%, and 7% of participants in the CIS, CIS+, and SOC groups, respectively, known to have died during study follow-up (RRCIS vs SOC = 0.87, 95% CI 0.40–1.91; RRCIS+ vs CIS = 0.88, 95% CI 0.45–1.74). The CIS also did not have a significant impact on mortality before (3%, RRCIS vs SOC = 0.78, 95% CI 0.46–1.32) or after ART initiation (3%, RRCIS vs SOC = 0.96, 95% CI 0.26–3.48); participants in the CIS+ group were less likely to die, though non-significantly so, before initiating ART compared to those in the CIS group (1% versus 3%, RRCIS+ vs CIS = 0.34, 95% CI 0.09–1.29).10.1371/journal.pmed.1002433.t003Table 3ART determination and initiation, disease progression, and death: CIS versus SOC and CIS+ versus CIS.\xa0OutcomeCIS(N = 744)CIS+(N = 493)SOC(N = 767)RR1 (95% CI), p-valueNPercentNPercentNPercentCIS versus SOC1CIS+ versus CIS1ART eligibility assessed744100%493100%59077%1.29 (1.08–1.54)p = 0.011.00 (0.89–1.12)p = 1.00Identified as ART eligible55775%37275%46460%1.24 (1.07–1.43)p = 0.011.01 (0.85–1.19)p = 0.91Initiated ART48465%33267%41654%1.20 (1.00–1.43)p = 0.051.03 (0.88–1.22)p = 0.59New WHO stage 3/4 or hospitalization71%31%233%0.38 (0.07–2.03)p = 0.220.65 (0.12–3.64)p = 0.53Death within 12 months466%275%547%0.87 (0.40–1.91)p = 0.690.88 (0.45–1.74)p = 0.63Death before ART initiation223%51%294%0.78 (0.46–1.32)p = 0.310.34 (0.09–1.29)p = 0.09Death after ART initiation243%224%253%0.96 (0.26–3.48)p = 0.941.38 (0.62–3.07)p = 0.331RR accounts for clustering within sites using random-intercept log-Poisson regression with empirical standard error estimates.ART, antiretroviral therapy; CIS, combination intervention strategy; RR, relative risk; SOC, standard of care.DiscussionWe conducted a cluster-randomized study in Mozambique to examine the effectiveness of a multi-component approach to increase linkage to and retention in HIV care—2 critical elements of the HIV care continuum—among adults newly diagnosed with HIV. The operational model of the CIS that we evaluated addresses known structural, biomedical, and behavioral barriers across the HIV care continuum and was composed of evidence-based, practical, and scalable interventions, including CD4 testing in VCT clinics with immediate turnaround of results, accelerated ART initiation for eligible individuals, and SMS health messages and appointment reminders. An enhanced version of the CIS additionally included FIs. In the spirit of implementation science, 2 of the interventions were implemented by existing health facility staff, rather than study staff, providing information on the real-world successes and challenges associated with the CIS that can be extrapolated to a range of settings with similar implementation contexts.Our study showed that participants receiving the CIS were 1.58 times more likely to link to HIV care at their diagnosing facility within 1 month of diagnosis and be retained in care at that same facility 12 months following diagnosis, representing not only a statistically significant but also a programmatically meaningful improvement. Particularly impressive gains were observed in timely linkage to care at the diagnosing facility: 89% of CIS participants linked to care on the day of diagnosis, representing a greater than 5-fold improvement compared to the SOC, and nearly universal linkage (96%) was achieved within 1 month of diagnosis. Notably, the intervention effect was greatest in subpopulations documented to have particularly poor outcomes across the HIV care continuum, including young adults [38,39] and those with high stigma perceptions [40–42]. The intervention also had beneficial effects on other important milestones in the HIV care continuum in the 12 months following diagnosis, including the likelihood of patients having their ART eligibility assessed and initiating ART. While the intervention significantly increased retention in HIV care at both 6 and 12 months following diagnosis, retention in the CIS group remained concerningly low and far short of what is needed to end the HIV epidemic in Mozambique and other high-burden countries.We found no additional gain in effectiveness from adding FIs to the CIS. Prior studies examining the effect of FIs in enhancing outcomes across the HIV care continuum among people living with HIV have shown inconsistent results. Studies from India, Uganda, and Democratic Republic of the Congo reported reductions in time to ART initiation and improvements in retention with the provision of incentives, while in the United States, randomized trials did not show any effect of FIs on linkage to care or viral load suppression [43–47]. While 89% of participants in the current study reported that the type of FI provided and the amount of the FIs (i.e., mobile phone air-time vouchers worth approximately US$5 at 3 points in time) were adequate, it is possible that the FIs were not sufficiently optimized to affect behaviors. Indeed, as reported elsewhere, patient reactions to the FIs were surprisingly tepid, with only 21% reporting it to be the “most useful” intervention for retention in care 12 months following diagnosis [21]. Additionally, fidelity to the FI component of the intervention package was imperfect, with, for example, 86% of participants eligible to receive the first incentive actually receiving it, which may have further limited the effect of this intervention [21]. However, given the benefits of FIs in other health sectors [48–50], further research is needed to understand whether and how they may be optimized to enhance outcomes across the HIV care continuum.This study has several important strengths. It is among the first studies to evaluate the impact of a multi-component approach on 2 important HIV care and treatment indicators: timely linkage to care following an HIV diagnosis and sustained retention in care. Improving performance for these 2 elements of the HIV care continuum is critical for realizing the individual and population benefits of HIV programming in sub-Saharan Africa. Further, while studies have examined the effectiveness of multi-component intervention packages that include FIs on HIV care outcomes [51,52], this study is the first to our knowledge to use a design that permits estimation of the additional benefit of including FIs as part of such a package.Our study also had limitations. First, in alignment with recent recommendations for implementation science studies [19], we used existing electronic medical records in the HIV clinics at the study sites to ascertain outcomes at the diagnosing facility, but such records may have limited data quality. However, data quality assessments were conducted regularly during the study period and ensured at least 85% concurrence between paper-based and electronic medical records on key data elements. Second, aside from the FI, we cannot unpack the effect of individual intervention components. Third, the relevance of point-of-care CD4 count testing may change as countries adopt “treatment for all” strategies, although our results suggest that providing people living with HIV with additional information on their health status immediately following diagnosis may be important in facilitating same-day linkage to care and likely same-day ART initiation. Fourth, the CIS+ cohort was enrolled once the target sample size had been reached in the CIS cohort, thus introducing the potential for secular trends to have biased the comparison of the CIS and CIS+ packages. However, because we found no difference in the primary outcome between the CIS+ and CIS groups, secular trends would have had to have operated in the direction of reducing overall linkage and retention for this bias to result in the failure to observe an additional benefit of FIs for linkage and retention. While this is plausible, we do not have any evidence that a substantial reduction in overall linkage and retention occurred over the relatively limited time frame of the study. Finally, while the study was implemented in 2 contrasting settings within Mozambique, study facilities were located primarily in urban and semi-urban areas within the city of Maputo and Inhambane Province, which may limit generalizability. Indeed, settings with lower education and cell phone coverage than those included in our study may experience greater challenges implementing the SMS health messages and appointment reminders. Similarly, while we set broad inclusion criteria, we did exclude people who did not understand Portuguese or Xitsua, were planning on leaving the community, or were not willing to receive services at the diagnosing facility, all factors that may have reduced generalizability. Finally, due to slower-than-expected enrollment, we enrolled fewer participants in the CIS+ group than intended, which decreased our power to detect statistically significant differences in study outcomes between the CIS+ and CIS groups. However, as the proportion achieving the combined outcome in the 2 groups was extremely similar (CIS 57% versus CIS+ 55%), it is unlikely that the inability to detect significant differences was primarily due to lack of power.ConclusionMulti-component intervention strategies have been proposed to address troubling gaps in the HIV care continuum [17,18]. To our knowledge, this is amongst the first studies to rigorously evaluate such an approach. The CIS we examined, comprising 3 evidence-based, practical, and scalable interventions, holds great promise as an approach to make much needed gains in the HIV care continuum in sub-Saharan Africa, particularly in the critical first step of timely linkage to care following diagnosis.Supporting informationS1 TextStudy protocol.(PDF)Click here for additional data file.S2 TextCONSORT checklist.(DOCX)Click here for additional data file.S1 DataData file.(CSV)Click here for additional data file.S2 DataData codebook.(XLSX)Click here for additional data file.We are grateful to the study participants, study staff, and participating health facilities for their contributions to this research. We also thank Antonia Mussa, Deborah Horowitz, Margaret McNairy, and Violante Viola for their inputs during study development and launch.AbbreviationsaRRadjusted relative riskARTantiretroviral therapyCIScombination intervention strategyFIfinancial incentiveICCintraclass correlation coefficientIQRinterquartile rangeIRBinstitutional review boardRRrelative riskSMSshort message serviceSOCstandard of careVCTvoluntary counseling and testingReferences1Joint United Nations Programme on HIV/AIDS. Fact sheet July 2017. Geneva: Joint United Nations Programme on HIV/AIDS; 2017 [cited 2017 Oct 18]. Available from: http://www.unaids.org/sites/default/files/media_asset/UNAIDS_FactSheet_en.pdf.2McGrathN, GlynnJR, SaulJ, KranzerK, JahnA, MwaunguluF, et al\nWhat happens to ART-eligible patients who do not start ART? Dropout between screening and ART initiation: a cohort study in Karonga, Malawi. 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Promoting healthy behaviours and improving health outcomes in low and middle income countries: a review of the impact of conditional cash transfer programmes. Prev Med. 2012;55(Suppl):S95–105.2217804350RasellaD, AquinoR, SantosCA, Paes-SousaR, BarretoML. Effect of a conditional cash transfer programme on childhood mortality: a nationwide analysis of Brazilian municipalities. Lancet. 2013;382(9886):57–64. doi: 10.1016/S0140-6736(13)60715-1\n2368359951SiednerMJ, SantorinoD, LankowskiAJ, KanyesigyeM, BwanaMB, HabererJE, et al\nA combination SMS and transportation reimbursement intervention to improve HIV care following abnormal CD4 test results in rural Uganda: a prospective observational cohort study. BMC Med. 2015;13:160\ndoi: 10.1186/s12916-015-0397-1\n2614972252McNairy M, Lamb M, Gachuhi A, Nuwagaba-Biribonwoha H, Burke S, Mazibuko S, et al. Link4Health: a cluster randomized-controlled trial evaluating the effectiveness of a combination strategy for linkage to and retention in HIV care in Swaziland. International AIDS Conference; 2016 Jul 18–22; Durban, South Africa.", 'title': 'A combination intervention strategy to improve linkage to and retention in HIV care following diagnosis in Mozambique: A cluster-randomized study.', 'date': '2017-11-15'}, '29112963': {'article_id': '29112963', 'content': "PLoS MedPLoS MedplosplosmedPLoS Medicine1549-12771549-1676Public Library of ScienceSan Francisco, CA USA29112963567537610.1371/journal.pmed.1002420PMEDICINE-D-17-02007Research ArticleBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesImmunodeficiency VirusesHIVBiology and life sciencesOrganismsVirusesRNA virusesRetrovirusesLentivirusHIVBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVBiology and Life SciencesOrganismsVirusesViral PathogensRetrovirusesLentivirusHIVBiology and Life SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesPublic and Occupational HealthPreventive MedicineVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapySocial SciencesEconomicsFinancePeople and PlacesGeographical LocationsAfricaSwazilandMedicine and Health SciencesHealth CareHealth Education and AwarenessMedicine and health sciencesEpidemiologyHIV epidemiologyMedicine and Health SciencesHealth CarePatientsMedicine and health sciencesDiagnostic medicineHIV diagnosis and managementEffectiveness of a combination strategy for linkage and retention in adult HIV care in Swaziland: The Link4Health cluster randomized trialLink4Health: A combination intervention to improve HIV carehttp://orcid.org/0000-0001-7853-633XMcNairyMargaret L.ConceptualizationData curationFormal analysisFunding acquisitionInvestigationMethodologyProject administrationSupervisionValidationWriting – original draftWriting – review & editing12*LambMatthew R.ConceptualizationData curationFormal analysisInvestigationMethodologyWriting – original draftWriting – review & editing13GachuhiAverie B.Data curationProject administrationSupervisionWriting – original draftWriting – review & editing1Nuwagaba-BiribonwohaHarrietData curationProject administrationSupervisionWriting – original draftWriting – review & editing13BurkeSeanData curationInvestigationProject administrationSupervisionWriting – review & editing1MazibukoSikhatheleConceptualizationInvestigationProject administrationWriting – review & editing4http://orcid.org/0000-0003-1155-2735OkelloVelephiConceptualizationSupervisionWriting – review & editing4http://orcid.org/0000-0003-2028-4779EhrenkranzPeterConceptualizationSupervisionWriting – original draftWriting – review & editing5http://orcid.org/0000-0002-0180-1649SahaboRubenConceptualizationProject administrationSupervisionWriting – review & editing1http://orcid.org/0000-0003-3735-9781El-SadrWafaa M.ConceptualizationFunding acquisitionMethodologyProject administrationSupervisionValidationWriting – original draftWriting – review & editing131\nICAP at Columbia University, New York, New York, United States of America2\nDepartment of Medicine, Weill Cornell Medical College, New York, New York, United States of America3\nDepartment of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, United States of America4\nMinistry of Health, Kingdom of Swaziland, Mbabane, Swaziland5\nBill and Melinda Gates Foundation, Seattle, Washington, United States of AmericaDeeksSteven G.Academic EditorSan Francisco General Hospital, UNITED STATESThe authors have declared that no competing interests exists.* E-mail: mm3780@columbia.edu71120171120171411e100242012620172992017© 2017 McNairy et al2017McNairy et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.BackgroundGaps in the HIV care continuum contribute to poor health outcomes and increase HIV transmission. A combination of interventions targeting multiple steps in the continuum is needed to achieve the full beneficial impact of HIV treatment.Methods and findingsLink4Health, a cluster-randomized controlled trial, evaluated the effectiveness of a combination intervention strategy (CIS) versus the standard of care (SOC) on the primary outcome of linkage to care within 1 month plus retention in care at 12 months after HIV-positive testing. Ten clusters of HIV clinics in Swaziland were randomized 1:1 to CIS versus SOC. The CIS included point-of-care CD4+ testing at the time of an HIV-positive test, accelerated antiretroviral therapy (ART) initiation for treatment-eligible participants, mobile phone appointment reminders, health educational packages, and noncash financial incentives. Secondary outcomes included each component of the primary outcome, mean time to linkage, assessment for ART eligibility, ART initiation and time to ART initiation, viral suppression defined as HIV-1 RNA < 1,000 copies/mL at 12 months after HIV testing among patients on ART ≥6 months, and loss to follow-up and death at 12 months after HIV testing. A total of 2,197 adults aged ≥18 years, newly tested HIV positive, were enrolled from 19 August 2013 to 21 November 2014 (1,096 CIS arm; 1,101 SOC arm) and followed for 12 months. The median participant age was 31 years (IQR 26–39), and 59% were women. In an intention-to-treat analysis, 64% (705/1,096) of participants at the CIS sites achieved the primary outcome versus 43% (477/1,101) at the SOC sites (adjusted relative risk [RR] 1.52, 95% CI 1.19–1.96, p = 0.002). Participants in the CIS arm versus the SOC arm had the following secondary outcomes: linkage to care regardless of retention at 12 months (RR 1.08, 95% CI 0.97–1.21, p = 0.13), mean time to linkage (2.5 days versus 7.5 days, p = 0.189), retention in care at 12 months regardless of time to linkage (RR 1.48, 95% CI 1.18–1.86, p = 0.002), assessment for ART eligibility (RR 1.20, 95% CI 1.07–1.34, p = 0.004), ART initiation (RR 1.16, 95% CI 0.96–1.40, p = 0.12), mean time to ART initiation from time of HIV testing (7 days versus 14 days, p < 0.001), viral suppression among those on ART for ≥6 months (RR 0.97, 95% CI 0.88–1.07, p = 0.55), loss to follow-up at 12 months after HIV testing (RR 0.56, 95% CI 0.40–0.79, p = 0.002), and death (N = 78) within 12 months of HIV testing (RR 0.80, 95% CI 0.46–1.35, p = 0.41). Limitations of this study include a small number of clusters and the inability to evaluate the incremental effectiveness of individual components of the combination strategy.ConclusionsA combination strategy inclusive of 5 evidence-based interventions aimed at multiple steps in the HIV care continuum was associated with significant increase in linkage to care plus 12-month retention. This strategy offers promise of enhanced outcomes for HIV-positive patients.Trial registrationClinicalTrials.gov NCT01904994.In a cluster-randomized trial done in Swaziland, Margaret McNairy and colleagues test a combined intervention for linking and retaining adults with HIV infection in care.Author summaryWhy was this study done?Linkage to care, retention in care, and achievement of viral load suppression on antiretroviral therapy (ART) among HIV-positive adults are necessary in order to achieve optimal health outcomes in terms of reduced morbidity and mortality and to decrease the risk of HIV transmission to others.Barriers to linkage to and retention in care are multifactorial and include both individual- and health system-level factors.We hypothesized that a multicomponent strategy using a combination of evidence-based interventions was needed to address the multiple gaps in linkage to and retention in care across the HIV care continuum.What did the researchers do and find?Ten clusters of affiliated HIV clinics in Swaziland were randomized to receive the standard of care (SOC; 1,101 participants) or a combination intervention strategy (CIS; 1,096 participants). The CIS included provision of participants with point-of-care CD4+ count testing at time of HIV testing, accelerated ART initiation among eligible patients, mobile phone appointment reminders, health educational packages, and noncash financial incentives.Participants were followed for 12 months from the time of testing HIV positive, and the primary study outcome was prompt linkage to care within 1 month of testing HIV-positive plus retention in care at 12 months after testing HIV positive. Secondary outcomes included additional steps in the HIV care continuum.We found that participants receiving care at HIV clinics randomized to the CIS study arm, as compared to the SOC study arm, were significantly more likely to achieve the primary outcome of prompt linkage to care plus 12-month retention (64% in the CIS arm versus 43% in the SOC arm, relative risk [RR] 1.52, 95% CI 1.19–1.96, p = 0.002).We also found that participants at CIS sites versus SOC sites had faster linkage to care, were more likely to be assessed for ART initiation, and had faster time to ART start. However, we did not find significant differences in viral suppression or mortality at 12-months after testing HIV positive.What do these findings mean?The Link4Health study showed that a CIS was 50% more effective than the SOC on prompt linkage to HIV care plus 12-month retention after HIV-testing and that the effect appeared to be primarily driven by enhanced retention in care.Limitations of this study include a small number of clusters and the inability to evaluate the contribution of each of the components of the strategy to the effect noted.The combination strategy used in this study could be easily adapted to other resource-limited settings and may be relevant to the challenges faced in engaging HIV-positive vulnerable and key populations.http://dx.doi.org/10.13039/100006492Division of Intramural Research, National Institute of Allergy and Infectious DiseasesRO1A1100059http://orcid.org/0000-0003-3735-9781El-SadrWafaa M.Gates FoundationOPP1145477http://orcid.org/0000-0001-7853-633XMcNairyMargaret L.This study was funded by the National Institutes of Health (NIH), NIH Award Number: RO1A1100059, and the Gates Foundation OPP1145477. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Data AvailabilityData are from the Link4Health study, which may be contacted at icap-partnerships@columbia.edu. Deidentified data are uploaded as S1 Table.Data AvailabilityData are from the Link4Health study, which may be contacted at icap-partnerships@columbia.edu. Deidentified data are uploaded as S1 Table.IntroductionAchieving the desired impact of HIV treatment, as measured by individual health outcomes and reduced transmission to others, is contingent upon completing all steps in the HIV care continuum, from identifying all individuals who are living with HIV and linking those found to be HIV positive to HIV care to retaining them in lifelong care and on antiretroviral therapy (ART) [1]. Over the past decade, the scale-up of HIV programs has been substantial, with over 18 million persons having initiated ART by the end of 2015 in low- and middle-income countries and an associated substantial decrease in HIV-related morbidity and mortality, as well as evidence of a decrease in HIV incidence in many of the most severely affected countries [2]. However, in order to achieve epidemic control, further optimization of the HIV care continuum is needed so as to achieve the Joint United Nations Programme on HIV/AIDS (UNAIDS) 90/90/90 targets, which require that 90% of individuals with HIV are aware of their diagnosis, that 90% of those aware of their HIV infection are initiated on ART, and that 90% of those on treatment achieve and maintain viral suppression [3].Findings from HIV programs indicate that linkage to and retention in HIV care currently fall far short of the desired goals [4–6]. Linkage of HIV-positive individuals to HIV care varies from less than half of individuals linking to care within 6 months of an HIV-positive test to 72% who ever linked [5,7,8]. Once linked to care, less than half of HIV-positive patients are retained in care prior to initiation of ART, with only two-thirds of ART-eligible individuals initiating ART [5,7]. Lastly, only approximately three-quarters of patients initiated on ART have been noted to be retained in care at 12 months, with retention decreasing over the ensuing follow-up years [4].Barriers to linkage to and retention in care are multifactorial and include both individual- and health system-level factors such as stigma, fear of disclosure, distance and cost of travel to clinic, attitudes of providers, and cumbersome clinic procedures with long waiting times [9,10]. Previous studies that aimed to overcome such barriers have largely focused on the assessment of 1 intervention primarily targeting a single step in the HIV care continuum [11–14]. We postulated that in order to address the multiple gaps across the care continuum, a multi-component intervention strategy is needed, with each component targeting one or more steps in the HIV care continuum.The Link4Health study evaluated the effectiveness of a combination intervention strategy (CIS) utilizing 5 evidence-based interventions that address structural, behavioral, and biomedical barriers across the continuum of care, to improve linkage to and retention in care among newly identified HIV-positive adults in Swaziland.MethodsEthicsThe study was approved by the institutional review boards at Columbia University and the Swaziland Scientific and Ethics Committee.Study designA detailed description of the study methods was previously reported [15]. In brief, Link4Health was an implementation science study using a cluster site-randomized trial design. The study unit of randomization consisted of a public secondary-level HIV clinic paired with its largest affiliated public primary-level HIV clinic. Ten study units were selected from a total of 11 existing secondary-level HIV clinics in the country, based on clinic patient volume. Study units were pair matched, first by implementing partner (matching the 2 study units from implementing partner A) and then by location (urban [4] versus rural [4]) and clinic size, based on the estimated number of adults testing HIV positive in the 2 years prior to study implementation (<50 versus >50 per month for rural study units and <100 versus >100 per month for urban study units). Matched study units were randomized by a computerized random number generator to the CIS or standard of care (SOC) study arm. A cluster design was chosen to avoid disruption of service delivery, enable better fit within the routine workings at the clinical site, and allow the clinic staff to more easily implement the study. The study staff and clinic providers at each study unit were not blinded to the assigned arm for the site.Study setting and populationSwaziland is located in Southern Africa and has the world’s highest HIV prevalence, with HIV as the leading cause of death in the country [16]. The estimated adult (age 18–49 years) HIV prevalence is 31%, and the estimated incidence is 2.4% (95% CI 2.1–2.8) [17, 18]. The country has made impressive strides in responding to the epidemic, with nearly 70% of persons estimated to be living with HIV having initiated ART as of 2015 [19]. Nevertheless, historic rates of linkage to and retention in care at 12 months after ART initiation remain suboptimal [20]. Data available from Swaziland at the time of the initiation of the study showed that among 1,105 adults who tested HIV positive at community testing venues, only 37% linked to HIV care within 12 months of HIV testing [21]. Retention among adults at 36 months after ART start was 68% in 2011 per national estimates [22].Inclusion criteria were as follows: adults aged ≥18 years, newly tested HIV positive, and willing to receive HIV care at the study unit and consent to study procedures. Exclusion criteria were as follows: planning on leaving the community during the study, prior enrollment in HIV care or initiation of ART in the past 6 months, currently on ART, reports a current pregnancy, or not able to speak English or SiSwati.Study interventionsAll adults who tested HIV positive at participating sites were informed of the study by their providers. Interested individuals were referred to a study nurse who provided further information, confirmed eligibility, and, if eligible, obtained written consent. All consenting participants provided baseline information and thereafter were managed based on the study arm to which the clinic was randomly assigned.SOCParticipants at study units randomized to the SOC arm were managed according to country guidelines. These guidelines recommend that individuals identified as HIV positive receive post-test counseling and be referred to an HIV clinic using a national referral form [21]. Thereafter, upon presentation at their first HIV clinic visit, such individuals are to present their referral form, receive a clinical assessment, and have blood drawn for a CD4+ count test as well as hematology and chemistry tests and are instructed to return in 1–2 weeks for receipt of their results. Upon return, those eligible for ART according to then prevailing national guidelines (i.e., with a CD4+ count ≤ 350 cells/mm3) are to receive the first of 3 counseling sessions. Patients who are prescribed ART are instructed to return to the clinic every month for 6 months and then every 3 months, if they are stable on treatment. Patients who are ineligible for ART are instructed to return to clinic every 3 months for follow-up. Peer counselors are encouraged to call patients within 7 days of a missed clinic appointment. All patients are prescribed cotrimoxazole prophylaxis, and condoms, and health informational materials are to be made available in the clinics.CISParticipants at clinics randomized to the CIS arm received a multicomponent strategy of 5 evidence-based interventions, targeting structural, biomedical, and behavioral barriers, which are described briefly below (Table 1) [15]. All components of the combination strategy utilized in this study were selected based on evidence of their effectiveness, feasibility, and suitability to patients in diverse healthcare settings.10.1371/journal.pmed.1002420.t001Table 1Comparison of combination intervention strategy (CIS) to standard of care (SOC) procedures.InterventionStandard of care (SOC)Combination intervention strategy (CIS)Type of interventionStep targeted in HIV care continuumPoint-of-care CD4+ count testing• Point-of-care CD4 assays available in some primary care clinics and some secondary health centers/hospitals for patients enrolled in HIV care but not at the HIV testing site• CD4+ count (Cyflow and FACS Caliber) after linkage to HIV care in the clinic or lab• Turnaround time approximately 2 weeks• Point-of-care CD4 assays at the HIV testing site at the time of HIV testing• Turnaround time immediateStructural and biomedicalLinkage, ART eligibility assessment, and ART initiationAccelerated ART initiationART initiation per national guidelines for patients with CD4+ count ≤ 350 cells/mm3 or WHO Stage III/VI• Requires 3 counseling sessions and receipt of baseline lab tests• Initiation 2 weeks to 1 month from determination of ART eligibility• Accelerated ART initiation for patients with point-of-care CD4+ count ≤ 350 cells/mm3 within 1 week from testing• Two counseling sessions (1 at the time of HIV testing and the other at the first HIV clinic visit) and collection of blood for other baseline lab tests• Initiation of ART for eligible patients prior to return of results with use of a checklistStructural and biomedicalART initiation and retentionCellular phone visit reminders• Telephone call within 7 days of missed visit for ART patients only• SMS (or voice if illiterate) visit reminders 3 days prior to each scheduled visit• SMS (or voice if illiterate) reminder within 7 days after a missed visit for all patientsBehavioralLinkage and retentionHealth education packages• Cotrimoxazole was prescribed for all patients once enrolled in HIV care• Condoms available• A health education package was provided approximately every 3 months at visits. Packages included condoms, soap, cotrimoxazole, a pill box, and pictorial education about use of materials and HIVBiomedical and behavioralRetentionNoncash financial incentive• None• Noncash financial incentive (mobile airtime) were provided for those linked to care within 1 month of testing and completion of 6- and 12-month visitsStructuralLinkage and retentionAbbreviations: ART, antiretroviral therapy; SMS, short message service.The first intervention was provision of point-of-care (POC) CD4+ count testing performed immediately after an HIV-positive test, in the same physical location as the HIV testing site, with the aim of improving linkage to care, assessment for ART eligibility, and prompt ART initiation. Several studies have reported higher linkage and ART initiation rates with POC CD4+ count testing as compared to traditional CD4+ count testing [23–26].The second intervention of accelerated ART initiation for eligible patients (CD4+ count ≤ 350 cells/mm3 or WHO stage III/IV) involved 2 rather than 3 counseling sessions and recommended ART initiation within the first week after linkage to care. Delays in ART initiation among those eligible for treatment have been shown to be associated with increased morbidity and mortality [27]. Late ART initiation is also associated with a longer period of increased infectiousness due to ongoing viral replication [28]. In this study, initiation of ART promptly rather than waiting for the return of baseline safety laboratory test results was strongly encouraged, and a checklist was made available to the providers to assist in identifying those potential participants at risk for renal insufficiency who would require waiting for the serum creatinine results prior to ART initiation.The third intervention involved use of short-message-service (SMS) appointment reminders, sent from a central server, which aimed at improving linkage to and retention in care among participants. SMS reminders were sent 3 days prior to an appointment and after a missed appointment. The message did not contain any information relating to HIV status. SMS communications have been used in HIV care and other chronic disease management to improve health communication and patient adherence [29–37].The fourth intervention was a health education package that included health information and supplies such as soap, a toothbrush, and a pill box, which also aimed to improve both linkage to and retention in care. A package of different materials and information was given every 3 months. A similar intervention has been evaluated in Uganda and was associated with high rates of cotrimoxazole use, condom use, and HIV testing of family members [38].Lastly, financial incentives of modest amount were provided that served to reimburse participants for expenses or lost wages or transport costs for clinic attendance [39]. This intervention was selected because there has been great interest in the use of financial incentives as a structural intervention to achieve positive health behaviors including retention in care [39–45]. A noncash type of financial incentive was provided in the form of a prepaid mobile phone card valued at US$8 and was given to participants upon linkage to care within 1 month of HIV testing and at completion of 6 and 12 months in follow-up care.Data collection and study measuresAll participants completed a baseline questionnaire, at the time of study enrollment, which solicited information on sociodemographic characteristics, HIV disease history, barriers to care, travel time to clinic, depression, social and family support, and HIV-related knowledge. Follow-up questionnaires were conducted at 1 and 12 months after enrollment, at the participant’s home or a prespecified location in the community, to collect information on changes in sociodemographic characteristics, self-reported linkage to care and retention, preferences about the study interventions, and vital status, if the latter was not known. Clinical data including CD4+ count, WHO Stage, date of ART initiation, ART regimen, and clinic and pharmacy visit dates were abstracted from participants’ medical charts—the data source for the primary outcome. These data were collected between 3–6 months after the participant reached the end of the study follow-up period. If the participant’s medical record was missing, he/she was assumed to have not achieved the primary outcome. Death was ascertained via medical record reviews or at the time of the 1- or 12-month interview. Viral load measurement was done using dried blood samples (DBSs) (HIV-1 RNA Abbott m2000rt system) collected at the time of the 12-month questionnaire at the participant’s home or a prespecified location [46].Study outcomesThe primary outcome was a combined outcome of linkage to HIV care within 1 month of HIV testing plus retention in care at 12 months from HIV testing among participants at the individual level. Linkage to care was defined by participant attendance of at least 1 visit to an HIV clinic with completion of an intake assessment including medical history and physical exam. Retention in care at 12 months after HIV testing was defined as no documented death and a clinic visit at the study unit within 90 days prior to the end of the study follow-up period. Participants with a missing medical record at the time of medical record abstraction were considered nonretained.Secondary endpoints included evaluation of the effectiveness of the CIS compared to the SOC with regard to the following: each component of the primary outcome described above, time to linkage, ART eligibility, ART initiation, time to ART initiation, viral suppression defined as HIV-1 RNA < 1,000 copies/mL at 12 months among patients on ART for at least 6 months, and death and loss to follow-up at 12 months after HIV testing. Death and transfer status were ascertained from medical records and through the 12-month follow-up visit questionnaire. Linkage and retention at clinics other than the assigned study unit were assessed in a sensitivity analysis using self-reported linkage and retention data from the 1- and 12-month questionnaires.Statistical analysisThe study sample size was calculated by estimating that 35% of the participants in the SOC study arm would achieve the primary outcome (assuming that 50% link to HIV care within 1 month of testing and that 70% of those linking within 1 month are retained at 12 months after testing). We estimated that approximately 2,750 adults would be eligible for study enrollment based on historic HIV testing volume and the proportion of individuals testing HIV positive at the study units in the year prior to the study start. Assuming 80% of eligible individuals would consent to enrollment, we estimated an average enrollment of 220 participants per study unit or 2,200 in total (1,110 per study arm). With this sample size and 5 study units per study arm, we then estimated the minimum difference in the primary outcome we could detect with 80% power, 2-sided alpha of 0.05, assuming an interclass correlation coefficient (ICC) of 0.05. In a post hoc analysis, we estimated the ICC of the primary outcome using the method outlined by Snijders and Bosker for binary outcome data [47].An intent-to-treat analysis compared the relative risk (RR) of achieving the primary outcome between study arms, with each having 5 clusters per arm. Within study unit clustering was accounted for using random-intercept multilevel models. For dichotomous outcomes, log-Poisson models with robust standard error were used. For continuous outcomes, random-intercept linear regression models were used. Assessment of potential confounding despite cluster randomization was performed by constructing multivariable random-intercept regression models including covariates found statistically different between treatment arms at an alpha of 0.01. Additionally, we conducted a per-protocol analysis comparing the RR of achieving the primary outcome among participants who received the full package of the CIS for the duration of study participation. Sensitivity analysis assessed any changes to the intent-to-treat analysis after including self-reported linkage and retention obtained from follow-up surveys. In post hoc analyses, assessment of the RR for achieving the primary outcome by key subgroups was done using interaction contrast ratios.ResultsStudy populationOf the 10 study units included in this study, 6 were located in urban areas, and 4 in rural areas. At study units randomized to the CIS study arm, a total of 1,234 individuals were screened for eligibility, with 1,096 (89%) enrolled in the study from 19 August 2013 to 21 November 2014 (Fig 1). At study units assigned to the SOC study arm, a total of 1,316 were screened, with 1,101 (84%) enrolled. Study refusal differed by study arm, with 23 refusals (1.9%) in the CIS arm and 114 refusals (8.7%) in the SOC arm (p < 0.001). Reasons for ineligibility are shown in Fig 1, with 111 participants ineligible in the CIS arm compared to 101 in the SOC arm.10.1371/journal.pmed.1002420.g001Fig 1Flow diagram of study enrollment.ART, antiretroviral therapy; CIS, combination intervention strategy; SOC, standard of care; SU, study unit.Among 2,197 participants included in this analysis, 1,294 (59%) were female, and the median age was 31 years (IQR 26–39), with 445 (20%) of the participants being young adults aged 18–24 years (Table 2). Forty-five percent reported no education or only primary schooling; approximately half were unemployed. Median individual weekly income was US$9 (IQR US$0–US$37). Eighty-four percent reported living in the current residence for more than 1 year, with 16% reporting travel away from home for over a 1-month duration in the past year. The median travel time from residence to HIV clinic was 30 minutes (IQR 20–50). The majority (80%) were diagnosed with HIV through a voluntary counseling and testing site, with the remainder having received HIV testing through provider-initiated testing and counseling at clinics within the study units. Over half (54%) of the participants reported that this was their first HIV test, while 89% indicated that it was their first positive HIV test.10.1371/journal.pmed.1002420.t002Table 2Participant characteristics at HIV testing (N = 2,197).CharacteristicsCIS armSOC armTotal\xa0\xa0N%N%N%\xa01,096\xa01,101\xa02,197\xa0Female\xa065760%63758%1,29459%Age (years)Median (IQR)32 (26–40)30 (25–39)31 (26–39)18–2421019%23521%44520%25–3961256%60455%1,21655%40–4915814%16615%32415%>5011611%959%21110%Missing/refused\xa0\xa010%10%EducationNone/primary47844%51947%99745%Secondary or higher61756%58153%1,19855%Missing/refused10%10%20%Weekly incomeMedian (IQR)US$9 (US$0-US$37)US$14 (US$0-US$37)US$9 (US$0-US$37)Unemployed\xa062457%53148%1,15553%Married\xa040036%40837%80837%Number of living children020619%20719%41319%1 to 364559%68062%1,32560%>324322%21419%45721%Missing/refused20%00%20%Lives alone\xa011611%16015%27613%Away from home >1 month in past year\xa017916%17015%34916%Time at current residence1 year or less16415%19217%35616%Greater than 1 year93085%90682%1,83684%Missing/refused20%30%50%Travel time to clinicMedian (IQR) time minutes30 (20–45)30 (20–60)30 (20–50)<30 minutes69063%58453%1,27458%31–60 minutes33030%32329%65330%>60 minutes626%19117%25311%Missing/refused141%30%171%Currently on TB treatment\xa081%141%221%HIV testing siteVCT93785%82074%1,75780%PITC15915%28025%43920%Missing/refused00%10%10%First HIV test\xa064259%53949%1,18154%First positive HIV test\xa096788%97889%1,94589%Household member with HIV\xa042739%34832%77535%Alcohol consumption in the last 7 daysEvery day161%182%342%Some days23521%23421%46921%Never84577%84977%1,69477%Abbreviations: CIS, combination intervention strategy; PITC, provider-initiated testing and counselling; SOC, standard of care; TB, tuberculosis; VCT, voluntary HIV counselling and testing.Primary outcomeIn the intent-to-treat analysis, 705 (64%) participants at sites randomized to the CIS study arm and 477 (43%) participants at sites randomized to the SOC study arm achieved the primary outcome of linkage to HIV care within 1 month of HIV-positive testing plus retention in HIV care at 12 months after HIV testing, for an RR of 1.48 (95% CI 1.37–1.61, p < 0.001). Accounting for clustering within study units, the RR was 1.52 (95% CI 1.19–1.96, p = 0.002) (Fig 2, Table 3). Additionally, adjusting for covariates significant in the bivariate analyses listed in Table 2 did not appreciably change the results. A total of 64 (6%) of participants in the CIS arm and 144 (13%) of participants in the SOC arm did not have a medical record and were classified as “not linked” to HIV care.10.1371/journal.pmed.1002420.g002Fig 2Proportion of participants who achieved the primary outcome of linkage to HIV care within 1 month of HIV testing plus retention in HIV care at 12 months after HIV testing by study arm (combination intervention strategy [CIS] and standard of care [SOC]).10.1371/journal.pmed.1002420.t003Table 3Primary and secondary outcomes for the combination intervention strategy (CIS) and standard of care (SOC) study arms.CIS group (N = 1,096)SOC group (N = 1,101)Relative risk (RR)N%N%RR95% CIp-ValuePrimary outcomeIntention to treat70564%47743%1.48(1.37–1.61)<0.001Intention to treat accounting for clustering170564%47743%1.52(1.19–1.96)0.002Intention to treat accounting for clustering and differences in covariates1,370564%47743%1.50(1.12–1.99)0.009Per protocol1,267269%44743%1.68(1.32–2.15)<0.001Sensitivity analysis1,476169%55751%1.41(1.13–1.74)0.004Secondary outcomesLinkageLinked to care (ever)1103294%95787%1.08(0.97–1.21)0.13Mean (SD) time from HIV testing to linkage2.5 days (19.5)7.5 days (46.6)0.189ART eligibilityAssessed for ART eligibility11,096100%92084%1.20(1.07–1.34)0.004Became ART eligible183376%72165%1.18(1.01–1.37)0.038Mean (SD) time from HIV testing to ART eligibility assessment50 (0)6.3 (35.5)<0.001ART initiation*Initiated ART (ever)1*71065%63558%1.16(0.96–1.40)0.12Median (IQR) time from testing HIV positive to ART initiation among ART eligible, days67.0 (3.0–21.0)14.0 (7.0–31.0)<0.001Retention regardless of time to linkage and ART statusRetained 12 months after HIV testing172066%49845%1.48(1.18–1.86)0.002Viral suppressionViral suppression (HIV-1 RNA < 1,000 copies/ml) among participants on ART for ≥6 months (N = 477 CIS and N = 451 SOC)1,741988%40690%0.97(0.88–1.07)0.55Deaths within 12 months of HIV testingTotal deaths1353%434%0.80(0.46–1.35)0.41Death before ART initiation1101%232%0.44(0.19–1.01)0.05Death after ART initiation1252%202%1.18(0.57–2.47)0.63Transfers within 12 months of HIV testingTotal transfers1232%262%0.88(0.44–1.77)0.71Transfers before ART initiation171%192%0.37(0.16–0.85)0.02Transfers after ART initiation1161%71%2.10(0.72–6.18)0.16Lost to follow-up within 12 months of HIV testingTotal lost to follow-up131829%53449%0.56(0.40–0.79)0.002Lost to follow-up before ART initiation124022%35732%0.60(0.40–0.89)0.014Lost to follow-up after ART initiation1787%17716%0.51(0.31–0.85)0.0131 Accounting for within-study unit clustering using random intercept log-Poisson regression models with robust standard error.2 The per-protocol analysis compared all patients in the SOC arm to those in the CIS arm self-reporting receipt of all interventions: point-of-care (POC) CD4+ count, accelerated antiretroviral therapy (ART) initiation (if eligible), health education package, short message service (SMS), and financial incentives. A total of 937 of the 1,096 patients in the CIS arm were included. Patients were excluded for the following: missing PIMA (2), ART counseling session #1 (24), ART counseling session #2 (14), first health education package (7), second health education package (12), third health education package (4), fourth health education package (2), financial incentive for linkage to care (86), second financial incentive (8), or third financial incentive (4).3 Additionally adjusting for covariates significantly different between groups at an alpha of 0.1: employment status, number of children, whether the participant lives alone, HIV testing location, family member with HIV, travel time to clinic, and whether this was the participant’s first HIV test.4 The sensitivity analysis considers participants linked to HIV care or retained in HIV care if they are recorded as linked and retained in their medical records or if they self-reported linkage or retention in the 1- and/or 12-month study questionnaire.5 All participants in the SOC arm were assessed for ART eligibility at the time of testing HIV positive. Of the SOC participants, 920/1,101 (84%) were assessed at enrollment into HIV care or clinical follow-up.6 Time to ART initiation measured from date of HIV-positive test to ART initiation among those becoming ART eligible. The p-values are Wilcoxon tests of differences between medians.7 The proportion of viral load suppression (<1,000 copies/ml) among participants who were on ART for ≥6 months with available viral loads is reported in the table. Among all participants who were on ART for ≥6 months, 85% (419/493) in the CIS arm and 89% (406/458) in the SOC arm had viral suppression.* In the CIS arm, 85% of those ART eligible initiated ART. In the SOC arm, 88% of those eligible initiated ART.The RR in the per-protocol analysis accounting for clustering for achieving the primary outcome was 1.68 (95% CI 1.32–2.15, p = 0.003) (Table 3). The RR in the sensitivity analysis, accounting for clustering, which included participants who self-reported linkage and retention in the 1- and 12-month surveys at a clinic other than 1 with their assigned study unit, was 1.41 (95% CI 1.13–1.74, p = 0.004), respectively (Table 3). Using this approach, we calculated an ICC of 0.086, similar to but slightly higher than the assumed ICC used in power and sample size estimation.The CIS strategy was delivered according to the study protocol to 937 (85%) of the 1,096 participants enrolled in study units assigned to the CIS. Reasons for not receiving all of the CIS strategy intervention components included missing POC CD4+ count testing (<1% CIS participants), missing an ART counseling session per accelerated ART procedures (3%), missing receipt of 1 healthcare bag (2%), and missing receipt of 1 financial incentive (9%). There was heterogeneity in the primary outcome across the 5 pairs of matched study units. The proportion of participants who achieved the primary outcome in study units randomized to the CIS ranged from 49% to 82%, while this ranged from 22% to 57% in the study units randomized to SOC.Secondary outcomesA similar proportion of participants linked to care anytime during the study follow-up period in both study arms: 1,032 (94%) in the CIS arm as compared to 957 (87%) in the SOC arm (RR 1.08, 95% CI 0.97–1.21, p = 0.13), with no significant differences in linkage within the same day or 1 month after testing (Table 3). The mean time to linkage to care was shorter in the CIS arm versus the SOC study arm but was not statistically different (2.5 compared to 7.5 days, p = 0.189). However, among those who ever linked to care (1,032 in the CIS study arm and 957 in the SOC study arm), significantly fewer patients (13%) in CIS sites versus SOC sites (18%) did not return for subsequent visits after the first clinic visit (p = 0.008).Assessment for ART eligibility through either a CD4+ count or WHO staging was done for all participants in the CIS arm as compared to 84% of participants in the SOC arm (RR 1.20, 95% CI 1.07–1.34, p = 0.004). The mean time to ART eligibility assessment was 0 days in the CIS study arm compared to 6.3 days in the SOC arm (p < 0.001). The median CD4+ count among 1,096 participants in the CIS arm who had POC CD4+ count testing done at the time of HIV testing was 311 cells/mm3 (IQR 159–443). Among the 907 (82%) participants in the SOC arm who linked to HIV care and had a CD4+ count done, the median CD4 count was 285 cells/mm3 (155–444) (p = 0.07).A total of 710 participants (85% of ART-eligible participants) in the CIS arm as compared to 635 (88% among ART-eligible participants) in the SOC arm initiated ART within the study follow-up period (RR 1.16, 95% CI 0.96–1.40, p = 0.12) (Table 3). The median time from HIV testing to ART initiation among eligible patients was 7.0 days (IQR 3.0–21.0) as compared to 14.0 days (IQR 7.0–13.0) in the CIS and SOC study arms, respectively (p < 0.001).Retention in care, regardless of time to linkage or ART status, at 12 months was significantly greater in participants in the CIS as compared to the SOC study arm, with an RR of 1.48 (95% CI 1.18–1.86, p = 0.002). Loss to follow-up during pre-ART care (RR = 0.60, 95% CI 0.40–0.89, p = 0.014) and after ART initiation (RR = 0.51, 95% CI 0.31–0.85, p = 0.013) was significantly lower in the CIS arm as compared to the SOC arm.For participants on ART for at least 6 months during follow-up regardless of retention status, viral load data were available for 97% (N = 477/493) of participants in the CIS arm and 98% (N = 451/458) in the SOC arm. Viral suppression among participants on ART ≥6 months with available viral loads was similar by study arm at 88% in CIS and 90% in SOC (RR 0.97, 95% CI 0.88–1.07, p = 0.55).There were 78 deaths (3.6% of the study population) that occurred during follow-up, and this did not differ by study arm (35 deaths [3%] in the CIS study arm versus 43 deaths [4%] in the SOC arm, with an RR of 0.80, 95% CI 0.46–1.35, p = 0.40) (Table 3). However, there was nonsignificantly lower mortality among participants prior to ART initiation in the CIS arm (10 deaths) compared to the SOC arm (23 deaths), with an RR of 0.44 (95% CI 0.19–1.01, p = 0.05). Fig 3 compares the CIS study arm versus the SOC study arm across the HIV care continuum from linkage to care within 1 month of testing through retention in care at 12 months after testing HIV positive.10.1371/journal.pmed.1002420.g003Fig 3HIV care continuum comparing the combination intervention strategy (CIS) study arm versus the standard of care (SOC) study arm.In post hoc analyses, we examined achievement of the primary outcome between study arms by key subgroups. The effect of the CIS, as compared to the SOC, was consistent across all prespecified subgroups, including by age, sex, income, employment, marital status, travel away from home in the past year, travel time to clinic, past HIV testing history, household members with HIV, and type of clinic (Fig 4, S1 Table).10.1371/journal.pmed.1002420.g004Fig 4Primary outcome by subgroups of participants.USD, US dollars; yrs, years.DiscussionIn this cluster-randomized study, a novel combination strategy, inclusive of 5 evidence-based interventions, was 50% more effective than the SOC in enhancing linkage to care plus retention in care among HIV-positive individuals. The robustness of this outcome is supported by the consistent findings in the per-protocol analysis, in sensitivity analyses, and across subgroups of participants. In addition, the combination strategy was associated with improvements across multiple steps of the care continuum, with an increased proportion of participants who were assessed for ART eligibility, decreased time to ART eligibility assessment, decreased time to ART initiation, increased retention at 12 months after HIV testing regardless of time to linkage and ART status, and decreased mortality among participants prior to ART initiation. However, high rates of viral suppression were similar among ART patients by study arm.In our study, the effect noted on the primary outcome appeared to be largely driven by enhanced retention rather than by the linkage-to-care component. This finding may be due to the high proportion of participants in both study arms who linked to care within 1 month of HIV testing in both arms of the study (87% in the SOC arm and 92% in the CIS arm), and thus, our sample size was insufficient to show a difference between the arms. The high proportion of participant linkage was likely influenced by a national campaign to improve linkage that was implemented during the study period [21].The combination strategy significantly reduced loss to follow-up among participants regardless of whether they were in pre-ART care or on treatment. Loss to follow-up, in both study arms, was higher among pre-ART participants, as compared to participants who had initiated ART. This is consistent with findings from other studies, including those from a large study of 390,603 HIV-positive adults in Kenya, Mozambique, Rwanda, and Tanzania, in which 34.8% of all patients who had not initiated ART were lost from care at 12 months, compared to 5.8% among patients on ART [6]. While the pre-ART care phase should largely be minimized with the release of the recent WHO guidelines that recommend offering ART to all HIV-positive individuals irrespective of CD4+ count or WHO disease stage, evidence suggests that retention in care and on ART remains a challenge even in the context of “treatment for all” [48]. For example, while adoption of Option B+, which entails initiation of ART for all HIV-positive pregnant women, has been associated with an increase in the number of pregnant women on ART, loss to follow-up has remained a challenge. Among 21,939 HIV-infected pregnant women who started ART as per Option B+ in Malawi, 17% were lost to follow-up at 6 months after treatment start, with a 5-fold higher loss to follow-up compared to those who initiated ART at a more advanced stage of HIV disease [49]. Thus, the findings from our study remain relevant even though the study was conducted at a time when a CD4+ count threshold was recommended for ART initiation.In this study, viral suppression was high among all participants on ART for a minimum of 6 months, irrespective of study arm. This confirms the potency of the first-line regimen, consisting of tenofovir, lamivudine, and efavirenz or nevirapine, and suggests that participants were highly adherent to their medications. These findings build upon those from the Population-based HIV Impact Assessment Project surveys that were conducted recently in Malawi, Zambia, Zimbabwe, and Swaziland, which included nationally representative samples of individuals in which 87% of HIV-positive adults who reported being on ART were virally suppressed (HIV-1 RNA < 1,000 copies/ml) [50,51]. Findings from this project survey in Swaziland showed that among adults who were aware of their HIV-positive status and who indicated being on ART, 92% had a suppressed viral load [52]. The finding of similarly high proportions of viral suppression among participants in both arms of our study suggests that the sample size was insufficient to detect a difference. In addition, it is important to note that the interventions used in this study were not designed with a focus specifically on enhancing medication adherence and viral suppression. Design of future combination strategies may prioritize the use of interventions that focus specifically on enhancing adherence to ART, such as the use of financial incentives to improve viral suppression [53].Every effort was made to ascertain accurate loss to follow-up and mortality outcomes in our study. It should be noted that reporting of accurate loss to follow-up and mortality outcomes by HIV programs has been a controversial topic. This is due to the fact that when tracing was done for individuals reported as lost to follow-up by HIV programs, a substantial proportion were found to have either died or transferred care to another health facility [54]. We feel confident that it is unlikely that such misclassification occurred in our study as home tracing was conducted for all study participants to ascertain their outcomes at the end of the 12-month follow-up period. While the study was not powered to detect a difference between the study arms in terms of mortality, the combination strategy appeared to have a meaningful—albeit not statistically significant—effect, with as much as 50% lower mortality noted among pre-ART patients. This may be due to better retention in care among participants in the intervention arm. Poor retention in care has been demonstrated to be associated with increased mortality, likely due to missed clinic visits that deprive patients of clinical and laboratory assessments for diagnosis of early complications and delay prompt initiation of ART [55].We observed substantial heterogeneity in the primary outcome across clinics in both the CIS and SOC study arms. This may reflect clinic-level differences such as clinic size and location. For example, the CIS study unit with the lowest achievement of the study’s primary outcome was the largest clinic in urban Swaziland. It is possible that individuals who test HIV positive at such a large clinic may seek ongoing care at clinics closer to their homes. Other reasons could be differences in patient-level factors, such as sex, age, and immunological status, which warrant further analyses.To date, most intervention studies to address gaps in the HIV care continuum have focused on 1 step in the continuum, largely that of ART initiation. The Rapid Initiation of Treatment trial showed that single-visit ART initiation that included POC CD4+ count testing was associated with significantly higher ART initiation (97%) compared to the standard of care (72%) [56]. The START-ART trial was a stepped-wedge cluster-randomized trial of 20 clinics in Uganda that evaluated an intervention aimed at improving ART initiation among eligible patients; this intervention was associated with a higher proportion of patients initiating ART (80%) within 14 days after determination of ART eligibility compared to 38% in the control group [13]. Finally, the Same Day ART Initiation Study in Haiti, which evaluated the effect of same-day ART initiation on the day of HIV diagnosis among asymptomatic HIV-positive adults with CD4+ count ≤ 500 cells/uL and WHO stage I or II disease, noted that a higher proportion (53%) of participants randomized to same-day ART initiation were retained in care at 12 months with viral suppression compared to those in the standard of care arm (44%) [14].Our study had several strengths, including the use of a pragmatic approach consistent with implementation science design. Specifically, it utilized broad eligibility criteria, was conducted within established health facilities, tested feasible interventions that were delivered primarily by available staff rather than research staff, and assessed the primary outcome largely through routinely available data. In addition, the study included the majority of clinics in Swaziland and involved cluster-randomized design rather than randomization of individual participants, which allowed for ease of implementation and avoided disruption of services within the clinics. The study also uniquely assessed the effect of the delivery of multiple interventions packaged in 1 strategy aimed at multiple steps in the HIV care continuum. Thus, implementation of the study strategy has the potential to achieve not only prompt ART initiation but also better retention in care and on ART, consequently enhancing individual and society benefits from the “treat all” approach.The primary limitations of this study included a limited number of clusters, although it was inclusive of all the available clusters in the country. At the time of study initiation, there were only 11 secondary health facilities offering HIV services in Swaziland, and we selected 10 of these for participation in this study. Consequently, it is possible that the cluster randomization did not evenly distribute all determinants of linkage and retention other than the study interventions between treatment arms. While it is encouraging that analyses adjusting for individual-level differences between treatment arms did not appreciably change the results, we cannot definitively rule out residual confounding as a potential explanation of the findings. In addition, the design focused on evaluation of a package of interventions as 1 strategy and, thus, it did not allow for evaluation of the effectiveness of individual components of the combination approach. Another limitation was use of self-reported linkage and retention at other clinics to ascertain undocumented transfers to other clinics outside of the study unit.ConclusionsThe Link4Health study demonstrated that a combination strategy of evidence-based interventions, aimed at gaps in various steps of the HIV care continuum, was highly effective in enhancing linkage of HIV-positive individuals to care plus increasing their retention in care and on ART. The study also showed that once participants initiated ART, viral load suppression was high irrespective of the study arm. Cost effectiveness and qualitative analyses are ongoing in order to inform decision makers considering adoption of this strategy. Our findings offer an effective strategy that can advance the quality of HIV programs in Swaziland and that can be adapted to other similar contexts.Supporting informationS1 TextConsolidated Standards of Reporting Trials (CONSORT) statement.(DOCX)Click here for additional data file.S1 DataLink4Health deidentified dataset.(XLSX)Click here for additional data file.S1 TablePrimary outcome by prespecified participant subgroup.(DOCX)Click here for additional data file.AbbreviationsARTantiretroviral therapyCIScombination intervention strategyCONSORTConsolidated Standards of Reporting TrialsDBSdried blood sampleICCinterclass correlation coefficientPITCprovider-initiated testing and counsellingPOCpoint of careRRrelative riskSMSshort message serviceSOCstandard of careSUstudy unitTBtuberculosisUNAIDSJoint United Nations Programme on HIV/AIDSVCTvoluntary HIV counselling and testingReferences1McNairyML, El-SadrWM. The HIV care continuum: no partial credit given. 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PLoS Med. 2016;13(8):e1002107\ndoi: 10.1371/journal.pmed.1002107 ; PubMed Central PMCID: PMC4978506.275046379GovindasamyD, FordN, KranzerK. Risk factors, barriers and facilitators for linkage to antiretroviral therapy care: a systematic review. AIDS. 2012;26(16):2059–67. Epub 2012/07/12. doi: 10.1097/QAD.0b013e3283578b9b .2278122710HallBJ, SouKL, BeanlandR, LackyM, TsoLS, MaQ, et al\nBarriers and Facilitators to Interventions Improving Retention in HIV Care: A Qualitative Evidence Meta-Synthesis. AIDS Behav. 2016;21(6):1755–67. doi: 10.1007/s10461-016-1537-0 .2758208811FoxMP, RosenS, GeldsetzerP, BarnighausenT, NegussieE, BeanlandR. Interventions to improve the rate or timing of initiation of antiretroviral therapy for HIV in sub-Saharan Africa: meta-analyses of effectiveness. J Int AIDS Soc. 2016;19(1):20888 10.7448/IAS.19.1.20888. 27507249; PubMed Central PMCID: PMC4978859. doi: 10.7448/IAS.19.1.20888\n2750724912GovindasamyD, MeghijJ, Kebede NegussiE, BaggaleyRC, FordN, KranzerK. Interventions to improve or facilitate linkage to or retention in pre-ART (HIV) care and initiation of ART in low- and middle-income settings—a systematic review. J Int AIDS Soc. 2014;17:19032\ndoi: 10.7448/IAS.17.1.19032 ; PubMed Central PMCID: PMC4122816.2509583113AmanyireG, SemitalaFC, NamusobyaJ, KaturamuR, KampiireL, WallentaJ, et al\nEffects of a multicomponent intervention to streamline initiation of antiretroviral therapy in Africa: a stepped-wedge cluster-randomised trial. Lancet HIV. 2016;3(11):e539–e48. doi: 10.1016/S2352-3018(16)30090-X .2765887314KoenigSP, DorvilN, DevieuxJG, Hedt-GauthierBL, RiviereC, FaustinM, et al\nSame-day HIV testing with initiation of antiretroviral therapy versus standard care for persons living with HIV: A randomized unblinded trial. 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Mbabane, Swaziland: Swaziland Ministry of Health, 2015.23LarsonBA, BrennaA, McNamaraL, LongL, RosenS, SanneI, et al\nLost Opportunities to complete CD4+ lymphocyte testing among patients who tested positive for HIV in South Africa. Bull World Health Organ. 2010;88(9):675–80. doi: 10.2471/BLT.09.068981 .2086507224JaniIV, SitoeNE, AlfaiER, ChongPL, QuevedoJI, RochaBM, et al\nEffect of point-of-care CD4 cell count tests on retention of patients and rates of antiretroviral therapy initiation in primary health clinics: an observational cohort study. Lancet. 2011;378(9802):1572–9. doi: 10.1016/S0140-6736(11)61052-0 .2195165625FaalM, NaidooN, GlenncrossDK, VenterWD, OsihR. Providing immediate CD4 count results at HIV testing improves ART initiation. J Acquir Immune Defic Syndr. 2011;58(3):e54–9. doi: 10.1097/QAI.0b013e3182303921 .2185735626LarsonBA, SchnippelK, NdibongoB, XuluT, BrennanA, LongL, et al\nRapid point-of-care CD4 testing at mobile HIV testing sites to increase linkage to care: an evaluation of a pilot program in South Africa. J Acquir Immune Defic Syndr. 2012;61(2):e13–7. doi: 10.1097/QAI.0b013e31825eec60 ; PubMed Central PMCID: PMC3458178.2265965027LahuertaM, UeF, HoffmanS, ElulB, KulkarniSG, WuY, et al\nThe problem of late ART initiation in Sub-Saharan Africa: a transient aspect of scale-up or a long-term phenomenon?\nJ Health Care Poor Underserved. 2013;24(1):359–83. doi: 10.1353/hpu.2013.0014 ; PubMed Central PMCID: PMC3655523.2337773928CohenMS, ChenYQ, McCauleyM, GambleT, HosseinipourMC, KumarasamyN, et al\nPrevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365(6):493–505. Epub 2011/07/20. doi: 10.1056/NEJMoa1105243 ; PubMed Central PMCID: PMC3200068.2176710329ChangL, KagaayiJ, NakigoziG, PackerAH, SerwaddaD, QuinnTC, et al\nResponding to the human resource crisis: peer health workers, mobile phones, and HIV care in Rakai, Uganda. AIDS Patient Care STDS. 2008;22(3):173–4. doi: 10.1089/apc.2007.0234 PubMed Central PMCID 2674572 1829075030DownerSR, MearJG, Da CostaAC, SethuramanK. SMS text messaging improves outpatient attendance. Aust Health Rev. 8\n2006;30(3):389–96. .1687909831FjeldsoeBS, MarshallAL, MillerYD. Behavior change interventions delivered by mobile telephone short-message service. Am J Prev Med. 2\n2009;36(2):165–73. doi: 10.1016/j.amepre.2008.09.040 .1913590732HabererJE, KiwanukaJ, NanseraD, WilsonIB, BangsbergDR. Challenges in using mobile phones for collection of antiretroviral therapy adherence data in a resource-limited setting. AIDS Behav. Dec\n2010;14(6):1294–301. doi: 10.1007/s10461-010-9720-1 .2053260533LesterRT, RitvoP, MillsEJ, KaririA, KaranjaS, ChungMH, et al\nEffects of a mobile phone short message service on antiretroviral treatment adherence in Kenya (WelTel Kenya1): a randomised trial. Lancet. 11\n27\n2010;376(9755):1838–45. doi: 10.1016/S0140-6736(10)61997-6 .2107107434LiewSM, TongSF, LeeVK, NgCJ, LeongKC, TengCL. Text messaging reminders to reduce non-attendance in chronic disease follow-up: a clinical trial. Br J Gen Pract. 12\n2009;59(569):916–20. doi: 10.3399/bjgp09X472250 .1971254435Mukund BahadurKC, MurrayPJ. Cell phone short messaging service (SMS) for HIV/AIDS in South Africa: a literature review. Stud Health Technol Inform. 2010;160(Pt 1):530–5. .2084174336Pop-ElechesC, ThirumurthyH, HabyarimanaJP, ZivinJG, GoldsteinMP, de WalqueD, et al\nMobile phone technologies improve adherence to antiretroviral treatment in a resource-limited setting: a randomized controlled trial of text message reminders. AIDS. Mar 27\n2011;25(6):825–34. doi: 10.1097/QAD.0b013e32834380c1 .2125263237ShetA, de CostaA. India calling: harnessing the promise of mobile phones for HIV healthcare. Trop Med Int Health. 2011;16(2):214–6. doi: 10.1111/j.1365-3156.2010.02678.x .2137121438ColindresP, MerminJ, EzatiE, KambabaziS, BuyungoP, SekabembeL, et al\nUtilization of a basic care and prevention package by HIV-infected persons in Uganda. AIDS Care. 2008;20(2):139–45. Epub 2007/09/27. doi: 10.1080/09540120701506804 .1789619639GiuffridaA, TorgersonDJ. Should we pay the patient? Review of financial incentives to enhance patient compliance. BMJ. 1997;315(7110):703–7. Epub 1997/10/07. ; PubMed Central PMCID: PMC2127496.931475440VolppKG, JohnLK, TroxelAB, NortonL, FassbenderJ, LoewensteinG. Financial incentive-based approaches for weight loss: a randomized trial. JAMA. 2008;300(22):2631–7. 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Tuberculosis screening and compliance with return for skin test reading among active drug users. Am J Public Health. 1998;88(5):792–6. Epub 1998/05/20. ; PubMed Central PMCID: PMC1508952.958574746WHO. Technical and Operational Considerations for Implementing HIV Viral Load Testing. Geneva: WHO, 2014.47SnijdersTA, BoskerRJ. Multilevel analysis: An introduction to basic and advanced mulitlevel modeling. Thousand Oaks, California: Sage; 1999.48WHO. Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV. Geneva: WHO, 2015 9\n2015.49TenthaniL, HaasAD, TweyaH, JahnA, van OosterhoutJJ, ChimbwandiraF, et al\nRetention in care under universal antiretroviral therapy for HIV-infected pregnant and breastfeeding women ('Option B+') in Malawi. AIDS. 2014;28(4):589–98. doi: 10.1097/QAD.0000000000000143 ; PubMed Central PMCID: PMC4009400.2446899950Columbia University. The Population HIV Impact Assessment (PHIA) Project. Accessed May 31 2017 at: www.phia.icap.columbia.edu.51Justman J. Real Progress in the HIV Epidemic: PHIA Findings from Zimbabwe, Malawi, and Zambia. Oral Abstract. Conference of Retroviruses and Opportunistic Infections February 13–15, 2017; Seattle, WA2017.52Nkambule R, Nuwagaba-Biribownwoha H, Mnisi Z, Ao T, Duong Y, Patel H, et al. Substantial progress in confronting the HIV epidemic in Swaziland: first evidence of national impact. Abstract 204LB. International AIDS Society 2017; July 24, 2017; Paris, France 2017.53El-SadrWM, DonnellD, BeauchampG, HallHI, TorianLV, ZingmanB, et al\nFinancial Incentives for Linkage to Care and Viral Suppression Among HIV-Positive Patients: A Randomized Clinical Trial (HPTN 065). JAMA. 2017;177(8):1083–92. doi: 10.1001/jamainternmed.2017.2158 .2862870254GengEH, GliddenDV, BwanaMB, MusinguziN, EmenyonuN, MuyindikeW, et al\nRetention in care and connection to care among HIV-infected patients on antiretroviral therapy in Africa: estimation via a sampling-based approach. PLoS ONE. 2011;6(7):e21797\ndoi: 10.1371/journal.pone.0021797 ; PubMed Central PMCID: PMC3144217.2181826555GiordanoTP, GiffordAL, WhiteACJr., Suarez-AlmazorME, RabeneckL, HartmanC, et al\nRetention in care: a challenge to survival with HIV infection. Clin Infect Dis. 2007;44(11):1493–9. Epub 2007/05/08. doi: 10.1086/516778 .1747994856RosenS, MaskewM, FoxMP, NyoniC, MongwenyanaC, MaleteG, et al\nInitiating Antiretroviral Therapy for HIV at a Patient's First Clinic Visit: The RapIT Randomized Controlled Trial. PLoS Med. 2016;13(5):e1002015\ndoi: 10.1371/journal.pmed.1002015 .27163694", 'title': 'Effectiveness of a combination strategy for linkage and retention in adult HIV care in Swaziland: The Link4Health cluster randomized trial.', 'date': '2017-11-08'}, '28542080': {'article_id': '28542080', 'content': 'Lack of accessible laboratory infrastructure limits HIV antiretroviral therapy (ART) initiation, monitoring, and retention in many resource-limited settings. Point-of-care testing (POCT) is advocated as a mechanism to overcome these limitations. We executed a pragmatic, prospective, randomized, controlled trial comparing the impact of POCT vs. standard of care (SOC) on treatment initiation and retention in care.\nSelected POC technologies were embedded at 3 primary health clinics in South Africa. Confirmed HIV-positive participants were randomized to either SOC or POC: SOC participants were venesected and specimens referred to the laboratory with patient follow-up as per algorithm (∼3 visits); POC participants had phlebotomy and POCT immediately on-site using Pima CD4 to assess ART eligibility followed by hematology, chemistry, and tuberculosis screening with the goal of receiving same-day adherence counseling and treatment initiation. Participant outcomes measured at recruitment 6 and 12 months after initiation.\nFour hundred thirty-two of 717 treatment eligible participants enrolled between May 2012 and September 2013: 198 (56.7%) SOC; 234 (63.6%) POC. Mean age was 37.4 years; 60.5% were female. Significantly more participants were initiated using POC [adjusted prevalence ratio (aPR) 0.83; 95% confidence interval (CI): 0.74 to 0.93; P < 0.0001], the median time to initiation was 1 day for POC and 26.5 days for SOC. The proportion of patients in care and on ART was similar for both arms at 6 months (47 vs. 50%) (aPR 0.96; 95% CI: 0.79 to 1.16) and 12 months (32 vs. 32%) (aPR 1.05; 95% CI: 0.80 to 1.38), with similar mortality rates. Loss to follow-up at 12 months was higher for POC (36% vs. 51%) (aPR 0.82; 95% CI: 0.65 to 1.04).\nAdoption of POCT accelerated ART initiation but once on treatment, there was unexpectedly higher loss to follow-up on POC and no improvement in outcomes at 12 months over SOC.', 'title': 'Multidisciplinary Point-of-Care Testing in South African Primary Health Care Clinics Accelerates HIV ART Initiation but Does Not Alter Retention in Care.', 'date': '2017-05-26'}}
| 0.666667
|
Public Health, Epidemiology & Health Systems
|
21
|
Is ART uptake at 12 months higher, lower, or the same when comparing rapid ART to standard initiation?
|
higher
|
moderate
|
yes
|
['28742880', '27658873', '29509839', '27163694']
| 31,206,168
| 2,019
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{'28742880': {'article_id': '28742880', 'content': 'PLoS MedPLoS MedplosplosmedPLoS Medicine1549-12771549-1676Public Library of ScienceSan Francisco, CA USA28742880552652610.1371/journal.pmed.1002357PMEDICINE-D-17-00266Research ArticleBiology and Life SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesPublic and Occupational HealthPreventive MedicineVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesImmunodeficiency VirusesHIVBiology and 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SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVHIV-1Medicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVHIV-1Biology and Life SciencesOrganismsVirusesViral PathogensRetrovirusesLentivirusHIVHIV-1Medicine and Health SciencesHealth CareHealth Care ProvidersMedical DoctorsPhysiciansPeople and PlacesPopulation GroupingsProfessionsMedical DoctorsPhysiciansPeople and placesGeographical locationsNorth AmericaCaribbeanHaitiBiology and Life SciencesMicrobiologyVirologyViral Transmission and InfectionViral LoadMedicine and health sciencesDiagnostic medicineHIV clinical manifestationsSame-day HIV testing with initiation of antiretroviral therapy versus standard care for persons living with HIV: A randomized unblinded trialSame-day HIV testing and antiretroviral therapy initiationhttp://orcid.org/0000-0001-7464-275XKoenigSerena P.ConceptualizationFunding acquisitionInvestigationMethodologySupervisionWriting – original draftWriting – review & editing12*DorvilNancyInvestigationMethodologyProject administrationSupervisionWriting – review & editing1DévieuxJessy G.ConceptualizationFunding acquisitionInvestigationMethodologySupervisionWriting – original draftWriting – review & editing3http://orcid.org/0000-0002-9689-5413Hedt-GauthierBethany L.ConceptualizationFormal analysisFunding acquisitionMethodologySoftwareSupervisionValidationVisualizationWriting – review & editing4RiviereCynthiaInvestigationMethodologyProject administrationSupervisionWriting – review & editing1FaustinMikerlyneInvestigationMethodologyProject administrationSupervisionWriting – review & editing1LavoileKerlyneInvestigationMethodologyProject administrationSupervisionWriting – review & editing1PerodinChristianFormal analysisInvestigationMethodologySoftwareValidationVisualizationWriting – review & editing1ApollonAlexandraConceptualizationInvestigationMethodologyProject administrationSupervisionWriting – review & editing1DuvergerLimatheInvestigationMethodologyProject administrationSupervisionWriting – review & editing1McNairyMargaret L.MethodologyWriting – review & editing56HennesseyKelly A.Formal analysisMethodologySoftwareValidationVisualizationWriting – review & editing1SouroutzidisAriadneFormal analysisMethodologySoftwareValidationVisualizationWriting – review & editing7CremieuxPierre-YvesFormal analysisMethodologySoftwareValidationVisualizationWriting – review & editing7SeverePatriceConceptualizationFunding acquisitionInvestigationMethodologyProject administrationSupervisionWriting – review & editing1PapeJean W.ConceptualizationFunding acquisitionInvestigationMethodologyProject administrationSupervisionWriting – review & editing151\nHaitian Study Group for Kaposi’s Sarcoma and Opportunistic Infections (GHESKIO), Port-au-Prince, Haiti2\nDivision of Global Health Equity, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America3\nAIDS Prevention Program, Florida International University, Miami, Florida, United States of America4\nDepartment of Global Health and Social Medicine, Harvard Medical School, Harvard University, Boston, Massachusetts, United States of America5\nCenter for Global Health, Department of Medicine, Weill Cornell Medical College, Cornell University, New York, New York, United States of America6\nDivision of General Internal Medicine, Department of Medicine, Weill Cornell Medical College, Cornell University, New York, New York, United States of America7\nAnalysis Group, Boston, Massachusetts, United States of AmericaGengElvin H.Academic EditorUniversity of California, San Francisco, UNITED STATESThe authors have declared that no competing interests exist.* E-mail: skoenig@bwh.harvard.edu257201772017147e100235724120171662017© 2017 Koenig et al2017Koenig et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThe science of rapid start—From the when to the how of antiretroviral initiation\nBackgroundAttrition during the period from HIV testing to antiretroviral therapy (ART) initiation is high worldwide. We assessed whether same-day HIV testing and ART initiation improves retention and virologic suppression.Methods and findingsWe conducted an unblinded, randomized trial of standard ART initiation versus same-day HIV testing and ART initiation among eligible adults ≥18 years old with World Health Organization Stage 1 or 2 disease and CD4 count ≤500 cells/mm3. The study was conducted among outpatients at the Haitian Group for the Study of Kaposi’s Sarcoma and Opportunistic infections (GHESKIO) Clinic in Port-au-Prince, Haiti. Participants were randomly assigned (1:1) to standard ART initiation or same-day HIV testing and ART initiation. The standard group initiated ART 3 weeks after HIV testing, and the same-day group initiated ART on the day of testing. The primary study endpoint was retention in care 12 months after HIV testing with HIV-1 RNA <50 copies/ml. We assessed the impact of treatment arm with a modified intention-to-treat analysis, using multivariable logistic regression controlling for potential confounders. Between August 2013 and October 2015, 762 participants were enrolled; 59 participants transferred to other clinics during the study period, and were excluded as per protocol, leaving 356 in the standard and 347 in the same-day ART groups. In the standard ART group, 156 (44%) participants were retained in care with 12-month HIV-1 RNA <50 copies, and 184 (52%) had <1,000 copies/ml; 20 participants (6%) died. In the same-day ART group, 184 (53%) participants were retained with HIV-1 RNA <50 copies/ml, and 212 (61%) had <1,000 copies/ml; 10 (3%) participants died. The unadjusted risk ratio (RR) of being retained at 12 months with HIV-1 RNA <50 copies/ml was 1.21 (95% CI: 1.04, 1.38; p = 0.015) for the same-day ART group compared to the standard ART group, and the unadjusted RR for being retained with HIV-1 RNA <1,000 copies was 1.18 (95% CI: 1.04, 1.31; p = 0.012). The main limitation of this study is that it was conducted at a single urban clinic, and the generalizability to other settings is uncertain.ConclusionsSame-day HIV testing and ART initiation is feasible and beneficial in this setting, as it improves retention in care with virologic suppression among patients with early clinical HIV disease.Trial registrationThis study is registered with ClinicalTrials.gov number NCT01900080In a randomized unblinded trial in Port-au-Prince, Haiti, Serena Koenig and colleagues investigate whether initiating ART on the day of HIV diagnosis improved retention in care and viral suppression.Author summaryWhy was this study done?Multiple visits for counseling, laboratory testing, and other procedures to prepare patients for initiation of antiretroviral therapy (ART) are burdensome and contribute to the high rate of attrition during the period from HIV testing to ART initiation.The World Health Organization (WHO) recently changed their guidelines to recommend ART for all persons living with HIV, facilitating ART initiation.This study was conducted to determine if ART initiation on the day of HIV diagnosis could improve treatment initiation rates, retention in care, and HIV viral suppression for patients with asymptomatic or minimally symptomatic HIV disease.What did the researchers do and find?We randomly assigned patients who presented for HIV testing at a clinic in Port-au-Prince, Haiti to standard ART initiation or same-day HIV testing and ART initiation (356 in the standard and 347 in the same-day groups).The standard group had 3 weekly visits with a social worker and physician and then started ART 21 days after the date of HIV diagnosis; the same-day ART group initiated ART on the day of HIV diagnosis.All participants in the same-day ART group and 92% of participants in the standard group initiated ART.At 12 months after HIV testing, a higher proportion of participants in the same-day ART group were retained in care (80% versus 72%), and a higher proportion were retained in care with viral load <50 copies/ml (53% versus 44%) and viral load <1,000 copies/ml (61% versus 52%).What do these findings mean?This study demonstrates that it is feasible to initiate ART on the day of HIV diagnosis for patients with early HIV clinical disease and that same-day treatment leads to increased ART uptake, retention in care, and viral suppression.Though same-day ART initiation improves outcomes, retention in care and viral suppression remain suboptimal, so further interventions to maximize long-term outcomes will be essential.The study is limited by being conducted at 1 clinic in urban Haiti. Further study will be necessary to determine if this strategy will be effective in other settings.http://dx.doi.org/10.13039/100000060National Institute of Allergy and Infectious DiseasesR01AI104344http://orcid.org/0000-0001-7464-275XKoenigSerena P.This project was supported by the National Institute of Allergy and Infectious Diseases, grant number R01AI104344. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Data AvailabilityWe have included the anonymized dataset as a Supporting Information file (S1 Data).Data AvailabilityWe have included the anonymized dataset as a Supporting Information file (S1 Data).IntroductionThe Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 targets state that 90% of HIV-infected persons know their status, 90% initiate antiretroviral therapy (ART), and 90% achieve virologic suppression by the year 2020 to curb the AIDS epidemic [1]. In 2015, the World Health Organization (WHO) updated their guidelines to recommend ART for all persons living with HIV based on evidence that earlier treatment improves outcomes and decreases transmission [2–4]. To achieve these goals, patients must be promptly linked to HIV services, initiated on ART, and retained in lifelong care [5].Attrition rates are particularly high during the period from HIV testing to ART initiation, with one-quarter to one-third of patients lost in the process of starting ART [6–9]. Even if many of these patients re-engage in care at a later date, they will return with more advanced disease. Though there are many factors that contribute to pretreatment attrition, the current standard of care in most settings, which requires multiple sequential visits for HIV testing and counseling, laboratory testing, and adherence counseling prior to ART initiation, creates barriers to treatment initiation. As of June 2016, WHO guidelines note inadequate evidence to support a recommendation of same-day HIV testing and ART initiation [2]. However, the availability of point-of-care tests, the fact that CD4 cell counts are no longer necessary prior to ART initiation, and the provision of same-day counseling can accelerate treatment initiation, potentially reducing attrition [10–12]. We conducted a randomized trial in Haiti to determine whether same-day HIV testing and ART initiation, as compared with standard ART initiation, improves retention in care with viral suppression.MethodsStudy design and settingWe conducted an unblinded, randomized controlled trial of standard ART initiation versus same-day HIV testing and ART initiation among HIV-infected adults at the Haitian Group for the Study of Kaposi’s Sarcoma and Opportunistic infections (GHESKIO) in Port-au-Prince, Haiti. Haiti is the poorest country in the Western Hemisphere, with adult HIV prevalence of 1.7% [13,14]. GHESKIO is a Haitian nongovernmental organization and the largest provider of HIV care in the Caribbean, treating up to 700 patients per day for HIV and/or tuberculosis (TB). All care is provided free of charge. The study was approved by the institutional review boards at Partners Healthcare, GHESKIO, Weill Cornell Medical College, and Florida International University. See supporting information files S1 Text for the study protocol and S2 Text for the CONSORT checklist.ParticipantsParticipants were recruited from the HIV voluntary counseling and testing center at GHESKIO from August 2013 to October 2015. They received HIV testing and posttest counseling; those with a positive HIV test were referred for same-day physician evaluation, CD4 count (FACS Count, Becton-Dickinson, Franklin Lakes, New Jersey), WHO staging, and chest radiograph. Patients were eligible for study inclusion if they were infected with HIV-1, ≥18 years of age, and had WHO Stage 1 or 2 disease and CD4 count ≤500 cells/mm3. Initially, enrollment was limited to patients with CD4 count ≤350 cells/mm3, but in February 2014, the cutoff was increased to ≤500 cells/mm3 in response to revised WHO and Haitian guidelines [15]. Patients were excluded if they were already aware of their HIV diagnosis, had received ART previously, were pregnant or breastfeeding, lived outside of the greater Port-au-Prince metropolitan area, planned to transfer care during the study period, or failed to demonstrate preparedness on an ART readiness survey, which was administered by a social worker prior to study enrollment. The survey includes a 5-point scale, with respondents ranking their preparedness from “not at all ready” to “completely ready” in response to 7 questions. Study inclusion required a response of “somewhat ready” or “completely ready” for all 7 questions (S3 Text) [16].Randomization and maskingAfter the patients had provided written informed consent, the study team performed a screening evaluation for study exclusion criteria, and eligible participants were enrolled and randomized on the day of HIV testing. Participants were randomly assigned with the use of a computer-generated random-number list to either standard ART or same-day ART initiation in a 1:1 ratio, with allocation concealment. The randomization sequence was generated by a computer in the GHESKIO data management unit by a data manager who had no other involvement in study procedures. Participants were enrolled in the study and assigned to groups by a study physician. Participants, site personnel, and study statisticians were not masked to group assignment.ProceduresAfter randomization, the standard group participants received ART initiation procedures that mirror national guidelines. Participants were referred to return on Day 7 for baseline laboratory tests (creatinine, alanine aminotransferase, aspartate aminotransferase, complete blood count, purified protein derivative [PPD]), physician evaluation, and counseling with a social worker. On Day 10, they received interpretation of PPD results, and on Days 14 and 21, they were seen by a physician and social worker for additional counseling, test results, and ongoing evaluations for opportunistic infections. Participants started ART on Day 21 and had an additional social worker and physician visit at Week 5 (Fig 1). The ART regimen was the same as that for nonstudy patients at GHESKIO. First-line therapy included a single combination tablet including tenofovir disoproxil fumarate, lamivudine, and efavirenz.10.1371/journal.pmed.1002357.g001Fig 1Study interventions for the standard ART and same-day ART groups.The same-day ART group had identical laboratory tests as the standard ART group, a 30-minute counseling session with a social worker, and physician evaluation, and then initiated the same ART regimen as the standard ART group. They returned on Day 3 for physician and social worker visits and receipt of baseline laboratory test results; those with creatinine clearance <50 mL/minute as calculated by the Cockcroft-Gault equation were switched from tenofovir to zidovudine or abacavir. They returned on Days 10 and 17 for additional physician and social worker visits and on Day 24 for a physician visit. The same number of scheduled physician visits and counseling sessions were provided to each group so that the only difference in care was in the schedule of visits during the first 5 weeks of the study and the timing of ART initiation.All care was delivered by GHESKIO clinic staff, and the same providers (physicians, nurses, social workers, pharmacists, and field workers) cared for both groups. A counseling manual was followed with an outline for the social workers to follow at each scheduled counseling visit; these were identical between groups, except for the timing of ART initiation, and each session took about 30 minutes. All counseling was provided for individual patients, rather than for groups. The counseling sessions were audiotaped and systematically evaluated for quality control purposes. If a participant in either group missed a study visit that included a scheduled social worker counseling session, the counseling was provided at the next visit.Participants in both groups had monthly physician visits throughout the follow-up period and received the same package of services provided to all HIV-infected patients at GHESKIO, including prophylactic treatment with trimethoprim-sulfamethoxazole and isoniazid. Field workers phoned patients who missed a visit and attempted a home visit for those not reachable by phone. Participants received a transportation subsidy of 100 Haitian gourdes (US$1.70) per visit.OutcomesThe primary endpoint was retention in care with HIV-1 RNA <50 copies/ml at 12 months after HIV testing. Retention was defined as attending the 12-month visit (1 clinic visit between 12 and 15 months after HIV testing). Lost to follow-up (LTFU) was defined as failure to attend the 12-month visit. Deaths were ascertained by review of medical records or report from family members. A National Institutes of Health Division of AIDS Expedited Adverse Event Form was filled out within 48 hours after the study team became aware of any death. Transfers were ascertained by confirmation that the participant was receiving care at a different site. Secondary outcomes include survival, ART initiation, retention in care with HIV-1 RNA <1,000 copies/ml at 12 months after HIV testing, adherence as measured by pharmacy refill records and self-report, and cost and cost-effectiveness of standard and same-day ART; the adherence and cost-effectiveness evaluations will be reported in separate manuscripts.Statistical analysisDemographic, clinical, and laboratory data from the electronic medical record and study forms were de-identified, entered into an Excel spreadsheet, and exported into Stata v14 software (StataCorp, 2011, College Station, Texas) for analysis. After study completion, all participants who were LTFU were recontacted to determine their vital status.The study was powered to detect a 10% absolute difference in the rate of retention with virologic suppression between the 2 groups at 12 months after enrollment (65% in the standard and 75% in the same-day ART group). At the α = 0.05 significance level, we estimated that we would need to enroll 349 participants per group (698 in total) to achieve 80% power to detect this difference. Because patients who transferred during the study period were excluded, we increased the total sample size to 762 participants. For all analyses, a modified intention-to-treat approach was used, in which all patients were analyzed according to their assignment group, excluding patients who transferred to another facility during the follow-up period, according to protocol.Baseline characteristics were summarized using simple frequencies and proportions and medians with interquartile ranges (IQRs) stratified by treatment arm. Among participants who died, baseline CD4 count was compared using the Wilcoxon rank-sum test. We compared the proportion of participants who were retained in care with HIV-1 RNA <50 copies/ml (primary endpoint), retained with HIV-1 RNA <1,000 copies/ml, retained regardless of HIV-1 RNA, initiated ART, and died (secondary endpoints) at 12 months after enrollment using a chi-square test. We conducted multivariable logistic regression including all covariates listed in Table 1 to control for any residual confounding. We present unadjusted and adjusted risk ratios (RR) with 95% confidence intervals. Because of the change in enrollment criteria mid-study, we conducted a sensitivity analysis that included only the participants who met the original enrollment criteria of CD4 count ≤350 cells/mm3. In response to a reviewer’s request, we also plotted retention in care, regardless of viral load, for both groups and compared the distributions with the log-rank test. The study is registered with ClinicalTrials.gov number NCT01900080.10.1371/journal.pmed.1002357.t001Table 1Baseline characteristics of study participants by group.CharacteristicStandard Group (n = 356)Same-Day ART Group (n = 347)Age (years)—Median (IQR)37 (30, 45)37 (29, 46)Female sex—no. (%)181 (51)166 (48)Education—no. (%)\xa0\xa0\xa0\xa0No school90 (25)93 (27)\xa0\xa0\xa0\xa0Primary school110 (31)111 (32)\xa0\xa0\xa0\xa0Secondary school or more156 (44)143 (41)Income—no. (%)\xa0\xa0\xa0\xa0No income92 (26)90 (26)\xa0\xa0\xa0\xa0>$0 to $1/day176 (49)159 (46)\xa0\xa0\xa0\xa0>$1 to $2/day67 (19)76 (22)\xa0\xa0\xa0\xa0>$2/day21 (6)22 (6)Marital status—no. (%)\xa0\xa0\xa0\xa0Single71 (20)71 (20)\xa0\xa0\xa0\xa0Currently married/living with partner222 (62)211 (61)\xa0\xa0\xa0\xa0Formerly married63 (18)65 (19)WHO Stage—no. (%)\xa0\xa0\xa0\xa0WHO Stage 1117 (33)101 (29)\xa0\xa0\xa0\xa0WHO Stage 2239 (67)246 (71)CD4 count (cells/mm3)—Median (IQR)247 (150, 349)249 (143, 336)Body mass index—Median (IQR)*21.6 (19.7, 23.9)20.9 (19.3, 23.5)* Body mass index differed significantly between the 2 groups (p = 0.025).ART, antiretroviral therapy; IQR, interquartile range, WHO, World Health Organization.ResultsA total of 821 patients were screened, and 762 were enrolled in the study and underwent randomization (Fig 2). After randomization, 59 participants (28 in the standard ART and 31 in same-day ART group) transferred to another clinic and were excluded from all analyses, as per protocol. The median age was 37 years old (IQR: 30–45 years), 347 (49%) were women, and the median CD4 count was 248 cells/mm3 (IQR: 148, 345).10.1371/journal.pmed.1002357.g002Fig 2Screening, randomization, and follow-up.Of the 356 participants in the standard group, 256 (72%) were retained in care, 20 (6%) died, and 80 (23%) were LTFU (Table 2). Among the 256 participants retained in the standard ART group, 156 (61% of retained and 44% overall) had HIV-1 RNA <50 copies/ml. Of the 347 participants in the same-day ART group, 277 (80%) were retained in care, 10 (3%) died, and 60 (17%) were LTFU. Among the 277 participants retained in the same-day ART group, 184 (66% of retained and 53% overall) had HIV-1 RNA <50 copies/ml. The unadjusted RR of being retained in care at 12 months and achieving HIV-1 RNA <50 copies/ml was 1.21 (95% CI: 1.04, 1.38; p = 0.015) for the same-day ART group compared to the standard group (Table 3); the adjusted RR for this comparison was 1.24 (95% CI: 1.06, 1.41; p = 0.008).10.1371/journal.pmed.1002357.t002Table 2Study outcomes by group.OutcomeStandard ART Group (n = 356)Same-Day ART Group (n = 347)Unadjusted Risk Difference (95% CI)p-valuePrimary OutcomeRetained in care at 12 months with VL <50 copies/ml156 (43.8%)184 (53.0%)9.2% (1.8%, 16.6%)0.015†Secondary OutcomesRetained in care at 12 months with VL <1,000 copies/ml184 (51.7%)212 (61.1%)9.4% (2.1%, 16.7%)0.012‡Retained in care at 12 months, regardless of VL results256 (71.9%)277 (79.8%)7.9% (1.6%, 14.2%)0.014††Died20 (5.6%)10 (2.9%)Lost to follow-up80 (22.5%)60 (17.3%)† p-value comparing the proportion of all patients who were retained in care with viral load <50 copies/ml between the 2 arms.‡ p-value comparing the proportion of all patients who were retained in care with viral load <1,000 copies/ml between the 2 arms.†† p-value comparing the proportion of all patients who were retained in care between the 2 arms.ART, antiretroviral therapy; VL, viral load.10.1371/journal.pmed.1002357.t003Table 3Unadjusted and adjusted risk ratios of study outcomes.UnadjustedAdjusted for All Baseline Co-variatesRR95% CIp-valueRR95% CIp-valueRetained in care with viral load <50 copies/mlStandard ART Group1.01.0Same-Day ART Group1.21(1.04, 1.38)0.0151.24(1.06, 1.41)0.008Retained in care with viral load <1,000 copies/mlStandard ART Group1.01.0Same-Day ART Group1.18(1.04, 1.31)0.0121.20(1.05, 1.33)0.008Mortality during study periodStandard ART Group1.01.0Same-Day ART Group0.51(0.24, 1.08)0.0730.43(0.19, 0.94)0.033ART, antiretroviral therapy; RR, risk ratio.In the standard ART group, 184 (72% of retained and 52% overall) participants who were retained in care had HIV-1 RNA <1,000 copies/ml. In the same-day ART group, 212 (77% of retained and 61% overall) participants who were retained in care had HIV-1 RNA <1,000 copies/ml. The unadjusted RR of being retained in care at 12 months and achieving HIV-1 RNA <1,000 copies/ml was 1.18 (95% CI: 1.04, 1.31; p = 0.012) for the same-day ART group compared to the standard ART group (Table 3); the adjusted RR for this comparison was 1.20 (95% CI: 1.05, 1.33; p = 0.008). In the sensitivity analysis that included only participants who met the original enrollment criteria (CD4 count ≤350 cells/mm3), the adjusted RR of being retained in care at 12 months and achieving HIV-1 RNA <50 copies/ml was 1.19 (95% CI: 0.99, 1.38; p = 0.060), and the adjusted RR of being retained in care at 12 months and achieving HIV-1 RNA < 1,000 copies/ml was 1.18 (95% CI: 1.01, 1.34; p = 0.035).Vital status at the end of the study was known for 328 (92%) participants in the standard ART group and 329 (95%) in the same-day ART group. The unadjusted RR for mortality was 0.51 (95% CI: 0.24, 1.08; p = 0.073) for the same-day group compared to the standard group; the adjusted RR for this comparison was 0.43 (95% CI: 0.19, 0.94; p = 0.033). In the sensitivity analysis that included only participants with CD4 count ≤350 cells/mm3, the adjusted RR for mortality was 0.41 (95% CI: 0.18, 0.93; p = 0.033). Among the participants who died, the median baseline CD4 count was 100 cells/mm3 (IQR: 45, 192) in the standard and 207 cells/mm3 (IQR: 112, 291) in the same-day ART group (p = 0.078). Eight of 20 (40%) deaths in the standard ART group occurred in participants who were LTFU prior to ART, 8 (40%) deaths occurred in those LTFU after starting ART, and 4 (20%) occurred while in care; the causes of death for those in care were stroke, trauma, and cancer in 3, and the fourth had pain and died after seeing a traditional healer. Three of the 10 (30%) deaths in the same-day ART group occurred in participants who were LTFU after starting ART; among the 7 (70%) participants who died while in care, 1 of each died of stroke, pneumonia, malaria, renal failure, and sudden death, and 2 died of gastroenteritis. No deaths for those in care were attributed to immune reconstitution syndrome or an opportunistic infection that was missed at ART initiation. In Fig 3, the Kaplan-Meier curve plots the retention in care, regardless of viral load, for both groups. The log-rank test comparing the curves between the standard and same-day ART group indicates a significant difference (p = 0.028).10.1371/journal.pmed.1002357.g003Fig 3Retention in care by study group.In the same-day ART group, 344 of 347 (99%) participants started ART on the day of HIV testing, and the remaining 3 patients started ART within the subsequent week. During the Day 3 follow-up visit, 13 patients (4%) in the same-day ART group had adjustments in their ART regimens (replacement of tenofovir with zidovudine or abacavir) because they had creatinine clearance <50 mL/minute on baseline testing. In the standard group, 281 (79%) participants initiated ART by Day 28, the end of the time window for the 3-week ART initiation visit. Thirty-six (10%) standard group participants initiated ART from Day 29 to Day 90, and 12 (3%) initiated ART after Day 90 due to late or missed visits. Twenty-seven (8%) standard group participants never started ART during the study period because they were LTFU or died prior to initiating treatment. Isoniazid prophylaxis was initiated for 337 (95%) participants in the standard group and 340 (98%) in the same-day group. Eight cases of TB were diagnosed during the first 3 months after ART initiation; 6 of these occurred in the standard group and 2 in the same-day ART group.DiscussionThe results of this randomized controlled trial show that among HIV-infected adults with early WHO Stage disease and CD4 count ≤500 cells/mm3, same-day HIV testing and ART initiation, as compared to standard care, improves retention in care with virologic suppression and, in the multivariable analysis, decreases mortality. These results are important given recent WHO 2016 guidelines stating the lack of evidence in support of same-day ART initiation.Our findings suggest that ART initiation as soon as possible after HIV testing may be beneficial for clinically stable patients. In resource-poor settings with fragile delivery systems, such as Haiti, the provision of immediate support by care providers at the time of HIV diagnosis can have both structural and individual impact. In addition to making treatment initiation logistically easier for patients, we believe that same-day counseling and ART initiation increase the sense of hope, optimism, and overall connectedness to the healthcare system for patients, which have been shown to be important for retention [17–20].Our findings are consistent with the results of the RapIT study, a randomized trial that included participants in South Africa with WHO Stage 3 or 4 disease or CD4 count ≤350 cells/mm3 [11]. Participants in the standard group in that study generally started ART at the sixth visit, and 72% of participants in the rapid group started ART on the day of study enrollment. Rapid ART initiation resulted in a 17% improvement in retention and 13% improvement in viral suppression. A stepped-wedge cluster-randomized trial in Uganda found an increase in ART initiation within 2 weeks after eligibility by implementing a multicomponent intervention to streamline ART initiation that included training healthcare workers, providing point-of-care CD4 count testing platforms, eliminating mandatory multiple preinitiation sessions, and giving feedback to facilities on their ART initiation rates [21]. A weighted proportion of 80% in the intervention group had started ART within 2 weeks after eligibility compared with 38% in the control group. A cohort study of same-day ART initiation in pregnant women in South Africa also found high rates of treatment initiation, with 91% initiating ART on the day of referral to the service [22]. In the intervention group of the Sustainable East Africa Research on Community Health (SEARCH) HIV test-and-treat study, a cluster-randomized controlled trial conducted in Kenya and Uganda, HIV-infected patients who were identified through community testing were referred to HIV care upon diagnosis and then offered immediate ART initiation; retention was high (89%) among patients newly linking to care [23].At ART initiation, it is critical that patients are ready to start lifelong therapy, that TB screening is conducted, and that renal function is evaluated to avoid the use of tenofovir in patients with renal insufficiency. In this study, ART readiness was remarkably high, with over 99% of patients screened for the study reporting they were ready to start lifelong ART. This is a particularly significant and timely finding for the provision of recommended universal ART because the majority of people living with HIV have early clinical disease, and there has been prior concern that healthier patients may be less willing to accept lifelong therapy [4]. Most patients with early clinical disease do not have TB symptoms (cough, fever, night sweats, or weight loss), so they do not require further work up to exclude TB, according to WHO guidelines [2]. With the exclusion of patients with a baseline chest x-ray that was suspicious for TB, we found that less than 1% of participants in the same-day ART group had TB that was missed at the time of ART initiation. We found that 4% of participants in the same-day ART group had creatinine clearance <50 mL/minute; ART regimens were adjusted on Day 3 for these patients.Both groups in our study received high-level care, with multiple counseling and physician visits in the first month, followed by monthly physician visits. At the time the study was started, this was the standard of care in Haiti. However, this standard has shifted over the past few years towards decreased frequency of visits and nonphysician providers [2,24–27]. We believe that same-day ART can be provided with fewer follow-up visits if proper counseling is provided during the early period after ART initiation. However, clinic-level procedures play a major role in the effectiveness of accelerated ART initiation strategies, as illustrated in Malawi, where among nearly 22,000 pregnant women who started ART for mother-to-child prevention, LTFU rates ranged from 0% to 58% between facilities and were highest among women who initiated ART on the day of HIV testing at large clinics [28].Though lower than anticipated, retention in both groups in our study was higher than reports of standard ART initiation from other resource-poor settings. Two studies from South Africa found that approximately one-third of patients remained in care from HIV testing through 12 months of ART, and systematic reviews of African studies have found high rates of pre-ART attrition [6,8,29,30]. In Haiti, data on pre-ART outcomes are limited, but 12-month retention after ART initiation is 73% nationwide [31]. We attribute the higher retention in our study in large part to faster ART initiation, even in the standard group, compared to many other HIV programs. We surmise that retention would have been lower in the standard group if there had been longer delays in ART initiation [5,11,30].The rates of retention with viral suppression in our study are lower than those reported from clinical trial cohorts, including at GHESKIO. In the GHESKIO Clinical Trials Unit, with a median monthly average of 483 subjects participating in NIH-funded clinical trials, retention is 97%. We attribute the lower retention and viral suppression rates in our study to 2 major reasons. First, nearly all patients meeting WHO stage and CD4 criteria were enrolled in the study on the day of HIV testing, including those with substantial barriers to retention in care and adherence. In contrast, over one-third of patients are generally lost to care prior to ART initiation or enrollment in clinical trials [6,8,29,30]. Second, the care that was provided in this study was similar to that received by nonstudy patients at GHESKIO, with the aim of producing findings that could be reproduced in other resource-poor settings. In order to achieve the UNAIDS 90-90-90 targets, it will be important to evaluate reasons for attrition and implement new strategies to improve retention in care. One approach that has been successful in a cohort of nonresearch patients at GHESKIO has been expedited follow-up care, with fewer visits of shorter duration for clinically stable patients [32]. Streamlined care has also been associated with high rates of retention in the SEARCH study, which is described above [23].Our study was conducted in a large urban clinic, which may limit the generalizability of our findings. In addition, though our study included patients with early clinical disease, the CD4 counts in our population were lower than would be expected with the provision of universal ART. It is possible that patients with higher CD4 counts may experience less benefit from same-day ART. It is also noteworthy that we conducted a chest x-ray prior to enrollment; if same-day ART is provided without a chest x-ray, it is possible that TB cases will be missed. Our study was not blinded. All participants in both groups received the same number of visits and the same retention plan, but we cannot exclude the possibility that awareness of study group impacted provider behavior.In conclusion, in a population of asymptomatic or minimally symptomatic HIV-infected patients, same-day HIV testing and ART initiation decreased mortality and improved the rate of retention in care with virologic suppression compared with standard ART initiation. Furthermore, human and material resources provided to each group were similar, so same-day ART is not expected to increase treatment costs. The new WHO recommendations to provide ART to all HIV-infected patients should facilitate same-day test and treat.Supporting informationS1 TextStudy protocol.(DOCX)Click here for additional data file.S2 TextCONSORT checklist.(DOC)Click here for additional data file.S3 TextHIV medication readiness scale.(PDF)Click here for additional data file.S1 DataAnonymized dataset.(XLSX)Click here for additional data file.Presented in part at the 21st International AIDS Conference, Durban, South Africa, July 18 to 22, 2016. We thank all of the patients who participated in this study and all of the GHESKIO staff who cared for them. We thank Drs. Paul Farmer, Daniel Fitzgerald, Martin Hirsch, Warren Johnson, Daniel Kuritzkes, and Paul Sax for expert advice on study design and Kaya Hedt and Anshul Saxena for manuscript formatting and preparation. We also thank Drs. Carlos del Rio, Kenneth Mayer, and Larry Moulton for serving on the data safety monitoring board and providing oversight of the study.AbbreviationsARTantiretroviral therapyGHESKIOHaitian Group for the Study of Kaposi’s Sarcoma and Opportunistic infectionsIQRinterquartile rangeLTFUlost to follow-upPPDpurified protein derivativeRRrisk ratioSEARCHSustainable East Africa Research on Community HealthUNAIDSThe Joint United Nations Programme on HIV/AIDSWHOWorld Health OrganizationReferences1UNAIDS Fast-Track, Ending the AIDS Epidemic by 2030. Accessed May 24, 2017 at: http://www.unaids.org/en/resources/campaigns/World-AIDS-Day-Report-2014.2Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection. Recommendations for a Public Health Approach. Second Edition, World Health Organization, 2016. 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PLoS Med. 2013;10(1):e1001369\ndoi: 10.1371/journal.pmed.1001369\n2334175318BernaysS, RhodesT, BarnettT. Hope: a new way to look at the HIV epidemic. AIDS. 2007;21\nSuppl 5:S5–11.19BarnettT, WestonM. Wealth, health, HIV and the economics of hope. AIDS. 2008;22\nSuppl 2:S27–34.20MasquillierC, WoutersE, MortelmansD, Booysen FleR. Families as catalysts for peer adherence support in enhancing hope for people living with HIV/AIDS in South Africa. J Int AIDS Soc. 2014;17:18802\ndoi: 10.7448/IAS.17.1.18802\n2470279721AmanyireG, SemitalaFC, NamusobyaJ, KaturamuR, KampiireL, WallentaJ, et al\nEffects of a multicomponent intervention to streamline initiation of antiretroviral therapy in Africa: a stepped-wedge cluster-randomised trial. Lancet HIV. 2016;3(11):e539–e48. doi: 10.1016/S2352-3018(16)30090-X\n2765887322MyerL, ZulligerR, BlackS, PienaarD, BekkerLG. Pilot programme for the rapid initiation of antiretroviral therapy in pregnancy in Cape Town, South Africa. AIDS Care. 2012;24(8):986–92. doi: 10.1080/09540121.2012.668173\n2251956123BrownLB, HavlirDV, AyiekoJ, MwangwaF, OwaraganiseA, KwarisiimaD, et al\nHigh levels of retention in care with streamlined care and universal test and treat in East Africa. AIDS. 2016;30(18):2855–64. doi: 10.1097/QAD.0000000000001250\n2760329024SanneI, OrrellC, FoxMP, ConradieF, IveP, ZeineckerJ, et al\nNurse versus doctor management of HIV-infected patients receiving antiretroviral therapy (CIPRA-SA): a randomised non-inferiority trial. Lancet. 2010;376(9734):33–40. doi: 10.1016/S0140-6736(10)60894-X\n2055792725LongL, BrennanA, FoxMP, NdibongoB, JaffrayI, SanneI, et al\nTreatment outcomes and cost-effectiveness of shifting management of stable ART patients to nurses in South Africa: an observational cohort. PLoS Med. 2011;8(7):e1001055\ndoi: 10.1371/journal.pmed.1001055\n2181140226HumphreysCP, WrightJ, WalleyJ, MamvuraCT, BaileyKA, NtshalintshaliSN, et al\nNurse led, primary care based antiretroviral treatment versus hospital care: a controlled prospective study in Swaziland. BMC Health Serv Res. 2010;10:229\ndoi: 10.1186/1472-6963-10-229\n2068795527FairallL, BachmannMO, LombardC, TimmermanV, UebelK, ZwarensteinM, et al\nTask shifting of antiretroviral treatment from doctors to primary-care nurses in South Africa (STRETCH): a pragmatic, parallel, cluster-randomised trial. Lancet. 2012;380(9845):889–98. doi: 10.1016/S0140-6736(12)60730-2\n2290195528TenthaniL, HaasAD, TweyaH, JahnA, van OosterhoutJJ, ChimbwandiraF, et al\nRetention in care under universal antiretroviral therapy for HIV-infected pregnant and breastfeeding women (\'Option B+\') in Malawi. AIDS. 2014;28(4):589–98. doi: 10.1097/QAD.0000000000000143\n2446899929FoxMP, ShearerK, MaskewM, Meyer-RathG, ClouseK, SanneI. Attrition through Multiple Stages of Pre-Treatment and ART HIV Care in South Africa. PLOS ONE. 2014;9(10):e110252\ndoi: 10.1371/journal.pone.0110252\n2533008730MugglinC, EstillJ, WandelerG, BenderN, EggerM, GsponerT, et al\nLoss to programme between HIV diagnosis and initiation of antiretroviral therapy in sub-Saharan Africa: systematic review and meta-analysis. Trop Med Int Health. 2012;17(12):1509–20. doi: 10.1111/j.1365-3156.2012.03089.x\n2299415131Bulletin de Surveillance, Epidemiologique VIH/SIDA, Programme National de Lutte contre les IST/VIH/SIDA, Juin, 2016.32Guiteau Moise C, Bellot C, Hennessey K, Rivera V, Severe P, Aubin D, et al. Retention of clinically stable ART patients in a rapid model of care in Haiti. Conference on Retroviruses and Opportunistic Infections (CROI), Boston, MA, USA, 2016.', 'title': 'Same-day HIV testing with initiation of antiretroviral therapy versus standard care for persons living with HIV: A randomized unblinded trial.', 'date': '2017-07-26'}, '27658873': {'article_id': '27658873', 'content': "In Africa, up to 30% of HIV-infected patients who are clinically eligible for antiretroviral therapy (ART) do not start timely treatment. We assessed the effects of an intervention targeting prevalent health systems barriers to ART initiation on timing and completeness of treatment initiation.\nIn this stepped-wedge, non-blinded, cluster-randomised controlled trial, 20 clinics in southwestern Uganda were randomly assigned in groups of five clinics every 6 months to the intervention by a computerised random number generator. This procedure continued until all clinics had crossed over from control (standard of care) to the intervention, which consisted of opinion-leader-led training and coaching of front-line health workers, a point-of-care CD4 cell count testing platform, a revised counselling approach without mandatory multiple pre-initiation sessions, and feedback to the facilities on their ART initiation rates and how they compared with other facilities. Treatment-naive, HIV-infected adults (aged ≥18 years) who were clinically eligible for ART during the study period were included in the study population. The primary outcome was ART initiation 14 days after first clinical eligibility for ART. This study is registered with ClinicalTrials.gov, number NCT01810289.\nBetween April 11, 2013, and Feb 2, 2015, 12\u2008024 eligible patients visited one of the 20 participating clinics. Median CD4 count was 310 cells per μL (IQR 179-424). 3753 of 4747 patients (weighted proportion 80%) in the intervention group had started ART by 2 weeks after eligibility compared with 2585 of 7066 patients (38%) in the control group (risk difference 41·9%, 95% CI 40·1-43·8). Vital status was ascertained in a random sample of 208 patients in the intervention group and 199 patients in the control group. Four deaths (2%) occurred in the intervention group and five (3%) occurred in the control group.\nA multicomponent intervention targeting health-care worker behaviour increased the probability of ART initiation 14 days after eligibility. This intervention consists of widely accessible components and has been tested in a real-world setting, and is therefore well positioned for use at scale.\nNational Institute of Allergy and Infectious Diseases (NIAID) and the President's Emergency Fund for AIDS Relief (PEPFAR).", 'title': 'Effects of a multicomponent intervention to streamline initiation of antiretroviral therapy in Africa: a stepped-wedge cluster-randomised trial.', 'date': '2016-10-30'}, '29509839': {'article_id': '29509839', 'content': 'Home-based HIV testing is a frequently used strategy to increase awareness of HIV status in sub-Saharan Africa. However, with referral to health facilities, less than half of those who test HIV positive link to care and initiate antiretroviral therapy (ART).\nTo determine whether offering same-day home-based ART to patients with HIV improves linkage to care and viral suppression in a rural, high-prevalence setting in sub-Saharan Africa.\nOpen-label, 2-group, randomized clinical trial (February 22, 2016-September 17, 2017), involving 6 health care facilities in northern Lesotho. During home-based HIV testing in 6655 households from 60 rural villages and 17 urban areas, 278 individuals aged 18 years or older who tested HIV positive and were ART naive from 268 households consented and enrolled. Individuals from the same household were randomized into the same group.\nParticipants were randomly assigned to be offered same-day home-based ART initiation (n\u2009=\u2009138) and subsequent follow-up intervals of 1.5, 3, 6, 9, and 12 months after treatment initiation at the health facility or to receive usual care (n\u2009=\u2009140) with referral to the nearest health facility for preparatory counseling followed by ART initiation and monthly follow-up visits thereafter.\nPrimary end points were rates of linkage to care within 3 months (presenting at the health facility within 90 days after the home visit) and viral suppression at 12 months, defined as a viral load of less than 100 copies/mL from 11 through 14 months after enrollment.\nAmong 278 randomized individuals (median age, 39 years [interquartile range, 28.0-52.0]; 180 women [65.7%]), 274 (98.6%) were included in the analysis (137 in the same-day group and 137 in the usual care group). In the same-day group, 134 (97.8%) indicated readiness to start ART that day and 2 (1.5%) within the next few days and were given a 1-month supply of ART. At 3 months, 68.6% (94) in same-day group vs 43.1% (59) in usual care group had linked to care (absolute difference, 25.6%; 95% CI, 13.8% to 36.3%; P\u2009<\u2009.001). At 12 months, 50.4% (69) in the same-day group vs 34.3% (47) in usual care group achieved viral suppression (absolute difference, 16.0%; 4.4%-27.2%; P\u2009=\u2009.007). Two deaths (1.5%) were reported in the same-day group, none in usual care group.\nAmong adults in rural Lesotho, a setting of high HIV prevalence, offering same-day home-based ART initiation to individuals who tested positive during home-based HIV testing, compared with usual care and standard clinic referral, significantly increased linkage to care at 3 months and HIV viral suppression at 12 months. These findings support the practice of offering same-day ART initiation during home-based HIV testing.\nclinicaltrials.gov Identifier: NCT02692027.', 'title': 'Effect of Offering Same-Day ART vs Usual Health Facility Referral During Home-Based HIV Testing on Linkage to Care and Viral Suppression Among Adults With HIV in Lesotho: The CASCADE Randomized Clinical Trial.', 'date': '2018-03-07'}, '27163694': {'article_id': '27163694', 'content': 'PLoS MedPLoS MedplosplosmedPLoS Medicine1549-12771549-1676Public Library of ScienceSan Francisco, CA USA27163694486268110.1371/journal.pmed.1002015PMEDICINE-D-15-03455Research ArticleBiology and Life SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesPublic and Occupational HealthPreventive MedicineVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesImmunodeficiency VirusesHIVBiology and life sciencesOrganismsVirusesRNA virusesRetrovirusesLentivirusHIVBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVBiology and Life SciencesOrganismsVirusesViral PathogensRetrovirusesLentivirusHIVPeople and placesGeographical locationsAfricaSouth AfricaBiology and Life SciencesAnatomyBody FluidsBloodBlood CountsMedicine and Health SciencesAnatomyBody FluidsBloodBlood CountsBiology and Life SciencesPhysiologyBody FluidsBloodBlood CountsMedicine and Health SciencesPhysiologyBody FluidsBloodBlood CountsMedicine and Health SciencesHematologyBloodBlood CountsMedicine and Health SciencesHealth CareHealth Care ProvidersNursesPeople and PlacesPopulation GroupingsProfessionsNursesBiology and Life SciencesMicrobiologyVirologyViral Transmission and InfectionViral LoadMedicine and Health SciencesInfectious DiseasesBacterial DiseasesTuberculosisMedicine and Health SciencesTropical DiseasesTuberculosisMedicine and Health SciencesPharmaceuticsDrug TherapyInitiating Antiretroviral Therapy for HIV at a Patient’s First Clinic Visit: The RapIT Randomized Controlled TrialSingle-Visit ART InitiationRosenSydney\n1\n\n2\n*MaskewMhairi\n2\nFoxMatthew P.\n2\n\n3\nNyoniCynthia\n2\nMongwenyanaConstance\n2\nhttp://orcid.org/0000-0003-1473-880XMaleteGiven\n2\nSanneIan\n2\nhttp://orcid.org/0000-0001-5800-1960BokabaDorah\n4\nSaulsCeleste\n2\nhttp://orcid.org/0000-0002-1180-8764RohrJulia\n1\nLongLawrence\n2\n\n1\nDepartment of Global Health, Boston University School of Public Health, Boston, Massachusetts, United States of America\n\n2\nHealth Economics and Epidemiology Research Office, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa\n\n3\nDepartment of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, United States of America\n\n4\nHealth Department, City of Johannesburg, Johannesburg, South Africa\nBinagwahoAgnesAcademic Editor\nRwanda Ministry of Health, RWANDA\nThe authors have declared that no competing interests exist.Conceived and designed the experiments: SR LL MM IS MPF. Performed the experiments: CN CM DB CS JR. Analyzed the data: MM GM SR. Wrote the first draft of the manuscript: SR MM. Contributed to the writing of the manuscript: SR MM LL MPF. Enrolled patients: CN. Agree with the manuscript’s results and conclusions: SR MM LL MPF CN CM GM IS DB CS JR. All authors have read, and confirm that they meet, ICMJE criteria for authorship.* E-mail: sbrosen@bu.edu105201652016135e1002015171120152232016© 2016 Rosen et al2016Rosen et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.BackgroundHigh rates of patient attrition from care between HIV testing and antiretroviral therapy (ART) initiation have been documented in sub-Saharan Africa, contributing to persistently low CD4 cell counts at treatment initiation. One reason for this is that starting ART in many countries is a lengthy and burdensome process, imposing long waits and multiple clinic visits on patients. We estimated the effect on uptake of ART and viral suppression of an accelerated initiation algorithm that allowed treatment-eligible patients to be dispensed their first supply of antiretroviral medications on the day of their first HIV-related clinic visit.Methods and FindingsRapIT (Rapid Initiation of Treatment) was an unblinded randomized controlled trial of single-visit ART initiation in two public sector clinics in South Africa, a primary health clinic (PHC) and a hospital-based HIV clinic. Adult (≥18 y old), non-pregnant patients receiving a positive HIV test or first treatment-eligible CD4 count were randomized to standard or rapid initiation. Patients in the rapid-initiation arm of the study (“rapid arm”) received a point-of-care (POC) CD4 count if needed; those who were ART-eligible received a POC tuberculosis (TB) test if symptomatic, POC blood tests, physical exam, education, counseling, and antiretroviral (ARV) dispensing. Patients in the standard-initiation arm of the study (“standard arm”) followed standard clinic procedures (three to five additional clinic visits over 2–4 wk prior to ARV dispensing). Follow up was by record review only. The primary outcome was viral suppression, defined as initiated, retained in care, and suppressed (≤400 copies/ml) within 10 mo of study enrollment. Secondary outcomes included initiation of ART ≤90 d of study enrollment, retention in care, time to ART initiation, patient-level predictors of primary outcomes, prevalence of TB symptoms, and the feasibility and acceptability of the intervention. A survival analysis was conducted comparing attrition from care after ART initiation between the groups among those who initiated within 90 d. Three hundred and seventy-seven patients were enrolled in the study between May 8, 2013 and August 29, 2014 (median CD4 count 210 cells/mm3). In the rapid arm, 119/187 patients (64%) initiated treatment and were virally suppressed at 10 mo, compared to 96/190 (51%) in the standard arm (relative risk [RR] 1.26 [1.05–1.50]). In the rapid arm 182/187 (97%) initiated ART ≤90 d, compared to 136/190 (72%) in the standard arm (RR 1.36, 95% confidence interval [CI], 1.24–1.49). Among 318 patients who did initiate ART within 90 d, the hazard of attrition within the first 10 mo did not differ between the treatment arms (hazard ratio [HR] 1.06; 95% CI 0.61–1.84). The study was limited by the small number of sites and small sample size, and the generalizability of the results to other settings and to non-research conditions is uncertain.ConclusionsOffering single-visit ART initiation to adult patients in South Africa increased uptake of ART by 36% and viral suppression by 26%. This intervention should be considered for adoption in the public sector in Africa.Trial RegistrationClinicalTrials.gov NCT01710397, and South African National Clinical Trials Register DOH-27-0213-4177.In the RapIT randomized controlled trial, Sydney Rosen and colleagues investigate whether accelerated initiation of antiretroviral therapy can improve viral suppression for HIV patients in South Africa.Author SummaryWhy Was This Study Done?One of the most persistent operational challenges facing antiretroviral therapy (ART) programs for HIV/AIDS in sub-Saharan Africa is late presentation of patients for care and high rates of attrition from care between HIV testing and ART initiation.One reason for this is that starting ART in many countries is a lengthy and burdensome process, imposing long waits and multiple clinic visits on patients; in South Africa, the country with the world’s largest HIV treatment program, patients must typically make five or six clinic visits, starting with an HIV test, before they receive medications.There have not yet been any controlled evaluations of an integrated, rapid HIV treatment initiation algorithm that allows patients to initiate ART in a single clinic visit, so the RapIT trial was done to find out if “same-day initiation” of ART would increase the number of patients starting treatment and improve overall health outcomes, compared to current practices.What Did the Researchers Do and Find?We randomly assigned 377 adult patients at two public clinics in Johannesburg, South Africa, who had provided consent to participate in the study to one of two groups.Patients in the group assigned to receive rapid treatment initiation were offered the chance to start treatment on the same day as their first clinic visit, using rapid, point-of-care laboratory tests and an accelerated sequence of other steps, including a physical exam, education, and counseling.Patients in the group assigned to receive standard treatment initiation followed the standard schedule for treatment initiation used by the clinics, which usually required three to five additional clinic visits over a 2–4 wk period.After the study enrollment visit, patients were followed up by reviewing their regular clinic medical records, to determine how many did start treatment and how many were still in care and had good outcomes, as indicated by a suppressed viral load, 10 mo later.We found that 97% of patients in the rapid initiation group had started ART by 90 d after study enrollment—three-quarters of them on the same day—compared to 72% of patients in the standard initiation group.By 10 mo after study enrollment, 64% of patients in the rapid group had good outcomes compared to 51% in the standard group.Rapid initiation group patients spent roughly two and a half hours in the clinic to complete all the steps required before they got their medications.What Do These Findings Mean?The RapIT (Rapid Initiation of Treatment) trial showed that it is possible to initiate nearly all eligible patients on HIV therapy, and to do so in a much shorter time interval than previously required.By showing that offering the opportunity to start treatment on the spot, without delay, overcomes many barriers patients would otherwise face, this study demonstrates that same-day ART initiation is an effective strategy for improving health outcomes.More patients in the rapid initiation group dropped out of care after starting treatment than in the standard initiation group; although the rapid initiation group still had better health outcomes overall, adherence support after starting treatment remains essential.The findings of this study are limited because the study took place in only two clinics in one part of South Africa and was carried out by study staff, not by regular clinic staff.Based on this study’s results, consideration could be given to accelerating the process of ART initiation in many different settings and for different types of patients.http://dx.doi.org/10.13039/100000060National Institute of Allergy and Infectious Diseases1U01AI100015RosenSydneyFunding for this study was provided by the U.S. National Institutes of Health (National Institute of Allergy and Infectious Diseases) under the terms of grant 1U01AI100015 to Boston University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Data AvailabilityData will be made publicly available in the Dryad repository (http://www.datadryad.org/) after the protocol has been closed (anticipated closure June 2018). Until then, data will remain under the supervision of the University of the Witwatersrand Human Research Ethics Committee (HREC). Requests should be sent to the HREC Research Administrator at: https://www.wits.ac.za/research/about-our-research/ethics-and-research-integrity/human-research-ethics-committee-medical/.Data AvailabilityData will be made publicly available in the Dryad repository (http://www.datadryad.org/) after the protocol has been closed (anticipated closure June 2018). Until then, data will remain under the supervision of the University of the Witwatersrand Human Research Ethics Committee (HREC). Requests should be sent to the HREC Research Administrator at: https://www.wits.ac.za/research/about-our-research/ethics-and-research-integrity/human-research-ethics-committee-medical/.IntroductionOne of the most persistent operational challenges facing antiretroviral therapy (ART) programs for HIV/AIDS in sub-Saharan Africa is late presentation of patients for care and high rates of attrition from care between HIV testing and ART initiation, with baseline median CD4 cell counts remaining well below 200 cells/mm3 in the region despite steadily rising eligibility thresholds [1]. Even among those who have been diagnosed and found to be treatment-eligible, loss to care before starting ART has consistently been estimated at a third to a quarter of patients [2,3]. While many of those who drop out of care prior to ART initiation will make their way back at a later time, they will almost certainly have lower CD4 counts and more symptoms of illness than when they first tested positive. Some will be very sick or die before treatment can be started, and those who do eventually start will have a poorer prognosis on treatment than if they had begun treatment earlier [4,5]. Offering ART to all who test positive regardless of CD4 count, as is now recommended by the World Health Organization [6], will make little difference if those who test positive fail to initiate treatment.There are likely many causes of loss to care before treatment initiation, but one reason observed is that starting ART in many countries is a lengthy and burdensome process, requiring long waits and multiple clinic visits [7,8]. In South Africa, the country with the world’s largest HIV treatment program [9], the process typically includes an HIV test (visit 1), determination of treatment eligibility (visit 2), adherence education and counseling and baseline blood tests (visits 3, 4, and 5), and physical examination and dispensing of antiretrovirals (ARVs) (visit 6). The proliferation of visits has three main causes. First, clinic receipt of printed test results from centralized laboratories typically takes several days, if not longer. Second, a belief remains that to ensure adherence, patients must participate in multiple preparatory educational and counseling sessions [2,10,11]. And third, clinics have had little motivation to accelerate the initiation process for patients who are not critically ill, as standard performance indicators do not include the proportion of eligible patients who actually initiate ART, nor the time required to do so.If patients are deterred from starting treatment by the complexity of the process, then one strategy for reducing loss of patients prior to ART initiation and encouraging earlier treatment initiation may be to shorten the time period, reduce the number of visits, and simplify the steps required before medications are dispensed. This strategy depends critically on two factors: a clinic’s willingness and ability to adjust its schedules and procedures to compress and accelerate the required steps, and the availability of rapid, point-of care (POC) laboratory assays that eliminate delays in receiving whatever lab results are required for initiation. There have not yet been any rigorous, controlled evaluations of an integrated, rapid HIV treatment initiation algorithm incorporating procedural changes and POC tests for adult, non-pregnant patients. We therefore conducted a randomized controlled trial of rapid ART initiation that allowed patients in public sector clinics in Johannesburg, South Africa to have treatment eligibility determined, all treatment preparation steps performed, and ARV medications dispensed on the day of their first HIV-related clinic visit.MethodsRapIT (Rapid Initiation of Treatment) was an unblinded, individually randomized, controlled trial of a service delivery intervention. It was approved by the Institutional Review Board of Boston University Medical Campus (H-31880) and the Human Research Ethics Committee (Medical) of the University of the Witwatersrand (M120843) and is registered with ClinicalTrials.gov, number NCT01710397.Study Sites, Infrastructure, and StaffingRapIT was conducted at two public sector outpatient clinics. Site 1 is a primary health clinic serving an urban informal settlement population on the edge of Johannesburg. Site 2 is a large, hospital-based HIV clinic serving an urban formal and informal population within Johannesburg. Both sites follow South African national treatment guidelines for ART initiation, ARV regimens, and monitoring [12]. During the period of study enrollment, May 8, 2013–August 29, 2014, the prevailing threshold for ART eligibility was a CD4 count ≤ 350 cells/mm3 or a WHO Stage 3/4 clinical condition. Requirements for care prior to initiating ART are not standardized in South Africa [13], but both sites generally required four to five clinic visits between HIV testing and dispensing the first month’s supply of ARVs.At each site, a small clinic room with security bars, running water, and basic furnishings was designated for study equipment and supplies, POC instruments, and files. As all the POC instruments were designed as desktop devices, no separate laboratory was needed. An outdoor booth for safe collection of sputum samples from tuberculosis (TB) suspects was constructed at Site 1 and made available for both study arms; existing facilities for this purpose were used at Site 2. Clinical procedures were performed by study nurses with the same level of clinical certification as existing primary health care nurses at the sites. Non-clinical procedures (consent, questionnaire, education, counseling, patient flow management) were implemented by study assistants with qualifications comparable to those of experienced lay counselors at the sites. All study staff received study and instrument-specific training. A small stipend (R1000/month, equivalent to US$86 at the exchange rate at the time of the study) was paid to clinic lay counselors at Site 1 and a messenger at Site 2 who assisted by referring potential study participants to the study assistant.Study PopulationThe study enrolled adult (≥18 y old), non-pregnant patients who presented to have an HIV test, provide a blood sample for a CD4 count if already known to be HIV-infected, or receive the results of the patient’s first treatment-eligible CD4 count. During pre-screening and screening, patients who had previously been found to be eligible for ART, were already on ART or reported receiving it in the past 12 mo, indicated that they intended to seek HIV care during the next 12 mo at a different clinic, were judged by clinic or study staff to be physically or emotionally unable to provide consent or participate in all study procedures, or did not meet other study inclusion criteria were excluded. Potential participants whose visit purpose was to have an HIV test were enrolled; those found post-enrollment not to be eligible for ART were subsequently withdrawn upon determination of ineligibility. Potential participants whose visit purpose was to receive a CD4 count result and were not eligible for treatment on the basis of that CD4 count were not enrolled.Participants were individually randomized 1:1 to either rapid treatment initiation or standard-of-care treatment initiation, using block randomization in blocks of 6. Sealed, opaque envelopes containing the allocations were prepared by the local principal investigator and numbered sequentially. The envelopes were kept in sequential, numbered order at the study sites. After obtaining written informed consent, the study assistant opened the next sequentially numbered envelope to reveal the allocation.Study Design and ProceduresProcedures for each study arm are illustrated in Fig 1. Standard-of-care treatment initiation followed existing procedures at the sites as closely as possible. Study staff interaction with participants was limited to screening for study eligibility, obtaining written informed consent, administering a questionnaire, and referring patients to clinic staff for either a blood draw for a CD4 count or a next visit appointment if the patient already had results of a CD4 count in hand. After referral, patients in the standard-initiation arm of the study were followed passively, through medical record review, and had no further interaction with the study. Standard-of-care procedures for ART initiation at both study sites included a CD4 count to determine eligibility, TB symptom screening followed by a TB test and TB treatment initiation if required, pre-initiation blood tests (hemoglobin, creatinine, and alanine aminotransferase (ALT)), group and individual counseling and education sessions, and a physical examination. All samples for laboratory tests were sent to centralized public sector laboratories, requiring patients to make separate clinic visits to provide biological samples and to receive results. Once ART eligibility was determined, initiation typically required three to four more clinic visits over a period of 2–4 wk. Patients who were very ill or found to have low CD4 counts could be “fast-tracked,” with the schedule shown in Fig 1 completed in as little as one week.10.1371/journal.pmed.1002015.g001Fig 1Standard initiation of treatment and rapid initiation procedures and visit schedule.For patients randomized to rapid initiation, all the same procedures were performed, but the use of a compressed and accelerated schedule and rapid laboratory instruments at point of care allowed them all to be completed in a single visit (Box 1). Patients offered rapid initiation typically completed each step in order, with little or no waiting time in between unless a TB test was required, which entailed a wait to process the sample. Patients who enrolled in the study too late in the day for all steps to be completed before the clinic closed were asked to return the next day to finish study procedures. Patients who were randomized to rapid initiation but did not have time to participate on the day of enrollment or wished to delay for other reasons were given up to 30 d to return and be initiated under rapid procedures. Those returning beyond 30 d were offered standard initiation by the clinic.Box 1. Rapid Initiation ProceduresCD4 countPatients who enrolled in the study and did not already have CD4 count results from a test performed within the previous 6 mo were given a rapid CD4 count using the Alere Pima CD4 Test (http://alerehiv.com/hiv-monitoring/alere-pima-cd4/) with venous blood draw. This test, previously evaluated in several studies in Africa [14–18], provides a CD4 count result from a capillary or venous blood sample in 20 min. Following the test, patients with a CD4 count ≤ 350 cells mm3 or evident physical symptoms or complaints that suggested a Stage 3 or 4 condition continued with study procedures. Those not eligible for ART were withdrawn from the study at this point and referred to the clinic for standard pre-ART monitoring.TB symptom screen and testWhile awaiting CD4 count results, a TB symptom screen was administered using South Africa’s four-question screening tool. All patients who reported symptoms were then asked to provide a sputum sample, which was immediately processed using the Cepheid Xpert MTB/RIF test (http://www.cepheid.com/us/cepheid-solutions/clinical-ivd-tests/critical-infectious-diseases/xpert-mtb-rif). This is the technology currently used for TB diagnosis in the public sector throughout South Africa, but it is located in centralized laboratories rather than at point of care [19]. It generates a TB diagnosis in 90 min [20]. Two sputum samples were run simultaneously to increase the reliability of results. Any patient who received a positive Xpert test was escorted to the clinic TB nurse to initiate TB treatment, which under national guidelines required a delay of at least 2 wk before ART could be initiated. Patients initiated on TB treatment were asked to return 2 wk later to complete rapid ART initiation on a second visit.Baseline testsOnce eligibility for ART was established, pre-initiation blood tests (hemoglobin, creatinine, and ALT) were run on a point-of-care Reflotron Plus instrument (Roche, http://www.roche-diagnostics.co.in/Products/Pages/ReflotronPlusDry.aspx)[14] using the same blood sample dawn for the CD4 count. This instrument takes approximately 2 min to complete each test. A standard clinic urine dipstick pregnancy test was also conducted for female patients of child-bearing age.Physical examA standard physical examination was conducted by the study nurse to identify any specific conditions or concerns prior to initiating ART. Initiation was delayed in patients found to have conditions that required referral to a hospital or consultation with the clinic’s doctor.Education sessionA condensed version of HIV/ART/adherence education was developed using the study clinics’ materials and provided to study participants. It was delivered in a one-on-one session by the study counselor in approximately 20 min.Counseling sessionAfter completing all tests, physical examination, and education session, each patient met individually with the study nurse, who reviewed results with the patient and provided an opportunity for the patient to ask any remaining questions and confirm that she or he was indeed ready for treatment initiation.Dispensing of ARVsThe study nurses, like other qualified nurses in South Africa, were authorized to write prescriptions for ARVs, which could then be filled directly by the nurse from study room stock (Site 1) or at the on-site clinic pharmacy (Site 2). Study patients at Site 2 were served at the pharmacy immediately, rather than being required to wait in pharmacy queues to fill prescriptions. Once the initial 4 wk supply of ARVs was dispensed, study interaction with rapid group patients ceased. Patients were asked to return to the clinic for monitoring and prescription refill by clinic staff in 1 mo, consistent with routine practice.After the enrollment visit, or completion of rapid initiation procedures for patients in the rapid-initiation arm of the study (“rapid arm”) who delayed initiation but returned to complete it within 30 d, the study team had no further contact with study patients. Patients who started ART in either arm received standard-of care treatment management from the clinic, which called for monitoring visits and medication refills at 1, 2, 3, 6, and 12 mo after initiation, with a routine viral load test at the 6 mo visit.Outcomes and DataThe primary, protocol-defined outcome for the study was viral suppression (≤400 copies/ml) within 10 mo of study enrollment, a time period selected to capture the 6 mo routine monitoring visit called for by national guidelines. Ten months was selected as the endpoint to allow patients to take up to 3 mo to initiate ART and to be up to 1 mo late for the 6 mo routine visit. Because the study sites occasionally omitted the 6 mo viral load and performed the test only at 12 mo, we considered a patient with a suppressed viral load test result any time from 3 to 12 mo after study enrollment to have achieved viral suppression. In this analysis, missing viral load test results were regarded as failures; only patients with recorded, suppressed viral load results were defined as virally suppressed. To account for the possibility that viral load results could be missing due to clinic oversight in not ordering the test, rather than patient default, and to investigate the possibility that rapid initiation merely shifts attrition from before to after treatment initiation, we also report the secondary outcome of retention in care at 10 mo after study enrollment, with retention defined as any HIV-related clinic visit in months 5–10 after study enrollment, regardless of viral load.Although viral suppression was the primary outcome assessed, the pathway by which the study aimed to increase suppression was reduction of attrition between HIV testing and treatment initiation. We therefore report initiation of treatment within 90 d of study enrollment as a secondary outcome, with initiation defined as being dispensed a first month’s supply of ARVs. We also report uptake of treatment within 180 d, as a CD4 count result is considered to be valid under South African guidelines for 6 mo—after that, a patient must have a new CD4 count to establish eligibility for ART. Finally, we report the distribution of time (d) to treatment initiation in each group.Other secondary outcomes evaluated in the study included the feasibility of the intervention, as indicated by the ability of both study sites to implement the accelerated algorithm; acceptability of the intervention, as measured by the proportion of patients offered rapid initiation who accepted it; patient-level predictors of the primary outcome; and, in the rapid arm, the prevalence of TB symptoms and confirmed TB disease and ART initiation among patients with TB.After the enrollment visit, all data collection for both groups was by passive medical record review. Both study sites routinely utilized an electronic medical record system called TherapyEdge-HIV, into which patient data were entered retrospectively by data clerks from paper files (Site 1) or by a combination of clinicians in real time and data clerks from paper files (Site 2)[21]. This record system improved the completeness of the follow-up dataset used in the study. In instances of incomplete follow-up data—for example, if the database reported a clinic visit 6 mo after ART initiation but contained no viral load test result—study staff searched the clinics’ paper files and registers and the online data portal of the National Health Laboratory Service to determine if any additional information existed but had not been recorded in the clinics’ databases. The study team had no further contact with study participants after the enrollment visit so as not to have any influence on retention in care, a study outcome.Data AnalysisWe designed the study to detect a 20% difference in viral suppression rates between the arms at 10 mo after study enrollment. With an α of 0.05, power of 90%, 1:1 randomization, and an uncorrected Fisher’s exact test, we estimated that we would need to enroll at least 124 HIV positive ART-eligible participants per group (248 total). We increased this to a maximum of 200 per group (400 total) to allow for stratification by site, sex, or age.Characteristics at study enrollment of all randomized participants who met ART initiation and study inclusion criteria were summarized using simple proportions and medians with interquartile ranges (IQR) stratified by treatment arm. For the remaining analyses, we excluded patients who were found after randomization not to be eligible for ART or not to meet study inclusion criteria. We compared the proportions of patients achieving each dichotomized study outcome and present crude risk ratios (RR) and risk differences (RD) with 95% confidence intervals (CI) stratified by group. Baseline predictors of outcomes that appeared imbalanced by treatment arm were also adjusted for using log-linear regression models to estimate adjusted risk ratios (aRR). We estimated time to treatment initiation in days using a cumulative incidence curve. To investigate whether attrition after initiation of ART differed between the study arms, we performed a survival analysis comparing attrition from care after ART initiation among those who initiated within 90 d between the groups. Person-time accrued from ART initiation date to the earliest of loss to follow up, transfer, or 10 mo of follow up, and hazard ratios of attrition from care were estimated with Cox proportional hazards models. A stratified analysis was performed to detect effect measure modification by site or patient-level factors. Finally, to confirm that no imbalance was created by excluding patients after randomization for reasons other than ineligibility for ART or evidence of a previous eligible CD4 count, we conducted sensitivity analysis incorporating the excluded patients and assigning each a negative outcome.ResultsBetween May 8, 2013, and August 29, 2014, 603 patients were screened for study eligibility and 463 provided written informed consent and were enrolled in the study (Fig 2). Of the 140 screened but excluded prior to randomization, 109 did not meet study eligibility criteria, including 43 who resided outside study clinic catchment areas or intended to seek further care elsewhere; 24 who were determined by the study assistant to be too ill for consent and study procedures; 16 who were not eligible on the basis of a prior CD4 count, were ineligible for ART, or were already on ART; 12 who were determined by the study assistant to be too emotionally upset to provide consent; 9 who did not speak any of the languages spoken by the study team; 3 who were found to be pregnant; and 2 who were excluded for other reasons. An additional 31 patients refused participation; of these, 18 were in a hurry and did not have time for study procedures, six did not wish to participate in the study, five stated that they would prefer standard care, and two were not willing to initiate therapy. Follow-up ended 10 mo after the last patient was enrolled (June 28, 2015).10.1371/journal.pmed.1002015.g002Fig 2Study enrollment and randomization.Characteristics of patients in each study arm at time of enrollment are reported in Table 1. There were no important differences between the study arms in the variables shown. Just over half the participants were female and the median age was 35 y. The median CD4 count was less than 200 cells/mm3. Age, sex, and CD4 count characteristics of the study sample were similar to those of the overall non-pregnant patient populations initiating ART at the study clinics in 2014.10.1371/journal.pmed.1002015.t001Table 1Baseline characteristics of study sample (n = 463).VariableStandard armRapid arm\nn (randomized participants)229234Enrollment site (n)\xa0\xa0\xa0\xa0Site 1 (primary health clinic)124126\xa0\xa0\xa0\xa0Site 2 (hospital-based HIV clinic)105108Age (median, IQR)35.8 (29.5–41.6)34.2 (29.0–40.1)Sex (% female)132 (58%)129 (55%)CD4 count (cells/mm3) (median, IQR)195 (103–322)224 (128–327)Purpose of clinic visit (%)\xa0\xa0\xa0\xa0Have HIV test (diagnosed today)100 (44%)90 (38%)\xa0\xa0\xa0\xa0Provide blood sample for CD4 count8 (4%)10 (4%)\xa0\xa0\xa0\xa0Receive first CD4 count results109 (47%)112 (48%)\xa0\xa0\xa0\xa0Other11 (5%)22 (10%)Reason for treatment eligibility (%)\xa0\xa0\xa0\xa0CD4 count below threshold182 (79%)183 (78%)\xa0\xa0\xa0\xa0Clinical condition Stage 3 or 43 (1%)4 (2%)\xa0\xa0\xa0\xa0Excluded (not eligible for treatment or study)44 (20%)47 (20%)Household composition\xa0\xa0\xa0\xa0Live alone (% yes)36 (16%)41 (18%)\xa0\xa0\xa0\xa0# other persons in house (median, IQR)2 (1–4)2 (1–3)Household type (%)\xa0\xa0\xa0\xa0Formal house or flat146 (63%)165 (71%)\xa0\xa0\xa0\xa0Informal dwelling or shack83 (37%)69 (29%)Travel time to clinic (minutes) (median, IQR)18 (9–24)15 (9–27)Employment status (%)\xa0\xa0\xa0\xa0Employed formally68 (30%)90 (38%)\xa0\xa0\xa0\xa0Work informally62 (27%)54 (23%)\xa0\xa0\xa0\xa0Unemployed, seeking work91 (40%)84 (36%)\xa0\xa0\xa0\xa0Unemployed, not seeking work8 (3%)6 (3%)Marital status (%)\xa0\xa0\xa0\xa0Married or long-term partner173 (76%)157 (67%)\xa0\xa0\xa0\xa0Single, no long-term partner41 (18%)57 (24%)\xa0\xa0\xa0\xa0Other (widowed, divorced)15 (6%)20 (9%)Reasons for excluding patients during the study screening process are reported in Fig 2. The 603 patients screened represent a subset of those pre-screened by clinic counselors and then referred to the study assistant for screening. While pre-screening data, which were collected by the counselors and not by study staff, are of uncertain quality, they do provide some indication of the proportion of all patients presenting at clinics who could be eligible for rapid initiation. At Site 1, for which the pre-screening data are more complete, a total of 2,636 patients presenting at the clinic’s HIV counseling and testing service were pre-screened. More than half of these were HIV-negative (1,468/2,636, 56%) or known to have CD4 counts above the eligibility threshold or already on ART (114/2,636, 4%). Of the remaining 1,054, 325 (31%) were referred for study screening. Another 293/1,054 (28%) were judged by the counselors not to meet study protocol eligibility criteria (age, residence location, language, not first CD4 count) but would likely have been eligible for the intervention if it were offered as routine care. A fifth (225/1,054, 21%) were regarded by the counselors as too sick for study participation (not necessarily for ART initiation) and were referred to a clinic doctor or nurse for immediate care; it is not clear if they would have been eligible for the intervention or not. The remainder (20%) included patients who refused study participation (36/1,054, 3%) or refused any further care (12/1,054, 1%), were deemed too upset or emotionally distressed to participate (25/1,054, 2%), were referred directly to the clinic’s HIV or TB nurse rather than the study assistant (75/1,054, 7%), or were in a hurry or had no reason stated (63/1,254, 6%).Among 463 patients screened and found eligible for study participation, 234 patients were randomized to rapid initiation and 229 to standard initiation (Fig 2). Upon completion of a CD4 count, which occurred after randomization for those who did not already have one in hand, 37 patients in each group were determined not to be eligible for ART under South African guidelines and were excluded from further data collection and from the analysis. An additional 12 patients were excluded after randomization, for reasons indicated in Fig 2. One hundred and ninety patients in the standard group and 187 in the rapid group (n = 377 total) were offered full study procedures and are included in the analysis below, with sensitivity analysis incorporating the six who were excluded after randomization for a reason other than ineligibility for ART or evidence of a prior eligible CD4 count.The protocol-defined primary outcome for the study was viral suppression within 10 mo of study enrollment. As presented in Table 2, viral suppression by 10 mo was 64% (119/187) in the rapid arm and 51% (96/190) in the standard arm, indicating a risk difference of 13% (3%–33%) and a crude relative risk of 1.26 (1.05–1.50).10.1371/journal.pmed.1002015.t002Table 2ART initiation, 10-mo retention in care, and 10-mo viral suppression.OutcomeStandard arm(%)n = 190Rapid arm(%)n = 187Crude risk difference(95% CI)Crude relative risk(95% CI)Initiated ≤ 90 d and suppressed by 10 mo (primary outcome)96 (51%)119 (64%)13% (3%–23%)1.26 (1.05–1.50)\xa0\xa0\xa0\xa0Of those\nnot\ninitiated ≤ 90 d and suppressed by 10 mo\n\n94 (49%)\n\n68 (36%)\n\n\xa0\xa0\xa0\xa0\xa0\xa0Not initiated\n\n54 (28%)\n\n5 (3%)\n\n\xa0\xa0\xa0\xa0\xa0\xa0Initiated but not suppressed\n\n40 (21%)\n\n63 (34%)\n\n\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0Of those initiated but not suppressed:\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0Retained, unsuppressed viral load test reported\n\n11 (6%)\n\n17 (9%)\n\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0Retained, no viral load test reported\n\n14 (7%)\n\n16 (9%)\n\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0Transferred to another clinic\n\n1 (1%)\n\n6 (3%)\n\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0Died\n\n3 (2%)\n\n0 (0%)\n\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0Lost to follow-up\n\n11 (6%)\n\n24 (13%)\nInitiated ≤ 90 d136 (72%)182 (97%)25% (19%–33%)1.36 (1.24–1.49)Initiated ≤ 90 d and retained at 10 mo (secondary outcome)121 (64%)151 (81%)17% (5%–23%)1.27 (1.12–1.44)\xa0\xa0\xa0\xa0Of those not initiated ≤ 90 d and retained at 10 mo:\n69 (36%)\n\n36 (19%)\n\xa0\xa0\xa0\xa0\xa0\xa0Initiated but not retained\n\n15 (8%)\n\n31 (17%)\n\xa0\xa0\xa0\xa0\xa0\xa0Not initiated\n\n54 (28%)\n\n5 (3%)\nBy 90 d after study enrollment, 97% (182/187) of participants in the rapid arm and 72% (136/190) of participants in the standard arm had initiated ART, equating to a risk difference of 25% (95% CI 19%–33%) and a crude relative risk of 1.36 (1.24–1.49) (Table 2). In adjusted analysis (S1 Table), neither age, sex, nor baseline CD4 count affected these values. By 180 d, one additional patient in the rapid arm and two in the standard arm had initiated, leaving four patients in the rapid arm and 52 in the standard arm who did not initiate within the period of validity of their CD4 count results. In the rapid arm, all four were referred to a clinic nurse or doctor for clinical confirmation of TB and did not return for ART initiation. In the standard arm, 73% (38/52) of the patients who did not initiate within 180 d made no further visits to the site after the visit in which they were enrolled in the study.\nFig 3 shows the cumulative incidence of treatment initiation in each study arm over the 180 d following enrollment. In the rapid arm, 72% (135/187) of patients started ART on the same day as study enrollment, an additional 7% (13/187) on the next day, and 96% (179/187) within 1 mo. In the standard arm, 58% of patients initiated within one month. The median (IQR) time to initiation in the standard arm for the subset who did initiate within 90 d (n = 136) was 17 (11–26) d. For rapid arm patients who did not initiate on the same day (n = 48), the reasons for delay were the need for clinical confirmation of TB or a Stage 3 or 4 condition or for TB treatment (25/48, 52%), insufficient time to complete all steps on the same day (6/48, 13%), patient preferences (5/48, 10%), lack of electricity in the clinic (2/48, 4%), and unknown reasons (10/48, 21%). Time to treatment initiation in the standard arm was shorter for patients who already had CD4 count results available upon study enrollment (median days 16, [IQR 11–22]) compared to those who enrolled in the study at the time of having an HIV test (22 [IQR 10–35]); the median for both types of patients in the rapid arm was 0 d (i.e., same-day initiation).10.1371/journal.pmed.1002015.g003Fig 3Time to ART initiation, by study arm.Cumulative incidence of ART initiation in each study arm, by number of days since study enrollment.All patients in the rapid arm had the opportunity to initiate treatment on the day of study enrollment (same-day initiation) unless one of the reasons for delay listed above pertained to them. To explore whether a delay in initiation was associated with different post-initiation outcomes, we compared patients who did initiate on the same day to those who delayed for any reason. There were no differences in either the primary outcome of viral suppression or the secondary outcome of retention in care between these two groups of patients (S3 Table). Because this analysis was limited to rapid arm patients, however, it is not a randomized comparison and should be interpreted with caution.Retention in care, defined as making a clinic visit between months 5 and 10 after study enrollment, was 81% (151/187) in the rapid arm and 64% (121/190) in the standard arm, for a risk difference of 17% (5%–23%) and a crude relative risk of 1.27 (1.12–1.44). Table 2 also indicates that 86% (31/36) of patients in the rapid arm who were not retained were lost from care after ART initiation, compared to just 22% (15/69) in the standard arm; the fall-off in the standard arm, in contrast, was mainly among those who never initiated (54/69, 78%). Although there was less loss to follow-up after initiation in the standard arm (15/190, 8% versus 31/187, 17%), this was more than offset by the higher pre-initiation loss in the standard arm (54/190, 28% versus 5/187, 3%), resulting in an overall increase in retention of 17%. Among the patients lost to care after initiation (15 in the standard arm and 31 in the rapid arm), a large majority of patients who initiated ART but were not retained in care either never came back after their initiation visit (40% of patients in the standard arm (6/15) and 45% in the rapid arm (14/31)) or came back just once (47% (7/15) and 35% (11/31), respectively), suggesting that most of these patients were never “established” on ART.To explore further the rate of loss to care, we estimated attrition from care within the first 10 mo after initiation among the subsample of 318 patients who did initiate ART within 90 d. In the standard arm, during 1,250 mo of total person-time, 22/136 (16%) dropped out of care after ART initiation, for an attrition rate of 1.8 per 100 person-months. In the rapid arm, during 1,626 mo of total person-time, 30/182 (16%) dropped out of care, for a rate of 1.8 per 100 person-months. The hazard of attrition within the first 10 mo after ART initiation among those who initiated within 90 d did not differ between the treatment arms (HR 1.06; 95% CI 0.61–1.84). We note that this result is subject to selection bias and confounding, however, due to the exclusion of those who did not start treatment within 90 d.In pooled analysis of both study arms, none of the variables presented in Table 1 predicted any of the outcomes reported above, with three exceptions (S2 Table). A slightly higher proportion of patients with baseline CD4 counts below 100 cells/mm3 initiated ART, but this difference did not persist through retention or viral suppression at 10 mo. As might be expected, patients who enrolled in the study at the time of receiving their CD4 count results (thus their second HIV-related clinic visit overall), rather than at the time of having an HIV test, were slightly more likely to achieve all three outcomes, though only for retention in care was this difference statistically significant. Finally, patients who reported being employed at the time of study enrollment, while no more likely to initiate ART, had significantly better retention in care and viral suppression than did those who reported being unemployed.In stratified analysis (S4 Table) we observed non-significant differences in effect sizes for the primary outcome (viral suppression at 10 mo) by sex, age group, and study site. A larger effect was seen among men aged <35 y (risk difference [95% CI] 34% [12%–55%]), while little effect was seen among men or women ≥35 (5% [-9%–19%]). The effect size was also greater at the primary health clinic (21% [8%–34%]), while little effect was seen at the hospital-based HIV clinic (2% [-12%–17%]). As noted, these differences were not statistically significant, and the study was not powered to detect differences among subgroups.In the rapid arm, for which TB diagnostic data were available, 29/187 patients (16%) presented with TB symptoms and were tested for TB using Xpert MTB/RIF. Four patients (17% of those with symptoms and 2% of all rapid arm patients) had a confirmed TB diagnosis. All four initiated ART within the 90-d outcome defined above, with a range of 11–54 d between study enrollment and ART initiation.The results of the sensitivity analysis incorporating the six patients who were excluded after randomization for reasons other than ART eligibility or prior CD4 count, and assigning each a negative outcome, did not differ substantively from the findings presented above, with a relative risk of viral suppression by 10 mo of 1.22 [1.02–1.46].Rapid initiation, using the procedures described above and as implemented by the study, appeared acceptable to patients at the time it was offered and feasible to implement at both study sites. We were not able to assess acceptability after patients received the intervention, as the study had no post-initiation interaction with those enrolled, and thus can surmise acceptability only on the basis of acceptance of the intervention. The study refusal rate was very low (31/603, 5%); nearly four out of five (148/187, 79%) patients offered the intervention accepted initiation on the same day or the next day, and rapid arm patients consistently expressed appreciation for the opportunity to start immediately.All steps in the rapid initiation process were completed on the same day as study enrollment for 72% (135/187) of those in the rapid arm, demonstrating the feasibility of the intervention, at least within the context of the study. From provision of informed consent (study enrollment) to dispensing of the first supply of ARV medications, rapid initiation took a median of 2.4 (IQR 2.1–2.8) hours for those who initiated on the same day as study enrollment. This interval was shorter for patients who already had CD4 count results in hand at study enrollment (median 2.25 hours). It was longer (median 4.5 hours) for those who required a TB test and did initiate ART on the same day, but 15/20 patients requiring TB tests did not initiate on the same day. The only obstacle encountered in implementing rapid procedures was fairly frequent power outages, a common occurrence in South Africa, at Site 1, which did not have a generator for backup power supply. Most rapid instrument tests could not be performed during power outages. The rapid test instruments otherwise performed well throughout the study, and no major delays or problems arose in the acceleration of clinic procedures.DiscussionIn this randomized controlled trial, we evaluated the effectiveness of an accelerated ART initiation algorithm that combined compressed and accelerated clinic procedures with point-of-care laboratory testing technologies that allowed eligible patients to initiate ART in a single clinic visit. This intervention increased the proportion of patients eligible for ART at study enrollment who initiated ART within 90 d by 25%, to 97% of all eligible patients and 100% of patients who were not delayed for TB treatment. By 10 mo after study enrollment, the intervention increased viral suppression among all treatment-eligible patients by 13% and retention in care by 17%. It was feasible and appeared acceptable at both study sites.The trial demonstrated that it is possible to initiate nearly all eligible patients on ART, and to do so in a much shorter time interval than previously required. The net benefit for overall viral suppression was clinically meaningful and may underestimate the true benefits of the intervention. Both the study sites were relatively well-managed, public sector clinics, resulting in a higher rate of ART initiation in the standard arm (72%) than is found elsewhere in the country, for example in rural KwaZulu Natal Province where the rate was 59% [2]. In addition, we observed a larger effect at Site 1, the primary health clinic, than at Site 2, the hospital-based HIV clinic. Primary health clinics, which have fewer resources than hospital-based clinics but treat 85% of HIV patients in South Africa, may struggle more with loss to follow-up before treatment initiation than do hospital-based clinics, creating a greater opportunity for a service delivery intervention like RapIT to be effective. The potential for reaching younger men, who have been among the least likely to access ART under standard care [22], is another important potential benefit of rapid initiation. Additional research is needed to explore further the non-significant differences in effect that we observed in our study.The patients who likely benefited most from RapIT were those who would not otherwise have initiated treatment at all, or who would have waited until they were sick enough to compromise their prognosis on treatment. In the standard arm, most patients who did not start treatment did not return to the study clinics for even one more visit, underscoring the importance of taking full advantage of the first visit to get as many patients started on treatment as possible. For those who would have initiated treatment, just not as soon, there is some evidence that even relatively short delays may be harmful. A recent modeling exercise using South African data estimated that compared to immediate initiation, a delay in initiating ART of 70 d would lead to a 34% increase in 12-mo mortality [22]. Delaying treatment initiation thus both deters some patients from starting at all and jeopardizes outcomes for those who do start.We hypothesize that the delays and multiple visits patients must endure before starting ART directly deter treatment initiation. Patients who cannot afford transport fare for multiple visits, have childcare obligations at home, or risk job or wage loss if they miss too many days of work may be directly deterred from returning. Others may simply grow impatient or lose their courage or motivation, particularly if they are asymptomatic when diagnosed. These patients are likely to drift away and only return when their CD4 counts are lower and symptoms have started, or to die before treatment can be started. Our results suggest that offering the opportunity to start treatment on the spot, without delay, overcomes these barriers, without risking poorer outcomes later on.Among patients who did initiate ART, post-initiation loss to care was higher in the rapid arm than the standard arm. This difference disappeared in the survival analysis, which controlled for number of months on ART but does not reflect the benefits of randomization. We speculate that some patients who did not want or were not ready for treatment chose to accept immediate initiation simply because it was offered or they wanted to participate in the study. For these patients, attrition from care was simply shifted from before ART initiation to after. While the intervention was successful in increasing the overall proportion of treatment-eligible patients with successful outcomes (viral suppression and/or retention in care), the rate of post-initiation attrition is a reminder that early retention in care and adherence support once patients start treatment remain high priorities for further research and intervention.Other studies have gauged the impact on treatment uptake of a single POC technology [23] or changes in service delivery [24], but we found only one prior report of a “single-visit initiation” intervention that was similar, to some degree, to RapIT. That study enrolled pregnant women initiating ART for prevention of mother-to-child transmission in South Africa and found very high uptake of ART among women offered rapid initiation, but it did not have a comparison arm to allow an effect to be estimated [25]. A study in Tanzania and Zambia compared the effect of community support on a two-visit algorithm and reported 99% uptake of ART in both study arms [26]. Taken together, these studies imply that accelerating ART initiation is effective in a wide range of settings.Nothing in the rapid initiation procedures used in this study differed fundamentally from existing clinic procedures. The intervention was delivered by study nurses and counselors with the same qualifications as existing clinic staff, though with study-specific training and supervision. The intervention imposed no major burdens on site management, though managerial acquiescence to the study and operational flexibility were needed to adjust the schedule and content of patient visits, staff responsibilities, and record keeping to allow for rapid initiation [27]. The main technical training required was in the use of the POC test instruments, which also required a secure location within the clinic, temperature control, and electricity.Although South Africa has better clinic infrastructure than do many other countries in the region, the RapIT intervention does not require anything that most urban and many rural clinics cannot provide. We speculate that the RapIT intervention would be feasible and potentially even more effective in other high HIV prevalence areas, where patients travel farther to reach clinics and results from centralized laboratories take even longer to return. As the new WHO guidelines are adopted, moreover, laboratory test results may not be required prior to ART initiation for patients who are asymptomatic, reducing the need for POC technology.The generalizability of our results is limited in several ways. The study was conducted in only two clinics in one province of one country. The trial intervention was delivered by study staff; it is uncertain if clinic staff delivering the same intervention will achieve the same outcomes (and whether their outcomes will be better or worse than those observed in the trial). As is typical in individually randomized trials of service delivery interventions, the possibility exists that quality of care in the standard arm was improved by the presence of the study, as clinic staff providing care for the standard arm may have been motivated by the study to make treatment initiation more efficient. If this occurred, the effect reported here would understate the true improvement in ART initiation that could be expected under routine implementation. As with many studies in which retention in care is an endpoint, we do not know the true outcomes of study patients who were not retained nor whether rapid arm patients who were not retained and who agreed to start treatment solely due to the presence of the study, and would otherwise not have done so, are at increased risk of developing ARV resistance. Finally, as reported above, rapid initiation under the study algorithm took 2–3 hours to complete, making same-day initiation impractical for patients who arrive late in the day (and for clinics with large numbers of such patients).We also do not know how clinic and patient characteristics will affect the net cost and cost-effectiveness of the intervention. Most of the changes introduced in the RapIT intervention entailed only adjustments in schedules and staff time, and we speculate that these will not result in a major net change to service delivery costs. The POC instruments used in the trial require an up-front investment, but it may be possible to initiate ART in a single visit without any POC instruments if there is no CD4 count threshold for initiation, patients with TB symptoms are identified and managed separately, and ARV regimen adjustments are routinely made at the first refill visit, rather than before initiation. Costs saved by patients, who must make just one clinic visit rather than four or five, should also be taken into account.The RapIT intervention as designed and implemented showed clinically meaningful improvements in ART uptake and viral suppression, providing “proof of principle” for a single-visit treatment initiation algorithm. Follow-on studies are needed to evaluate effectiveness and cost-effectiveness in routine practice in a variety of settings, and variations on the algorithm could also be considered. The RapIT trial has demonstrated that accelerating ART initiation can be effective and feasible in this setting and appeared acceptable to patients to whom it was offered; the next challenge will be adapting it to the range of settings and conditions found in clinics throughout Africa.Supporting InformationS1 TableStudy outcomes adjusted for baseline CD4 count, age, and sex.(DOCX)Click here for additional data file.S2 TableCrude patient-level predictors of treatment uptake, viral suppression, and retention in care.(DOCX)Click here for additional data file.S3 TableStudy outcomes stratified by immediate versus delayed initiation (rapid arm patients initiating ≤90 d only).(DOCX)Click here for additional data file.S4 TableAbsolute and relative effect measure modification of primary outcome (initiated ≤90 d and suppressed by 10 mo).(DOCX)Click here for additional data file.S1 TextResearch protocol.(PDF)Click here for additional data file.S2 TextCONSORT statement.(PDF)Click here for additional data file.AbbreviationsALTalanine aminotransferaseaRRadjusted risk ratioARTantiretroviral therapyARVantiretroviralIQRinterquartile rangeCIconfidence intervalHRhazard ratioPHCprimary health clinicPOCpoint-of-careRapITRapid Initiation of TreatmentRDrisk differenceRRrelative riskTBtuberculosisReferences1\nSiednerMJ, NgCK, Bassett IV, KatzIT, BangsbergDR, TsaiAC. Trends in CD4 count at presentation to care and treatment initiation in sub-Saharan Africa, 2002–2013: a meta-analysis. Clin Infect Dis. 2014; 60:1120–1127. 10.1093/cid/ciu1137\n255161892\nPlazyM, Dray-SpiraR, Orne-GliemannJ, DabisF, Newell M-L. Continuum in HIV care from entry to ART initiation in rural KwaZulu-Natal, South Africa. Trop Med Int Health. 2014; 19:680–689. 10.1111/tmi.12301\n246549903\nClouseK, PettiforAE, MaskewM, BassettJ, VanRie A, BehetsF, et al\nPatient retention from HIV diagnosis through one year on antiretroviral therapy at a primary health care clinic in Johannesburg, South Africa. J Acquir Immune Defic Syndr. 2013; 62: 39–46.4\nLahuertaM, UeF, HoffmanS, ElulB, KulkarniSG, WuY, et al\nThe problem of late ART initiation in Sub-Saharan Africa: a transient aspect of scale-up or a long-term phenomenon?\nJ Health Care Poor Underserved. 2013; 24: 359–383. 10.1353/hpu.2013.0014\n233777395\nINSIGHT START Study Group. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. 2015; 373: 795–807. 10.1056/NEJMoa1506816\n261928736\nWorld Health Organization. Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV\nGeneva: World Health Organization; 2015.7\nGovindasamyD, FordN, KranzerK. Risk factors, barriers and facilitators for linkage to ART care in sub-Saharan Africa: a systematic review. AIDS. 2012; 26: 2059–2067. 10.1097/QAD.0b013e3283578b9b\n227812278\nSiednerMJ, LankowskiA, HabererJE, KembabaziA, EmenyonuN, TsaiAC, et al\nRethinking the “‘pre’” in pre-therapy counseling: no benefit of additional visits prior to therapy on adherence or viremia in Ugandans initiating ARVs. PLoS ONE. 2012; 7: e39894\n10.1371/journal.pone.0039894\n227619249\nWorld Health Organization. Global update on the health sector response to HIV, 2014\nGeneva: World Health Organization; 2014.10\nIngleSM, MayM, UebelK, TimmermanV, KotzeE, BachmannM, et al\nOutcomes in patients waiting for antiretroviral treatment in the Free State Province, South Africa: prospective linkage study. AIDS. 2010; 24: 2717–2725. 10.1097/QAD.0b013e32833fb71f\n2093555411\nMyerL, ZulligerR, PienaarD. Diversity of patient preparation activities before initiation of antiretroviral therapy in Cape Town, South Africa. Trop Med Int Heal. 2012; 17: 972–977. 10.1111/j.1365-3156.2012.03033.x\n12\nNational Department of Health. The South African Antiretroviral Treatment Guideline 2013\nPretoria: National Department of Health; 2013.13\nScottV, ZweigenthalV, JenningsK. Between HIV diagnosis and initiation of antiretroviral therapy: assessing the effectiveness of care for people living with HIV in the public primary care service in Cape Town, South Africa. Trop Med Int Heal. 2011; 16:1384–1391. 10.1111/j.1365-3156.2011.02842.x\n14\nGousN, ScottL, PotgieterJ, NtabeniL, EnslinS, NewmanR, et al\nFeasibility of performing multiple point of care testing for HIV anti-retroviral treatment initiation and monitoring from multiple or single fingersticks. PLoS ONE. 2013; 8: e85265\n10.1371/journal.pone.0085265\n2437687315\nJani IV, SitoeNE, ChongoPL, AlfaiER, QuevedoJI, TobaiwaO, et al\nAccurate CD4 T-cell enumeration and antiretroviral drug toxicity monitoring in primary healthcare clinics using point-of-care testing. AIDS. 2011; 25:807–812. 10.1097/QAD.0b013e328344f424\n2137853516\nMnyaniCN, McIntyreJA, MyerL. The reliability of point-of-care CD4 testing in identifying HIV-infected pregnant women eligible for antiretroviral therapy. J Acquir Immune Defic Syndr. 2012; 60: 260–264. 10.1097/QAI.0b013e318256b651\n2248758917\nWadeD, DaneauG, AboudS, VercauterenGH, UrassaWSK, KestensL, et al\nWHO multicenter evaluation of FACSCount CD4 and Pima CD4 t-cell count systems\u202f: instrument performance and misclassification of HIV-infected patients. J Acquir Immune Defic Syndr. 2014; 66:98–107.18\nScottLE, CampbellJ, WestermanL, KestensL, VojnovL, KohastsuL, et al\nA meta-analysis of the performance of the Pima CD4 for point of care testing. BMC Med. 2015; 13:168\n10.1186/s12916-015-0396-2\n2620886719\nMeyer-RathG, SchnippelK, LongL, MacleodW, SanneI, StevensW, et al\nThe impact and cost of scaling up GeneXpert MTB/RIF in South Africa. PLoS ONE. 2012; 7:e36966\n10.1371/journal.pone.0036966. 10.1371/journal.pone.0036966\n2269356120\nUNITAID. Tuberculosis diagnostics technology and market landscape\nGeneva: UNITAID; 2013.21\nFoxMP, MaskewM, MacPhailA. Cohort profile: the Themba Lethu Clinical Cohort, Johannesburg, South Africa. International Journal of Epidemiology. 2013; 42:430–439. 10.1093/ije/dys029\n2243486022\nHoffmannCJ, LewisJJ, DowdyDW, FieldingKL, GrantAD, MartinsonN, et al\nMortality associated with delays between clinic entry and ART initiation in resource-limited settings: results of a transition-state model. J Acquir Immune Defic Syndr. 2013; 63:105–111. 10.1097/QAI.0b013e3182893fb4\n2339245723\nJani IV, SitoeNE, AlfaiER, ChongoPL, QuevedoJI, RochaBM, et al\nEffect of point-of-care CD4 cell count tests on retention of patients and rates of antiretroviral therapy initiation in primary health clinics: An observational cohort study. Lancet. 2011; 378:1572–1579. 10.1016/S0140-6736(11)61052-0\n2195165624\nBurtleD, WelfareW, EldenS, MamvuraC, VandelanotteJ, PetherickE, et al\nIntroduction and evaluation of a “pre-ART care” service in Swaziland: an operational research study. BMJ Open. 2012; 2:e000195\n10.1136/bmjopen-2011-000195\n25\nBlackS, ZulligerR, MyerL, MarcusR, JenekerS, HonsBA, et al\nSafety, feasibility and efficacy of a rapid ART initiation in pregnancy pilot programme in Cape Town, South Africa. S Afr Med J. 2013; 103:557–562. 10.7196/SAMJ.6565\n2388573926\nMfinangaS, ChandaD, KivuyoSL, GuinnessL, BottomleyC, SimmsV, et al\nCryptococcal meningitis screening and community-based early adherence support in people with advanced HIV infection starting antiretroviral therapy in Tanzania and Zambia: an open-label, randomised controlled trial. Lancet. 2015; 385:2173–2182. 10.1016/S0140-6736(15)60164-7\n2576569827\nClouseK, Page-ShippL, DanseyH, MoatlhodiB, ScottL, BassettJ, et al\nImplementation of Xpert MTB/RIF for routine point-of-care diagnosis of tuberculosis at the primary care level. S Afr Med J. 2012; 102:805–807. 10.7196/SAMJ.5851\n23034211', 'title': "Initiating Antiretroviral Therapy for HIV at a Patient's First Clinic Visit: The RapIT Randomized Controlled Trial.", 'date': '2016-05-11'}}
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Public Health, Epidemiology & Health Systems
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22
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Is viral suppression at 12 months higher, lower, or the same when comparing rapid ART to standard initiation?
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higher
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moderate
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yes
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['28742880', '27658873', '29509839', '27163694']
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{'28742880': {'article_id': '28742880', 'content': 'PLoS MedPLoS MedplosplosmedPLoS Medicine1549-12771549-1676Public Library of ScienceSan Francisco, CA USA28742880552652610.1371/journal.pmed.1002357PMEDICINE-D-17-00266Research ArticleBiology and Life SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesPublic and Occupational HealthPreventive MedicineVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesImmunodeficiency VirusesHIVBiology and 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SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVHIV-1Medicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVHIV-1Biology and Life SciencesOrganismsVirusesViral PathogensRetrovirusesLentivirusHIVHIV-1Medicine and Health SciencesHealth CareHealth Care ProvidersMedical DoctorsPhysiciansPeople and PlacesPopulation GroupingsProfessionsMedical DoctorsPhysiciansPeople and placesGeographical locationsNorth AmericaCaribbeanHaitiBiology and Life SciencesMicrobiologyVirologyViral Transmission and InfectionViral LoadMedicine and health sciencesDiagnostic medicineHIV clinical manifestationsSame-day HIV testing with initiation of antiretroviral therapy versus standard care for persons living with HIV: A randomized unblinded trialSame-day HIV testing and antiretroviral therapy initiationhttp://orcid.org/0000-0001-7464-275XKoenigSerena P.ConceptualizationFunding acquisitionInvestigationMethodologySupervisionWriting – original draftWriting – review & editing12*DorvilNancyInvestigationMethodologyProject administrationSupervisionWriting – review & editing1DévieuxJessy G.ConceptualizationFunding acquisitionInvestigationMethodologySupervisionWriting – original draftWriting – review & editing3http://orcid.org/0000-0002-9689-5413Hedt-GauthierBethany L.ConceptualizationFormal analysisFunding acquisitionMethodologySoftwareSupervisionValidationVisualizationWriting – review & editing4RiviereCynthiaInvestigationMethodologyProject administrationSupervisionWriting – review & editing1FaustinMikerlyneInvestigationMethodologyProject administrationSupervisionWriting – review & editing1LavoileKerlyneInvestigationMethodologyProject administrationSupervisionWriting – review & editing1PerodinChristianFormal analysisInvestigationMethodologySoftwareValidationVisualizationWriting – review & editing1ApollonAlexandraConceptualizationInvestigationMethodologyProject administrationSupervisionWriting – review & editing1DuvergerLimatheInvestigationMethodologyProject administrationSupervisionWriting – review & editing1McNairyMargaret L.MethodologyWriting – review & editing56HennesseyKelly A.Formal analysisMethodologySoftwareValidationVisualizationWriting – review & editing1SouroutzidisAriadneFormal analysisMethodologySoftwareValidationVisualizationWriting – review & editing7CremieuxPierre-YvesFormal analysisMethodologySoftwareValidationVisualizationWriting – review & editing7SeverePatriceConceptualizationFunding acquisitionInvestigationMethodologyProject administrationSupervisionWriting – review & editing1PapeJean W.ConceptualizationFunding acquisitionInvestigationMethodologyProject administrationSupervisionWriting – review & editing151\nHaitian Study Group for Kaposi’s Sarcoma and Opportunistic Infections (GHESKIO), Port-au-Prince, Haiti2\nDivision of Global Health Equity, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America3\nAIDS Prevention Program, Florida International University, Miami, Florida, United States of America4\nDepartment of Global Health and Social Medicine, Harvard Medical School, Harvard University, Boston, Massachusetts, United States of America5\nCenter for Global Health, Department of Medicine, Weill Cornell Medical College, Cornell University, New York, New York, United States of America6\nDivision of General Internal Medicine, Department of Medicine, Weill Cornell Medical College, Cornell University, New York, New York, United States of America7\nAnalysis Group, Boston, Massachusetts, United States of AmericaGengElvin H.Academic EditorUniversity of California, San Francisco, UNITED STATESThe authors have declared that no competing interests exist.* E-mail: skoenig@bwh.harvard.edu257201772017147e100235724120171662017© 2017 Koenig et al2017Koenig et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThe science of rapid start—From the when to the how of antiretroviral initiation\nBackgroundAttrition during the period from HIV testing to antiretroviral therapy (ART) initiation is high worldwide. We assessed whether same-day HIV testing and ART initiation improves retention and virologic suppression.Methods and findingsWe conducted an unblinded, randomized trial of standard ART initiation versus same-day HIV testing and ART initiation among eligible adults ≥18 years old with World Health Organization Stage 1 or 2 disease and CD4 count ≤500 cells/mm3. The study was conducted among outpatients at the Haitian Group for the Study of Kaposi’s Sarcoma and Opportunistic infections (GHESKIO) Clinic in Port-au-Prince, Haiti. Participants were randomly assigned (1:1) to standard ART initiation or same-day HIV testing and ART initiation. The standard group initiated ART 3 weeks after HIV testing, and the same-day group initiated ART on the day of testing. The primary study endpoint was retention in care 12 months after HIV testing with HIV-1 RNA <50 copies/ml. We assessed the impact of treatment arm with a modified intention-to-treat analysis, using multivariable logistic regression controlling for potential confounders. Between August 2013 and October 2015, 762 participants were enrolled; 59 participants transferred to other clinics during the study period, and were excluded as per protocol, leaving 356 in the standard and 347 in the same-day ART groups. In the standard ART group, 156 (44%) participants were retained in care with 12-month HIV-1 RNA <50 copies, and 184 (52%) had <1,000 copies/ml; 20 participants (6%) died. In the same-day ART group, 184 (53%) participants were retained with HIV-1 RNA <50 copies/ml, and 212 (61%) had <1,000 copies/ml; 10 (3%) participants died. The unadjusted risk ratio (RR) of being retained at 12 months with HIV-1 RNA <50 copies/ml was 1.21 (95% CI: 1.04, 1.38; p = 0.015) for the same-day ART group compared to the standard ART group, and the unadjusted RR for being retained with HIV-1 RNA <1,000 copies was 1.18 (95% CI: 1.04, 1.31; p = 0.012). The main limitation of this study is that it was conducted at a single urban clinic, and the generalizability to other settings is uncertain.ConclusionsSame-day HIV testing and ART initiation is feasible and beneficial in this setting, as it improves retention in care with virologic suppression among patients with early clinical HIV disease.Trial registrationThis study is registered with ClinicalTrials.gov number NCT01900080In a randomized unblinded trial in Port-au-Prince, Haiti, Serena Koenig and colleagues investigate whether initiating ART on the day of HIV diagnosis improved retention in care and viral suppression.Author summaryWhy was this study done?Multiple visits for counseling, laboratory testing, and other procedures to prepare patients for initiation of antiretroviral therapy (ART) are burdensome and contribute to the high rate of attrition during the period from HIV testing to ART initiation.The World Health Organization (WHO) recently changed their guidelines to recommend ART for all persons living with HIV, facilitating ART initiation.This study was conducted to determine if ART initiation on the day of HIV diagnosis could improve treatment initiation rates, retention in care, and HIV viral suppression for patients with asymptomatic or minimally symptomatic HIV disease.What did the researchers do and find?We randomly assigned patients who presented for HIV testing at a clinic in Port-au-Prince, Haiti to standard ART initiation or same-day HIV testing and ART initiation (356 in the standard and 347 in the same-day groups).The standard group had 3 weekly visits with a social worker and physician and then started ART 21 days after the date of HIV diagnosis; the same-day ART group initiated ART on the day of HIV diagnosis.All participants in the same-day ART group and 92% of participants in the standard group initiated ART.At 12 months after HIV testing, a higher proportion of participants in the same-day ART group were retained in care (80% versus 72%), and a higher proportion were retained in care with viral load <50 copies/ml (53% versus 44%) and viral load <1,000 copies/ml (61% versus 52%).What do these findings mean?This study demonstrates that it is feasible to initiate ART on the day of HIV diagnosis for patients with early HIV clinical disease and that same-day treatment leads to increased ART uptake, retention in care, and viral suppression.Though same-day ART initiation improves outcomes, retention in care and viral suppression remain suboptimal, so further interventions to maximize long-term outcomes will be essential.The study is limited by being conducted at 1 clinic in urban Haiti. Further study will be necessary to determine if this strategy will be effective in other settings.http://dx.doi.org/10.13039/100000060National Institute of Allergy and Infectious DiseasesR01AI104344http://orcid.org/0000-0001-7464-275XKoenigSerena P.This project was supported by the National Institute of Allergy and Infectious Diseases, grant number R01AI104344. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Data AvailabilityWe have included the anonymized dataset as a Supporting Information file (S1 Data).Data AvailabilityWe have included the anonymized dataset as a Supporting Information file (S1 Data).IntroductionThe Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 targets state that 90% of HIV-infected persons know their status, 90% initiate antiretroviral therapy (ART), and 90% achieve virologic suppression by the year 2020 to curb the AIDS epidemic [1]. In 2015, the World Health Organization (WHO) updated their guidelines to recommend ART for all persons living with HIV based on evidence that earlier treatment improves outcomes and decreases transmission [2–4]. To achieve these goals, patients must be promptly linked to HIV services, initiated on ART, and retained in lifelong care [5].Attrition rates are particularly high during the period from HIV testing to ART initiation, with one-quarter to one-third of patients lost in the process of starting ART [6–9]. Even if many of these patients re-engage in care at a later date, they will return with more advanced disease. Though there are many factors that contribute to pretreatment attrition, the current standard of care in most settings, which requires multiple sequential visits for HIV testing and counseling, laboratory testing, and adherence counseling prior to ART initiation, creates barriers to treatment initiation. As of June 2016, WHO guidelines note inadequate evidence to support a recommendation of same-day HIV testing and ART initiation [2]. However, the availability of point-of-care tests, the fact that CD4 cell counts are no longer necessary prior to ART initiation, and the provision of same-day counseling can accelerate treatment initiation, potentially reducing attrition [10–12]. We conducted a randomized trial in Haiti to determine whether same-day HIV testing and ART initiation, as compared with standard ART initiation, improves retention in care with viral suppression.MethodsStudy design and settingWe conducted an unblinded, randomized controlled trial of standard ART initiation versus same-day HIV testing and ART initiation among HIV-infected adults at the Haitian Group for the Study of Kaposi’s Sarcoma and Opportunistic infections (GHESKIO) in Port-au-Prince, Haiti. Haiti is the poorest country in the Western Hemisphere, with adult HIV prevalence of 1.7% [13,14]. GHESKIO is a Haitian nongovernmental organization and the largest provider of HIV care in the Caribbean, treating up to 700 patients per day for HIV and/or tuberculosis (TB). All care is provided free of charge. The study was approved by the institutional review boards at Partners Healthcare, GHESKIO, Weill Cornell Medical College, and Florida International University. See supporting information files S1 Text for the study protocol and S2 Text for the CONSORT checklist.ParticipantsParticipants were recruited from the HIV voluntary counseling and testing center at GHESKIO from August 2013 to October 2015. They received HIV testing and posttest counseling; those with a positive HIV test were referred for same-day physician evaluation, CD4 count (FACS Count, Becton-Dickinson, Franklin Lakes, New Jersey), WHO staging, and chest radiograph. Patients were eligible for study inclusion if they were infected with HIV-1, ≥18 years of age, and had WHO Stage 1 or 2 disease and CD4 count ≤500 cells/mm3. Initially, enrollment was limited to patients with CD4 count ≤350 cells/mm3, but in February 2014, the cutoff was increased to ≤500 cells/mm3 in response to revised WHO and Haitian guidelines [15]. Patients were excluded if they were already aware of their HIV diagnosis, had received ART previously, were pregnant or breastfeeding, lived outside of the greater Port-au-Prince metropolitan area, planned to transfer care during the study period, or failed to demonstrate preparedness on an ART readiness survey, which was administered by a social worker prior to study enrollment. The survey includes a 5-point scale, with respondents ranking their preparedness from “not at all ready” to “completely ready” in response to 7 questions. Study inclusion required a response of “somewhat ready” or “completely ready” for all 7 questions (S3 Text) [16].Randomization and maskingAfter the patients had provided written informed consent, the study team performed a screening evaluation for study exclusion criteria, and eligible participants were enrolled and randomized on the day of HIV testing. Participants were randomly assigned with the use of a computer-generated random-number list to either standard ART or same-day ART initiation in a 1:1 ratio, with allocation concealment. The randomization sequence was generated by a computer in the GHESKIO data management unit by a data manager who had no other involvement in study procedures. Participants were enrolled in the study and assigned to groups by a study physician. Participants, site personnel, and study statisticians were not masked to group assignment.ProceduresAfter randomization, the standard group participants received ART initiation procedures that mirror national guidelines. Participants were referred to return on Day 7 for baseline laboratory tests (creatinine, alanine aminotransferase, aspartate aminotransferase, complete blood count, purified protein derivative [PPD]), physician evaluation, and counseling with a social worker. On Day 10, they received interpretation of PPD results, and on Days 14 and 21, they were seen by a physician and social worker for additional counseling, test results, and ongoing evaluations for opportunistic infections. Participants started ART on Day 21 and had an additional social worker and physician visit at Week 5 (Fig 1). The ART regimen was the same as that for nonstudy patients at GHESKIO. First-line therapy included a single combination tablet including tenofovir disoproxil fumarate, lamivudine, and efavirenz.10.1371/journal.pmed.1002357.g001Fig 1Study interventions for the standard ART and same-day ART groups.The same-day ART group had identical laboratory tests as the standard ART group, a 30-minute counseling session with a social worker, and physician evaluation, and then initiated the same ART regimen as the standard ART group. They returned on Day 3 for physician and social worker visits and receipt of baseline laboratory test results; those with creatinine clearance <50 mL/minute as calculated by the Cockcroft-Gault equation were switched from tenofovir to zidovudine or abacavir. They returned on Days 10 and 17 for additional physician and social worker visits and on Day 24 for a physician visit. The same number of scheduled physician visits and counseling sessions were provided to each group so that the only difference in care was in the schedule of visits during the first 5 weeks of the study and the timing of ART initiation.All care was delivered by GHESKIO clinic staff, and the same providers (physicians, nurses, social workers, pharmacists, and field workers) cared for both groups. A counseling manual was followed with an outline for the social workers to follow at each scheduled counseling visit; these were identical between groups, except for the timing of ART initiation, and each session took about 30 minutes. All counseling was provided for individual patients, rather than for groups. The counseling sessions were audiotaped and systematically evaluated for quality control purposes. If a participant in either group missed a study visit that included a scheduled social worker counseling session, the counseling was provided at the next visit.Participants in both groups had monthly physician visits throughout the follow-up period and received the same package of services provided to all HIV-infected patients at GHESKIO, including prophylactic treatment with trimethoprim-sulfamethoxazole and isoniazid. Field workers phoned patients who missed a visit and attempted a home visit for those not reachable by phone. Participants received a transportation subsidy of 100 Haitian gourdes (US$1.70) per visit.OutcomesThe primary endpoint was retention in care with HIV-1 RNA <50 copies/ml at 12 months after HIV testing. Retention was defined as attending the 12-month visit (1 clinic visit between 12 and 15 months after HIV testing). Lost to follow-up (LTFU) was defined as failure to attend the 12-month visit. Deaths were ascertained by review of medical records or report from family members. A National Institutes of Health Division of AIDS Expedited Adverse Event Form was filled out within 48 hours after the study team became aware of any death. Transfers were ascertained by confirmation that the participant was receiving care at a different site. Secondary outcomes include survival, ART initiation, retention in care with HIV-1 RNA <1,000 copies/ml at 12 months after HIV testing, adherence as measured by pharmacy refill records and self-report, and cost and cost-effectiveness of standard and same-day ART; the adherence and cost-effectiveness evaluations will be reported in separate manuscripts.Statistical analysisDemographic, clinical, and laboratory data from the electronic medical record and study forms were de-identified, entered into an Excel spreadsheet, and exported into Stata v14 software (StataCorp, 2011, College Station, Texas) for analysis. After study completion, all participants who were LTFU were recontacted to determine their vital status.The study was powered to detect a 10% absolute difference in the rate of retention with virologic suppression between the 2 groups at 12 months after enrollment (65% in the standard and 75% in the same-day ART group). At the α = 0.05 significance level, we estimated that we would need to enroll 349 participants per group (698 in total) to achieve 80% power to detect this difference. Because patients who transferred during the study period were excluded, we increased the total sample size to 762 participants. For all analyses, a modified intention-to-treat approach was used, in which all patients were analyzed according to their assignment group, excluding patients who transferred to another facility during the follow-up period, according to protocol.Baseline characteristics were summarized using simple frequencies and proportions and medians with interquartile ranges (IQRs) stratified by treatment arm. Among participants who died, baseline CD4 count was compared using the Wilcoxon rank-sum test. We compared the proportion of participants who were retained in care with HIV-1 RNA <50 copies/ml (primary endpoint), retained with HIV-1 RNA <1,000 copies/ml, retained regardless of HIV-1 RNA, initiated ART, and died (secondary endpoints) at 12 months after enrollment using a chi-square test. We conducted multivariable logistic regression including all covariates listed in Table 1 to control for any residual confounding. We present unadjusted and adjusted risk ratios (RR) with 95% confidence intervals. Because of the change in enrollment criteria mid-study, we conducted a sensitivity analysis that included only the participants who met the original enrollment criteria of CD4 count ≤350 cells/mm3. In response to a reviewer’s request, we also plotted retention in care, regardless of viral load, for both groups and compared the distributions with the log-rank test. The study is registered with ClinicalTrials.gov number NCT01900080.10.1371/journal.pmed.1002357.t001Table 1Baseline characteristics of study participants by group.CharacteristicStandard Group (n = 356)Same-Day ART Group (n = 347)Age (years)—Median (IQR)37 (30, 45)37 (29, 46)Female sex—no. (%)181 (51)166 (48)Education—no. (%)\xa0\xa0\xa0\xa0No school90 (25)93 (27)\xa0\xa0\xa0\xa0Primary school110 (31)111 (32)\xa0\xa0\xa0\xa0Secondary school or more156 (44)143 (41)Income—no. (%)\xa0\xa0\xa0\xa0No income92 (26)90 (26)\xa0\xa0\xa0\xa0>$0 to $1/day176 (49)159 (46)\xa0\xa0\xa0\xa0>$1 to $2/day67 (19)76 (22)\xa0\xa0\xa0\xa0>$2/day21 (6)22 (6)Marital status—no. (%)\xa0\xa0\xa0\xa0Single71 (20)71 (20)\xa0\xa0\xa0\xa0Currently married/living with partner222 (62)211 (61)\xa0\xa0\xa0\xa0Formerly married63 (18)65 (19)WHO Stage—no. (%)\xa0\xa0\xa0\xa0WHO Stage 1117 (33)101 (29)\xa0\xa0\xa0\xa0WHO Stage 2239 (67)246 (71)CD4 count (cells/mm3)—Median (IQR)247 (150, 349)249 (143, 336)Body mass index—Median (IQR)*21.6 (19.7, 23.9)20.9 (19.3, 23.5)* Body mass index differed significantly between the 2 groups (p = 0.025).ART, antiretroviral therapy; IQR, interquartile range, WHO, World Health Organization.ResultsA total of 821 patients were screened, and 762 were enrolled in the study and underwent randomization (Fig 2). After randomization, 59 participants (28 in the standard ART and 31 in same-day ART group) transferred to another clinic and were excluded from all analyses, as per protocol. The median age was 37 years old (IQR: 30–45 years), 347 (49%) were women, and the median CD4 count was 248 cells/mm3 (IQR: 148, 345).10.1371/journal.pmed.1002357.g002Fig 2Screening, randomization, and follow-up.Of the 356 participants in the standard group, 256 (72%) were retained in care, 20 (6%) died, and 80 (23%) were LTFU (Table 2). Among the 256 participants retained in the standard ART group, 156 (61% of retained and 44% overall) had HIV-1 RNA <50 copies/ml. Of the 347 participants in the same-day ART group, 277 (80%) were retained in care, 10 (3%) died, and 60 (17%) were LTFU. Among the 277 participants retained in the same-day ART group, 184 (66% of retained and 53% overall) had HIV-1 RNA <50 copies/ml. The unadjusted RR of being retained in care at 12 months and achieving HIV-1 RNA <50 copies/ml was 1.21 (95% CI: 1.04, 1.38; p = 0.015) for the same-day ART group compared to the standard group (Table 3); the adjusted RR for this comparison was 1.24 (95% CI: 1.06, 1.41; p = 0.008).10.1371/journal.pmed.1002357.t002Table 2Study outcomes by group.OutcomeStandard ART Group (n = 356)Same-Day ART Group (n = 347)Unadjusted Risk Difference (95% CI)p-valuePrimary OutcomeRetained in care at 12 months with VL <50 copies/ml156 (43.8%)184 (53.0%)9.2% (1.8%, 16.6%)0.015†Secondary OutcomesRetained in care at 12 months with VL <1,000 copies/ml184 (51.7%)212 (61.1%)9.4% (2.1%, 16.7%)0.012‡Retained in care at 12 months, regardless of VL results256 (71.9%)277 (79.8%)7.9% (1.6%, 14.2%)0.014††Died20 (5.6%)10 (2.9%)Lost to follow-up80 (22.5%)60 (17.3%)† p-value comparing the proportion of all patients who were retained in care with viral load <50 copies/ml between the 2 arms.‡ p-value comparing the proportion of all patients who were retained in care with viral load <1,000 copies/ml between the 2 arms.†† p-value comparing the proportion of all patients who were retained in care between the 2 arms.ART, antiretroviral therapy; VL, viral load.10.1371/journal.pmed.1002357.t003Table 3Unadjusted and adjusted risk ratios of study outcomes.UnadjustedAdjusted for All Baseline Co-variatesRR95% CIp-valueRR95% CIp-valueRetained in care with viral load <50 copies/mlStandard ART Group1.01.0Same-Day ART Group1.21(1.04, 1.38)0.0151.24(1.06, 1.41)0.008Retained in care with viral load <1,000 copies/mlStandard ART Group1.01.0Same-Day ART Group1.18(1.04, 1.31)0.0121.20(1.05, 1.33)0.008Mortality during study periodStandard ART Group1.01.0Same-Day ART Group0.51(0.24, 1.08)0.0730.43(0.19, 0.94)0.033ART, antiretroviral therapy; RR, risk ratio.In the standard ART group, 184 (72% of retained and 52% overall) participants who were retained in care had HIV-1 RNA <1,000 copies/ml. In the same-day ART group, 212 (77% of retained and 61% overall) participants who were retained in care had HIV-1 RNA <1,000 copies/ml. The unadjusted RR of being retained in care at 12 months and achieving HIV-1 RNA <1,000 copies/ml was 1.18 (95% CI: 1.04, 1.31; p = 0.012) for the same-day ART group compared to the standard ART group (Table 3); the adjusted RR for this comparison was 1.20 (95% CI: 1.05, 1.33; p = 0.008). In the sensitivity analysis that included only participants who met the original enrollment criteria (CD4 count ≤350 cells/mm3), the adjusted RR of being retained in care at 12 months and achieving HIV-1 RNA <50 copies/ml was 1.19 (95% CI: 0.99, 1.38; p = 0.060), and the adjusted RR of being retained in care at 12 months and achieving HIV-1 RNA < 1,000 copies/ml was 1.18 (95% CI: 1.01, 1.34; p = 0.035).Vital status at the end of the study was known for 328 (92%) participants in the standard ART group and 329 (95%) in the same-day ART group. The unadjusted RR for mortality was 0.51 (95% CI: 0.24, 1.08; p = 0.073) for the same-day group compared to the standard group; the adjusted RR for this comparison was 0.43 (95% CI: 0.19, 0.94; p = 0.033). In the sensitivity analysis that included only participants with CD4 count ≤350 cells/mm3, the adjusted RR for mortality was 0.41 (95% CI: 0.18, 0.93; p = 0.033). Among the participants who died, the median baseline CD4 count was 100 cells/mm3 (IQR: 45, 192) in the standard and 207 cells/mm3 (IQR: 112, 291) in the same-day ART group (p = 0.078). Eight of 20 (40%) deaths in the standard ART group occurred in participants who were LTFU prior to ART, 8 (40%) deaths occurred in those LTFU after starting ART, and 4 (20%) occurred while in care; the causes of death for those in care were stroke, trauma, and cancer in 3, and the fourth had pain and died after seeing a traditional healer. Three of the 10 (30%) deaths in the same-day ART group occurred in participants who were LTFU after starting ART; among the 7 (70%) participants who died while in care, 1 of each died of stroke, pneumonia, malaria, renal failure, and sudden death, and 2 died of gastroenteritis. No deaths for those in care were attributed to immune reconstitution syndrome or an opportunistic infection that was missed at ART initiation. In Fig 3, the Kaplan-Meier curve plots the retention in care, regardless of viral load, for both groups. The log-rank test comparing the curves between the standard and same-day ART group indicates a significant difference (p = 0.028).10.1371/journal.pmed.1002357.g003Fig 3Retention in care by study group.In the same-day ART group, 344 of 347 (99%) participants started ART on the day of HIV testing, and the remaining 3 patients started ART within the subsequent week. During the Day 3 follow-up visit, 13 patients (4%) in the same-day ART group had adjustments in their ART regimens (replacement of tenofovir with zidovudine or abacavir) because they had creatinine clearance <50 mL/minute on baseline testing. In the standard group, 281 (79%) participants initiated ART by Day 28, the end of the time window for the 3-week ART initiation visit. Thirty-six (10%) standard group participants initiated ART from Day 29 to Day 90, and 12 (3%) initiated ART after Day 90 due to late or missed visits. Twenty-seven (8%) standard group participants never started ART during the study period because they were LTFU or died prior to initiating treatment. Isoniazid prophylaxis was initiated for 337 (95%) participants in the standard group and 340 (98%) in the same-day group. Eight cases of TB were diagnosed during the first 3 months after ART initiation; 6 of these occurred in the standard group and 2 in the same-day ART group.DiscussionThe results of this randomized controlled trial show that among HIV-infected adults with early WHO Stage disease and CD4 count ≤500 cells/mm3, same-day HIV testing and ART initiation, as compared to standard care, improves retention in care with virologic suppression and, in the multivariable analysis, decreases mortality. These results are important given recent WHO 2016 guidelines stating the lack of evidence in support of same-day ART initiation.Our findings suggest that ART initiation as soon as possible after HIV testing may be beneficial for clinically stable patients. In resource-poor settings with fragile delivery systems, such as Haiti, the provision of immediate support by care providers at the time of HIV diagnosis can have both structural and individual impact. In addition to making treatment initiation logistically easier for patients, we believe that same-day counseling and ART initiation increase the sense of hope, optimism, and overall connectedness to the healthcare system for patients, which have been shown to be important for retention [17–20].Our findings are consistent with the results of the RapIT study, a randomized trial that included participants in South Africa with WHO Stage 3 or 4 disease or CD4 count ≤350 cells/mm3 [11]. Participants in the standard group in that study generally started ART at the sixth visit, and 72% of participants in the rapid group started ART on the day of study enrollment. Rapid ART initiation resulted in a 17% improvement in retention and 13% improvement in viral suppression. A stepped-wedge cluster-randomized trial in Uganda found an increase in ART initiation within 2 weeks after eligibility by implementing a multicomponent intervention to streamline ART initiation that included training healthcare workers, providing point-of-care CD4 count testing platforms, eliminating mandatory multiple preinitiation sessions, and giving feedback to facilities on their ART initiation rates [21]. A weighted proportion of 80% in the intervention group had started ART within 2 weeks after eligibility compared with 38% in the control group. A cohort study of same-day ART initiation in pregnant women in South Africa also found high rates of treatment initiation, with 91% initiating ART on the day of referral to the service [22]. In the intervention group of the Sustainable East Africa Research on Community Health (SEARCH) HIV test-and-treat study, a cluster-randomized controlled trial conducted in Kenya and Uganda, HIV-infected patients who were identified through community testing were referred to HIV care upon diagnosis and then offered immediate ART initiation; retention was high (89%) among patients newly linking to care [23].At ART initiation, it is critical that patients are ready to start lifelong therapy, that TB screening is conducted, and that renal function is evaluated to avoid the use of tenofovir in patients with renal insufficiency. In this study, ART readiness was remarkably high, with over 99% of patients screened for the study reporting they were ready to start lifelong ART. This is a particularly significant and timely finding for the provision of recommended universal ART because the majority of people living with HIV have early clinical disease, and there has been prior concern that healthier patients may be less willing to accept lifelong therapy [4]. Most patients with early clinical disease do not have TB symptoms (cough, fever, night sweats, or weight loss), so they do not require further work up to exclude TB, according to WHO guidelines [2]. With the exclusion of patients with a baseline chest x-ray that was suspicious for TB, we found that less than 1% of participants in the same-day ART group had TB that was missed at the time of ART initiation. We found that 4% of participants in the same-day ART group had creatinine clearance <50 mL/minute; ART regimens were adjusted on Day 3 for these patients.Both groups in our study received high-level care, with multiple counseling and physician visits in the first month, followed by monthly physician visits. At the time the study was started, this was the standard of care in Haiti. However, this standard has shifted over the past few years towards decreased frequency of visits and nonphysician providers [2,24–27]. We believe that same-day ART can be provided with fewer follow-up visits if proper counseling is provided during the early period after ART initiation. However, clinic-level procedures play a major role in the effectiveness of accelerated ART initiation strategies, as illustrated in Malawi, where among nearly 22,000 pregnant women who started ART for mother-to-child prevention, LTFU rates ranged from 0% to 58% between facilities and were highest among women who initiated ART on the day of HIV testing at large clinics [28].Though lower than anticipated, retention in both groups in our study was higher than reports of standard ART initiation from other resource-poor settings. Two studies from South Africa found that approximately one-third of patients remained in care from HIV testing through 12 months of ART, and systematic reviews of African studies have found high rates of pre-ART attrition [6,8,29,30]. In Haiti, data on pre-ART outcomes are limited, but 12-month retention after ART initiation is 73% nationwide [31]. We attribute the higher retention in our study in large part to faster ART initiation, even in the standard group, compared to many other HIV programs. We surmise that retention would have been lower in the standard group if there had been longer delays in ART initiation [5,11,30].The rates of retention with viral suppression in our study are lower than those reported from clinical trial cohorts, including at GHESKIO. In the GHESKIO Clinical Trials Unit, with a median monthly average of 483 subjects participating in NIH-funded clinical trials, retention is 97%. We attribute the lower retention and viral suppression rates in our study to 2 major reasons. First, nearly all patients meeting WHO stage and CD4 criteria were enrolled in the study on the day of HIV testing, including those with substantial barriers to retention in care and adherence. In contrast, over one-third of patients are generally lost to care prior to ART initiation or enrollment in clinical trials [6,8,29,30]. Second, the care that was provided in this study was similar to that received by nonstudy patients at GHESKIO, with the aim of producing findings that could be reproduced in other resource-poor settings. In order to achieve the UNAIDS 90-90-90 targets, it will be important to evaluate reasons for attrition and implement new strategies to improve retention in care. One approach that has been successful in a cohort of nonresearch patients at GHESKIO has been expedited follow-up care, with fewer visits of shorter duration for clinically stable patients [32]. Streamlined care has also been associated with high rates of retention in the SEARCH study, which is described above [23].Our study was conducted in a large urban clinic, which may limit the generalizability of our findings. In addition, though our study included patients with early clinical disease, the CD4 counts in our population were lower than would be expected with the provision of universal ART. It is possible that patients with higher CD4 counts may experience less benefit from same-day ART. It is also noteworthy that we conducted a chest x-ray prior to enrollment; if same-day ART is provided without a chest x-ray, it is possible that TB cases will be missed. Our study was not blinded. All participants in both groups received the same number of visits and the same retention plan, but we cannot exclude the possibility that awareness of study group impacted provider behavior.In conclusion, in a population of asymptomatic or minimally symptomatic HIV-infected patients, same-day HIV testing and ART initiation decreased mortality and improved the rate of retention in care with virologic suppression compared with standard ART initiation. Furthermore, human and material resources provided to each group were similar, so same-day ART is not expected to increase treatment costs. The new WHO recommendations to provide ART to all HIV-infected patients should facilitate same-day test and treat.Supporting informationS1 TextStudy protocol.(DOCX)Click here for additional data file.S2 TextCONSORT checklist.(DOC)Click here for additional data file.S3 TextHIV medication readiness scale.(PDF)Click here for additional data file.S1 DataAnonymized dataset.(XLSX)Click here for additional data file.Presented in part at the 21st International AIDS Conference, Durban, South Africa, July 18 to 22, 2016. We thank all of the patients who participated in this study and all of the GHESKIO staff who cared for them. We thank Drs. Paul Farmer, Daniel Fitzgerald, Martin Hirsch, Warren Johnson, Daniel Kuritzkes, and Paul Sax for expert advice on study design and Kaya Hedt and Anshul Saxena for manuscript formatting and preparation. We also thank Drs. Carlos del Rio, Kenneth Mayer, and Larry Moulton for serving on the data safety monitoring board and providing oversight of the study.AbbreviationsARTantiretroviral therapyGHESKIOHaitian Group for the Study of Kaposi’s Sarcoma and Opportunistic infectionsIQRinterquartile rangeLTFUlost to follow-upPPDpurified protein derivativeRRrisk ratioSEARCHSustainable East Africa Research on Community HealthUNAIDSThe Joint United Nations Programme on HIV/AIDSWHOWorld Health OrganizationReferences1UNAIDS Fast-Track, Ending the AIDS Epidemic by 2030. Accessed May 24, 2017 at: http://www.unaids.org/en/resources/campaigns/World-AIDS-Day-Report-2014.2Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection. Recommendations for a Public Health Approach. Second Edition, World Health Organization, 2016. 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Conference on Retroviruses and Opportunistic Infections (CROI), Boston, MA, USA, 2016.', 'title': 'Same-day HIV testing with initiation of antiretroviral therapy versus standard care for persons living with HIV: A randomized unblinded trial.', 'date': '2017-07-26'}, '27658873': {'article_id': '27658873', 'content': "In Africa, up to 30% of HIV-infected patients who are clinically eligible for antiretroviral therapy (ART) do not start timely treatment. We assessed the effects of an intervention targeting prevalent health systems barriers to ART initiation on timing and completeness of treatment initiation.\nIn this stepped-wedge, non-blinded, cluster-randomised controlled trial, 20 clinics in southwestern Uganda were randomly assigned in groups of five clinics every 6 months to the intervention by a computerised random number generator. This procedure continued until all clinics had crossed over from control (standard of care) to the intervention, which consisted of opinion-leader-led training and coaching of front-line health workers, a point-of-care CD4 cell count testing platform, a revised counselling approach without mandatory multiple pre-initiation sessions, and feedback to the facilities on their ART initiation rates and how they compared with other facilities. Treatment-naive, HIV-infected adults (aged ≥18 years) who were clinically eligible for ART during the study period were included in the study population. The primary outcome was ART initiation 14 days after first clinical eligibility for ART. This study is registered with ClinicalTrials.gov, number NCT01810289.\nBetween April 11, 2013, and Feb 2, 2015, 12\u2008024 eligible patients visited one of the 20 participating clinics. Median CD4 count was 310 cells per μL (IQR 179-424). 3753 of 4747 patients (weighted proportion 80%) in the intervention group had started ART by 2 weeks after eligibility compared with 2585 of 7066 patients (38%) in the control group (risk difference 41·9%, 95% CI 40·1-43·8). Vital status was ascertained in a random sample of 208 patients in the intervention group and 199 patients in the control group. Four deaths (2%) occurred in the intervention group and five (3%) occurred in the control group.\nA multicomponent intervention targeting health-care worker behaviour increased the probability of ART initiation 14 days after eligibility. This intervention consists of widely accessible components and has been tested in a real-world setting, and is therefore well positioned for use at scale.\nNational Institute of Allergy and Infectious Diseases (NIAID) and the President's Emergency Fund for AIDS Relief (PEPFAR).", 'title': 'Effects of a multicomponent intervention to streamline initiation of antiretroviral therapy in Africa: a stepped-wedge cluster-randomised trial.', 'date': '2016-10-30'}, '29509839': {'article_id': '29509839', 'content': 'Home-based HIV testing is a frequently used strategy to increase awareness of HIV status in sub-Saharan Africa. However, with referral to health facilities, less than half of those who test HIV positive link to care and initiate antiretroviral therapy (ART).\nTo determine whether offering same-day home-based ART to patients with HIV improves linkage to care and viral suppression in a rural, high-prevalence setting in sub-Saharan Africa.\nOpen-label, 2-group, randomized clinical trial (February 22, 2016-September 17, 2017), involving 6 health care facilities in northern Lesotho. During home-based HIV testing in 6655 households from 60 rural villages and 17 urban areas, 278 individuals aged 18 years or older who tested HIV positive and were ART naive from 268 households consented and enrolled. Individuals from the same household were randomized into the same group.\nParticipants were randomly assigned to be offered same-day home-based ART initiation (n\u2009=\u2009138) and subsequent follow-up intervals of 1.5, 3, 6, 9, and 12 months after treatment initiation at the health facility or to receive usual care (n\u2009=\u2009140) with referral to the nearest health facility for preparatory counseling followed by ART initiation and monthly follow-up visits thereafter.\nPrimary end points were rates of linkage to care within 3 months (presenting at the health facility within 90 days after the home visit) and viral suppression at 12 months, defined as a viral load of less than 100 copies/mL from 11 through 14 months after enrollment.\nAmong 278 randomized individuals (median age, 39 years [interquartile range, 28.0-52.0]; 180 women [65.7%]), 274 (98.6%) were included in the analysis (137 in the same-day group and 137 in the usual care group). In the same-day group, 134 (97.8%) indicated readiness to start ART that day and 2 (1.5%) within the next few days and were given a 1-month supply of ART. At 3 months, 68.6% (94) in same-day group vs 43.1% (59) in usual care group had linked to care (absolute difference, 25.6%; 95% CI, 13.8% to 36.3%; P\u2009<\u2009.001). At 12 months, 50.4% (69) in the same-day group vs 34.3% (47) in usual care group achieved viral suppression (absolute difference, 16.0%; 4.4%-27.2%; P\u2009=\u2009.007). Two deaths (1.5%) were reported in the same-day group, none in usual care group.\nAmong adults in rural Lesotho, a setting of high HIV prevalence, offering same-day home-based ART initiation to individuals who tested positive during home-based HIV testing, compared with usual care and standard clinic referral, significantly increased linkage to care at 3 months and HIV viral suppression at 12 months. These findings support the practice of offering same-day ART initiation during home-based HIV testing.\nclinicaltrials.gov Identifier: NCT02692027.', 'title': 'Effect of Offering Same-Day ART vs Usual Health Facility Referral During Home-Based HIV Testing on Linkage to Care and Viral Suppression Among Adults With HIV in Lesotho: The CASCADE Randomized Clinical Trial.', 'date': '2018-03-07'}, '27163694': {'article_id': '27163694', 'content': 'PLoS MedPLoS MedplosplosmedPLoS Medicine1549-12771549-1676Public Library of ScienceSan Francisco, CA USA27163694486268110.1371/journal.pmed.1002015PMEDICINE-D-15-03455Research ArticleBiology and Life SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesPublic and Occupational HealthPreventive MedicineVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesImmunodeficiency VirusesHIVBiology and life sciencesOrganismsVirusesRNA virusesRetrovirusesLentivirusHIVBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVBiology and Life SciencesOrganismsVirusesViral PathogensRetrovirusesLentivirusHIVPeople and placesGeographical locationsAfricaSouth AfricaBiology and Life SciencesAnatomyBody FluidsBloodBlood CountsMedicine and Health SciencesAnatomyBody FluidsBloodBlood CountsBiology and Life SciencesPhysiologyBody FluidsBloodBlood CountsMedicine and Health SciencesPhysiologyBody FluidsBloodBlood CountsMedicine and Health SciencesHematologyBloodBlood CountsMedicine and Health SciencesHealth CareHealth Care ProvidersNursesPeople and PlacesPopulation GroupingsProfessionsNursesBiology and Life SciencesMicrobiologyVirologyViral Transmission and InfectionViral LoadMedicine and Health SciencesInfectious DiseasesBacterial DiseasesTuberculosisMedicine and Health SciencesTropical DiseasesTuberculosisMedicine and Health SciencesPharmaceuticsDrug TherapyInitiating Antiretroviral Therapy for HIV at a Patient’s First Clinic Visit: The RapIT Randomized Controlled TrialSingle-Visit ART InitiationRosenSydney\n1\n\n2\n*MaskewMhairi\n2\nFoxMatthew P.\n2\n\n3\nNyoniCynthia\n2\nMongwenyanaConstance\n2\nhttp://orcid.org/0000-0003-1473-880XMaleteGiven\n2\nSanneIan\n2\nhttp://orcid.org/0000-0001-5800-1960BokabaDorah\n4\nSaulsCeleste\n2\nhttp://orcid.org/0000-0002-1180-8764RohrJulia\n1\nLongLawrence\n2\n\n1\nDepartment of Global Health, Boston University School of Public Health, Boston, Massachusetts, United States of America\n\n2\nHealth Economics and Epidemiology Research Office, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa\n\n3\nDepartment of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, United States of America\n\n4\nHealth Department, City of Johannesburg, Johannesburg, South Africa\nBinagwahoAgnesAcademic Editor\nRwanda Ministry of Health, RWANDA\nThe authors have declared that no competing interests exist.Conceived and designed the experiments: SR LL MM IS MPF. Performed the experiments: CN CM DB CS JR. Analyzed the data: MM GM SR. Wrote the first draft of the manuscript: SR MM. Contributed to the writing of the manuscript: SR MM LL MPF. Enrolled patients: CN. Agree with the manuscript’s results and conclusions: SR MM LL MPF CN CM GM IS DB CS JR. All authors have read, and confirm that they meet, ICMJE criteria for authorship.* E-mail: sbrosen@bu.edu105201652016135e1002015171120152232016© 2016 Rosen et al2016Rosen et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.BackgroundHigh rates of patient attrition from care between HIV testing and antiretroviral therapy (ART) initiation have been documented in sub-Saharan Africa, contributing to persistently low CD4 cell counts at treatment initiation. One reason for this is that starting ART in many countries is a lengthy and burdensome process, imposing long waits and multiple clinic visits on patients. We estimated the effect on uptake of ART and viral suppression of an accelerated initiation algorithm that allowed treatment-eligible patients to be dispensed their first supply of antiretroviral medications on the day of their first HIV-related clinic visit.Methods and FindingsRapIT (Rapid Initiation of Treatment) was an unblinded randomized controlled trial of single-visit ART initiation in two public sector clinics in South Africa, a primary health clinic (PHC) and a hospital-based HIV clinic. Adult (≥18 y old), non-pregnant patients receiving a positive HIV test or first treatment-eligible CD4 count were randomized to standard or rapid initiation. Patients in the rapid-initiation arm of the study (“rapid arm”) received a point-of-care (POC) CD4 count if needed; those who were ART-eligible received a POC tuberculosis (TB) test if symptomatic, POC blood tests, physical exam, education, counseling, and antiretroviral (ARV) dispensing. Patients in the standard-initiation arm of the study (“standard arm”) followed standard clinic procedures (three to five additional clinic visits over 2–4 wk prior to ARV dispensing). Follow up was by record review only. The primary outcome was viral suppression, defined as initiated, retained in care, and suppressed (≤400 copies/ml) within 10 mo of study enrollment. Secondary outcomes included initiation of ART ≤90 d of study enrollment, retention in care, time to ART initiation, patient-level predictors of primary outcomes, prevalence of TB symptoms, and the feasibility and acceptability of the intervention. A survival analysis was conducted comparing attrition from care after ART initiation between the groups among those who initiated within 90 d. Three hundred and seventy-seven patients were enrolled in the study between May 8, 2013 and August 29, 2014 (median CD4 count 210 cells/mm3). In the rapid arm, 119/187 patients (64%) initiated treatment and were virally suppressed at 10 mo, compared to 96/190 (51%) in the standard arm (relative risk [RR] 1.26 [1.05–1.50]). In the rapid arm 182/187 (97%) initiated ART ≤90 d, compared to 136/190 (72%) in the standard arm (RR 1.36, 95% confidence interval [CI], 1.24–1.49). Among 318 patients who did initiate ART within 90 d, the hazard of attrition within the first 10 mo did not differ between the treatment arms (hazard ratio [HR] 1.06; 95% CI 0.61–1.84). The study was limited by the small number of sites and small sample size, and the generalizability of the results to other settings and to non-research conditions is uncertain.ConclusionsOffering single-visit ART initiation to adult patients in South Africa increased uptake of ART by 36% and viral suppression by 26%. This intervention should be considered for adoption in the public sector in Africa.Trial RegistrationClinicalTrials.gov NCT01710397, and South African National Clinical Trials Register DOH-27-0213-4177.In the RapIT randomized controlled trial, Sydney Rosen and colleagues investigate whether accelerated initiation of antiretroviral therapy can improve viral suppression for HIV patients in South Africa.Author SummaryWhy Was This Study Done?One of the most persistent operational challenges facing antiretroviral therapy (ART) programs for HIV/AIDS in sub-Saharan Africa is late presentation of patients for care and high rates of attrition from care between HIV testing and ART initiation.One reason for this is that starting ART in many countries is a lengthy and burdensome process, imposing long waits and multiple clinic visits on patients; in South Africa, the country with the world’s largest HIV treatment program, patients must typically make five or six clinic visits, starting with an HIV test, before they receive medications.There have not yet been any controlled evaluations of an integrated, rapid HIV treatment initiation algorithm that allows patients to initiate ART in a single clinic visit, so the RapIT trial was done to find out if “same-day initiation” of ART would increase the number of patients starting treatment and improve overall health outcomes, compared to current practices.What Did the Researchers Do and Find?We randomly assigned 377 adult patients at two public clinics in Johannesburg, South Africa, who had provided consent to participate in the study to one of two groups.Patients in the group assigned to receive rapid treatment initiation were offered the chance to start treatment on the same day as their first clinic visit, using rapid, point-of-care laboratory tests and an accelerated sequence of other steps, including a physical exam, education, and counseling.Patients in the group assigned to receive standard treatment initiation followed the standard schedule for treatment initiation used by the clinics, which usually required three to five additional clinic visits over a 2–4 wk period.After the study enrollment visit, patients were followed up by reviewing their regular clinic medical records, to determine how many did start treatment and how many were still in care and had good outcomes, as indicated by a suppressed viral load, 10 mo later.We found that 97% of patients in the rapid initiation group had started ART by 90 d after study enrollment—three-quarters of them on the same day—compared to 72% of patients in the standard initiation group.By 10 mo after study enrollment, 64% of patients in the rapid group had good outcomes compared to 51% in the standard group.Rapid initiation group patients spent roughly two and a half hours in the clinic to complete all the steps required before they got their medications.What Do These Findings Mean?The RapIT (Rapid Initiation of Treatment) trial showed that it is possible to initiate nearly all eligible patients on HIV therapy, and to do so in a much shorter time interval than previously required.By showing that offering the opportunity to start treatment on the spot, without delay, overcomes many barriers patients would otherwise face, this study demonstrates that same-day ART initiation is an effective strategy for improving health outcomes.More patients in the rapid initiation group dropped out of care after starting treatment than in the standard initiation group; although the rapid initiation group still had better health outcomes overall, adherence support after starting treatment remains essential.The findings of this study are limited because the study took place in only two clinics in one part of South Africa and was carried out by study staff, not by regular clinic staff.Based on this study’s results, consideration could be given to accelerating the process of ART initiation in many different settings and for different types of patients.http://dx.doi.org/10.13039/100000060National Institute of Allergy and Infectious Diseases1U01AI100015RosenSydneyFunding for this study was provided by the U.S. National Institutes of Health (National Institute of Allergy and Infectious Diseases) under the terms of grant 1U01AI100015 to Boston University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Data AvailabilityData will be made publicly available in the Dryad repository (http://www.datadryad.org/) after the protocol has been closed (anticipated closure June 2018). Until then, data will remain under the supervision of the University of the Witwatersrand Human Research Ethics Committee (HREC). Requests should be sent to the HREC Research Administrator at: https://www.wits.ac.za/research/about-our-research/ethics-and-research-integrity/human-research-ethics-committee-medical/.Data AvailabilityData will be made publicly available in the Dryad repository (http://www.datadryad.org/) after the protocol has been closed (anticipated closure June 2018). Until then, data will remain under the supervision of the University of the Witwatersrand Human Research Ethics Committee (HREC). Requests should be sent to the HREC Research Administrator at: https://www.wits.ac.za/research/about-our-research/ethics-and-research-integrity/human-research-ethics-committee-medical/.IntroductionOne of the most persistent operational challenges facing antiretroviral therapy (ART) programs for HIV/AIDS in sub-Saharan Africa is late presentation of patients for care and high rates of attrition from care between HIV testing and ART initiation, with baseline median CD4 cell counts remaining well below 200 cells/mm3 in the region despite steadily rising eligibility thresholds [1]. Even among those who have been diagnosed and found to be treatment-eligible, loss to care before starting ART has consistently been estimated at a third to a quarter of patients [2,3]. While many of those who drop out of care prior to ART initiation will make their way back at a later time, they will almost certainly have lower CD4 counts and more symptoms of illness than when they first tested positive. Some will be very sick or die before treatment can be started, and those who do eventually start will have a poorer prognosis on treatment than if they had begun treatment earlier [4,5]. Offering ART to all who test positive regardless of CD4 count, as is now recommended by the World Health Organization [6], will make little difference if those who test positive fail to initiate treatment.There are likely many causes of loss to care before treatment initiation, but one reason observed is that starting ART in many countries is a lengthy and burdensome process, requiring long waits and multiple clinic visits [7,8]. In South Africa, the country with the world’s largest HIV treatment program [9], the process typically includes an HIV test (visit 1), determination of treatment eligibility (visit 2), adherence education and counseling and baseline blood tests (visits 3, 4, and 5), and physical examination and dispensing of antiretrovirals (ARVs) (visit 6). The proliferation of visits has three main causes. First, clinic receipt of printed test results from centralized laboratories typically takes several days, if not longer. Second, a belief remains that to ensure adherence, patients must participate in multiple preparatory educational and counseling sessions [2,10,11]. And third, clinics have had little motivation to accelerate the initiation process for patients who are not critically ill, as standard performance indicators do not include the proportion of eligible patients who actually initiate ART, nor the time required to do so.If patients are deterred from starting treatment by the complexity of the process, then one strategy for reducing loss of patients prior to ART initiation and encouraging earlier treatment initiation may be to shorten the time period, reduce the number of visits, and simplify the steps required before medications are dispensed. This strategy depends critically on two factors: a clinic’s willingness and ability to adjust its schedules and procedures to compress and accelerate the required steps, and the availability of rapid, point-of care (POC) laboratory assays that eliminate delays in receiving whatever lab results are required for initiation. There have not yet been any rigorous, controlled evaluations of an integrated, rapid HIV treatment initiation algorithm incorporating procedural changes and POC tests for adult, non-pregnant patients. We therefore conducted a randomized controlled trial of rapid ART initiation that allowed patients in public sector clinics in Johannesburg, South Africa to have treatment eligibility determined, all treatment preparation steps performed, and ARV medications dispensed on the day of their first HIV-related clinic visit.MethodsRapIT (Rapid Initiation of Treatment) was an unblinded, individually randomized, controlled trial of a service delivery intervention. It was approved by the Institutional Review Board of Boston University Medical Campus (H-31880) and the Human Research Ethics Committee (Medical) of the University of the Witwatersrand (M120843) and is registered with ClinicalTrials.gov, number NCT01710397.Study Sites, Infrastructure, and StaffingRapIT was conducted at two public sector outpatient clinics. Site 1 is a primary health clinic serving an urban informal settlement population on the edge of Johannesburg. Site 2 is a large, hospital-based HIV clinic serving an urban formal and informal population within Johannesburg. Both sites follow South African national treatment guidelines for ART initiation, ARV regimens, and monitoring [12]. During the period of study enrollment, May 8, 2013–August 29, 2014, the prevailing threshold for ART eligibility was a CD4 count ≤ 350 cells/mm3 or a WHO Stage 3/4 clinical condition. Requirements for care prior to initiating ART are not standardized in South Africa [13], but both sites generally required four to five clinic visits between HIV testing and dispensing the first month’s supply of ARVs.At each site, a small clinic room with security bars, running water, and basic furnishings was designated for study equipment and supplies, POC instruments, and files. As all the POC instruments were designed as desktop devices, no separate laboratory was needed. An outdoor booth for safe collection of sputum samples from tuberculosis (TB) suspects was constructed at Site 1 and made available for both study arms; existing facilities for this purpose were used at Site 2. Clinical procedures were performed by study nurses with the same level of clinical certification as existing primary health care nurses at the sites. Non-clinical procedures (consent, questionnaire, education, counseling, patient flow management) were implemented by study assistants with qualifications comparable to those of experienced lay counselors at the sites. All study staff received study and instrument-specific training. A small stipend (R1000/month, equivalent to US$86 at the exchange rate at the time of the study) was paid to clinic lay counselors at Site 1 and a messenger at Site 2 who assisted by referring potential study participants to the study assistant.Study PopulationThe study enrolled adult (≥18 y old), non-pregnant patients who presented to have an HIV test, provide a blood sample for a CD4 count if already known to be HIV-infected, or receive the results of the patient’s first treatment-eligible CD4 count. During pre-screening and screening, patients who had previously been found to be eligible for ART, were already on ART or reported receiving it in the past 12 mo, indicated that they intended to seek HIV care during the next 12 mo at a different clinic, were judged by clinic or study staff to be physically or emotionally unable to provide consent or participate in all study procedures, or did not meet other study inclusion criteria were excluded. Potential participants whose visit purpose was to have an HIV test were enrolled; those found post-enrollment not to be eligible for ART were subsequently withdrawn upon determination of ineligibility. Potential participants whose visit purpose was to receive a CD4 count result and were not eligible for treatment on the basis of that CD4 count were not enrolled.Participants were individually randomized 1:1 to either rapid treatment initiation or standard-of-care treatment initiation, using block randomization in blocks of 6. Sealed, opaque envelopes containing the allocations were prepared by the local principal investigator and numbered sequentially. The envelopes were kept in sequential, numbered order at the study sites. After obtaining written informed consent, the study assistant opened the next sequentially numbered envelope to reveal the allocation.Study Design and ProceduresProcedures for each study arm are illustrated in Fig 1. Standard-of-care treatment initiation followed existing procedures at the sites as closely as possible. Study staff interaction with participants was limited to screening for study eligibility, obtaining written informed consent, administering a questionnaire, and referring patients to clinic staff for either a blood draw for a CD4 count or a next visit appointment if the patient already had results of a CD4 count in hand. After referral, patients in the standard-initiation arm of the study were followed passively, through medical record review, and had no further interaction with the study. Standard-of-care procedures for ART initiation at both study sites included a CD4 count to determine eligibility, TB symptom screening followed by a TB test and TB treatment initiation if required, pre-initiation blood tests (hemoglobin, creatinine, and alanine aminotransferase (ALT)), group and individual counseling and education sessions, and a physical examination. All samples for laboratory tests were sent to centralized public sector laboratories, requiring patients to make separate clinic visits to provide biological samples and to receive results. Once ART eligibility was determined, initiation typically required three to four more clinic visits over a period of 2–4 wk. Patients who were very ill or found to have low CD4 counts could be “fast-tracked,” with the schedule shown in Fig 1 completed in as little as one week.10.1371/journal.pmed.1002015.g001Fig 1Standard initiation of treatment and rapid initiation procedures and visit schedule.For patients randomized to rapid initiation, all the same procedures were performed, but the use of a compressed and accelerated schedule and rapid laboratory instruments at point of care allowed them all to be completed in a single visit (Box 1). Patients offered rapid initiation typically completed each step in order, with little or no waiting time in between unless a TB test was required, which entailed a wait to process the sample. Patients who enrolled in the study too late in the day for all steps to be completed before the clinic closed were asked to return the next day to finish study procedures. Patients who were randomized to rapid initiation but did not have time to participate on the day of enrollment or wished to delay for other reasons were given up to 30 d to return and be initiated under rapid procedures. Those returning beyond 30 d were offered standard initiation by the clinic.Box 1. Rapid Initiation ProceduresCD4 countPatients who enrolled in the study and did not already have CD4 count results from a test performed within the previous 6 mo were given a rapid CD4 count using the Alere Pima CD4 Test (http://alerehiv.com/hiv-monitoring/alere-pima-cd4/) with venous blood draw. This test, previously evaluated in several studies in Africa [14–18], provides a CD4 count result from a capillary or venous blood sample in 20 min. Following the test, patients with a CD4 count ≤ 350 cells mm3 or evident physical symptoms or complaints that suggested a Stage 3 or 4 condition continued with study procedures. Those not eligible for ART were withdrawn from the study at this point and referred to the clinic for standard pre-ART monitoring.TB symptom screen and testWhile awaiting CD4 count results, a TB symptom screen was administered using South Africa’s four-question screening tool. All patients who reported symptoms were then asked to provide a sputum sample, which was immediately processed using the Cepheid Xpert MTB/RIF test (http://www.cepheid.com/us/cepheid-solutions/clinical-ivd-tests/critical-infectious-diseases/xpert-mtb-rif). This is the technology currently used for TB diagnosis in the public sector throughout South Africa, but it is located in centralized laboratories rather than at point of care [19]. It generates a TB diagnosis in 90 min [20]. Two sputum samples were run simultaneously to increase the reliability of results. Any patient who received a positive Xpert test was escorted to the clinic TB nurse to initiate TB treatment, which under national guidelines required a delay of at least 2 wk before ART could be initiated. Patients initiated on TB treatment were asked to return 2 wk later to complete rapid ART initiation on a second visit.Baseline testsOnce eligibility for ART was established, pre-initiation blood tests (hemoglobin, creatinine, and ALT) were run on a point-of-care Reflotron Plus instrument (Roche, http://www.roche-diagnostics.co.in/Products/Pages/ReflotronPlusDry.aspx)[14] using the same blood sample dawn for the CD4 count. This instrument takes approximately 2 min to complete each test. A standard clinic urine dipstick pregnancy test was also conducted for female patients of child-bearing age.Physical examA standard physical examination was conducted by the study nurse to identify any specific conditions or concerns prior to initiating ART. Initiation was delayed in patients found to have conditions that required referral to a hospital or consultation with the clinic’s doctor.Education sessionA condensed version of HIV/ART/adherence education was developed using the study clinics’ materials and provided to study participants. It was delivered in a one-on-one session by the study counselor in approximately 20 min.Counseling sessionAfter completing all tests, physical examination, and education session, each patient met individually with the study nurse, who reviewed results with the patient and provided an opportunity for the patient to ask any remaining questions and confirm that she or he was indeed ready for treatment initiation.Dispensing of ARVsThe study nurses, like other qualified nurses in South Africa, were authorized to write prescriptions for ARVs, which could then be filled directly by the nurse from study room stock (Site 1) or at the on-site clinic pharmacy (Site 2). Study patients at Site 2 were served at the pharmacy immediately, rather than being required to wait in pharmacy queues to fill prescriptions. Once the initial 4 wk supply of ARVs was dispensed, study interaction with rapid group patients ceased. Patients were asked to return to the clinic for monitoring and prescription refill by clinic staff in 1 mo, consistent with routine practice.After the enrollment visit, or completion of rapid initiation procedures for patients in the rapid-initiation arm of the study (“rapid arm”) who delayed initiation but returned to complete it within 30 d, the study team had no further contact with study patients. Patients who started ART in either arm received standard-of care treatment management from the clinic, which called for monitoring visits and medication refills at 1, 2, 3, 6, and 12 mo after initiation, with a routine viral load test at the 6 mo visit.Outcomes and DataThe primary, protocol-defined outcome for the study was viral suppression (≤400 copies/ml) within 10 mo of study enrollment, a time period selected to capture the 6 mo routine monitoring visit called for by national guidelines. Ten months was selected as the endpoint to allow patients to take up to 3 mo to initiate ART and to be up to 1 mo late for the 6 mo routine visit. Because the study sites occasionally omitted the 6 mo viral load and performed the test only at 12 mo, we considered a patient with a suppressed viral load test result any time from 3 to 12 mo after study enrollment to have achieved viral suppression. In this analysis, missing viral load test results were regarded as failures; only patients with recorded, suppressed viral load results were defined as virally suppressed. To account for the possibility that viral load results could be missing due to clinic oversight in not ordering the test, rather than patient default, and to investigate the possibility that rapid initiation merely shifts attrition from before to after treatment initiation, we also report the secondary outcome of retention in care at 10 mo after study enrollment, with retention defined as any HIV-related clinic visit in months 5–10 after study enrollment, regardless of viral load.Although viral suppression was the primary outcome assessed, the pathway by which the study aimed to increase suppression was reduction of attrition between HIV testing and treatment initiation. We therefore report initiation of treatment within 90 d of study enrollment as a secondary outcome, with initiation defined as being dispensed a first month’s supply of ARVs. We also report uptake of treatment within 180 d, as a CD4 count result is considered to be valid under South African guidelines for 6 mo—after that, a patient must have a new CD4 count to establish eligibility for ART. Finally, we report the distribution of time (d) to treatment initiation in each group.Other secondary outcomes evaluated in the study included the feasibility of the intervention, as indicated by the ability of both study sites to implement the accelerated algorithm; acceptability of the intervention, as measured by the proportion of patients offered rapid initiation who accepted it; patient-level predictors of the primary outcome; and, in the rapid arm, the prevalence of TB symptoms and confirmed TB disease and ART initiation among patients with TB.After the enrollment visit, all data collection for both groups was by passive medical record review. Both study sites routinely utilized an electronic medical record system called TherapyEdge-HIV, into which patient data were entered retrospectively by data clerks from paper files (Site 1) or by a combination of clinicians in real time and data clerks from paper files (Site 2)[21]. This record system improved the completeness of the follow-up dataset used in the study. In instances of incomplete follow-up data—for example, if the database reported a clinic visit 6 mo after ART initiation but contained no viral load test result—study staff searched the clinics’ paper files and registers and the online data portal of the National Health Laboratory Service to determine if any additional information existed but had not been recorded in the clinics’ databases. The study team had no further contact with study participants after the enrollment visit so as not to have any influence on retention in care, a study outcome.Data AnalysisWe designed the study to detect a 20% difference in viral suppression rates between the arms at 10 mo after study enrollment. With an α of 0.05, power of 90%, 1:1 randomization, and an uncorrected Fisher’s exact test, we estimated that we would need to enroll at least 124 HIV positive ART-eligible participants per group (248 total). We increased this to a maximum of 200 per group (400 total) to allow for stratification by site, sex, or age.Characteristics at study enrollment of all randomized participants who met ART initiation and study inclusion criteria were summarized using simple proportions and medians with interquartile ranges (IQR) stratified by treatment arm. For the remaining analyses, we excluded patients who were found after randomization not to be eligible for ART or not to meet study inclusion criteria. We compared the proportions of patients achieving each dichotomized study outcome and present crude risk ratios (RR) and risk differences (RD) with 95% confidence intervals (CI) stratified by group. Baseline predictors of outcomes that appeared imbalanced by treatment arm were also adjusted for using log-linear regression models to estimate adjusted risk ratios (aRR). We estimated time to treatment initiation in days using a cumulative incidence curve. To investigate whether attrition after initiation of ART differed between the study arms, we performed a survival analysis comparing attrition from care after ART initiation among those who initiated within 90 d between the groups. Person-time accrued from ART initiation date to the earliest of loss to follow up, transfer, or 10 mo of follow up, and hazard ratios of attrition from care were estimated with Cox proportional hazards models. A stratified analysis was performed to detect effect measure modification by site or patient-level factors. Finally, to confirm that no imbalance was created by excluding patients after randomization for reasons other than ineligibility for ART or evidence of a previous eligible CD4 count, we conducted sensitivity analysis incorporating the excluded patients and assigning each a negative outcome.ResultsBetween May 8, 2013, and August 29, 2014, 603 patients were screened for study eligibility and 463 provided written informed consent and were enrolled in the study (Fig 2). Of the 140 screened but excluded prior to randomization, 109 did not meet study eligibility criteria, including 43 who resided outside study clinic catchment areas or intended to seek further care elsewhere; 24 who were determined by the study assistant to be too ill for consent and study procedures; 16 who were not eligible on the basis of a prior CD4 count, were ineligible for ART, or were already on ART; 12 who were determined by the study assistant to be too emotionally upset to provide consent; 9 who did not speak any of the languages spoken by the study team; 3 who were found to be pregnant; and 2 who were excluded for other reasons. An additional 31 patients refused participation; of these, 18 were in a hurry and did not have time for study procedures, six did not wish to participate in the study, five stated that they would prefer standard care, and two were not willing to initiate therapy. Follow-up ended 10 mo after the last patient was enrolled (June 28, 2015).10.1371/journal.pmed.1002015.g002Fig 2Study enrollment and randomization.Characteristics of patients in each study arm at time of enrollment are reported in Table 1. There were no important differences between the study arms in the variables shown. Just over half the participants were female and the median age was 35 y. The median CD4 count was less than 200 cells/mm3. Age, sex, and CD4 count characteristics of the study sample were similar to those of the overall non-pregnant patient populations initiating ART at the study clinics in 2014.10.1371/journal.pmed.1002015.t001Table 1Baseline characteristics of study sample (n = 463).VariableStandard armRapid arm\nn (randomized participants)229234Enrollment site (n)\xa0\xa0\xa0\xa0Site 1 (primary health clinic)124126\xa0\xa0\xa0\xa0Site 2 (hospital-based HIV clinic)105108Age (median, IQR)35.8 (29.5–41.6)34.2 (29.0–40.1)Sex (% female)132 (58%)129 (55%)CD4 count (cells/mm3) (median, IQR)195 (103–322)224 (128–327)Purpose of clinic visit (%)\xa0\xa0\xa0\xa0Have HIV test (diagnosed today)100 (44%)90 (38%)\xa0\xa0\xa0\xa0Provide blood sample for CD4 count8 (4%)10 (4%)\xa0\xa0\xa0\xa0Receive first CD4 count results109 (47%)112 (48%)\xa0\xa0\xa0\xa0Other11 (5%)22 (10%)Reason for treatment eligibility (%)\xa0\xa0\xa0\xa0CD4 count below threshold182 (79%)183 (78%)\xa0\xa0\xa0\xa0Clinical condition Stage 3 or 43 (1%)4 (2%)\xa0\xa0\xa0\xa0Excluded (not eligible for treatment or study)44 (20%)47 (20%)Household composition\xa0\xa0\xa0\xa0Live alone (% yes)36 (16%)41 (18%)\xa0\xa0\xa0\xa0# other persons in house (median, IQR)2 (1–4)2 (1–3)Household type (%)\xa0\xa0\xa0\xa0Formal house or flat146 (63%)165 (71%)\xa0\xa0\xa0\xa0Informal dwelling or shack83 (37%)69 (29%)Travel time to clinic (minutes) (median, IQR)18 (9–24)15 (9–27)Employment status (%)\xa0\xa0\xa0\xa0Employed formally68 (30%)90 (38%)\xa0\xa0\xa0\xa0Work informally62 (27%)54 (23%)\xa0\xa0\xa0\xa0Unemployed, seeking work91 (40%)84 (36%)\xa0\xa0\xa0\xa0Unemployed, not seeking work8 (3%)6 (3%)Marital status (%)\xa0\xa0\xa0\xa0Married or long-term partner173 (76%)157 (67%)\xa0\xa0\xa0\xa0Single, no long-term partner41 (18%)57 (24%)\xa0\xa0\xa0\xa0Other (widowed, divorced)15 (6%)20 (9%)Reasons for excluding patients during the study screening process are reported in Fig 2. The 603 patients screened represent a subset of those pre-screened by clinic counselors and then referred to the study assistant for screening. While pre-screening data, which were collected by the counselors and not by study staff, are of uncertain quality, they do provide some indication of the proportion of all patients presenting at clinics who could be eligible for rapid initiation. At Site 1, for which the pre-screening data are more complete, a total of 2,636 patients presenting at the clinic’s HIV counseling and testing service were pre-screened. More than half of these were HIV-negative (1,468/2,636, 56%) or known to have CD4 counts above the eligibility threshold or already on ART (114/2,636, 4%). Of the remaining 1,054, 325 (31%) were referred for study screening. Another 293/1,054 (28%) were judged by the counselors not to meet study protocol eligibility criteria (age, residence location, language, not first CD4 count) but would likely have been eligible for the intervention if it were offered as routine care. A fifth (225/1,054, 21%) were regarded by the counselors as too sick for study participation (not necessarily for ART initiation) and were referred to a clinic doctor or nurse for immediate care; it is not clear if they would have been eligible for the intervention or not. The remainder (20%) included patients who refused study participation (36/1,054, 3%) or refused any further care (12/1,054, 1%), were deemed too upset or emotionally distressed to participate (25/1,054, 2%), were referred directly to the clinic’s HIV or TB nurse rather than the study assistant (75/1,054, 7%), or were in a hurry or had no reason stated (63/1,254, 6%).Among 463 patients screened and found eligible for study participation, 234 patients were randomized to rapid initiation and 229 to standard initiation (Fig 2). Upon completion of a CD4 count, which occurred after randomization for those who did not already have one in hand, 37 patients in each group were determined not to be eligible for ART under South African guidelines and were excluded from further data collection and from the analysis. An additional 12 patients were excluded after randomization, for reasons indicated in Fig 2. One hundred and ninety patients in the standard group and 187 in the rapid group (n = 377 total) were offered full study procedures and are included in the analysis below, with sensitivity analysis incorporating the six who were excluded after randomization for a reason other than ineligibility for ART or evidence of a prior eligible CD4 count.The protocol-defined primary outcome for the study was viral suppression within 10 mo of study enrollment. As presented in Table 2, viral suppression by 10 mo was 64% (119/187) in the rapid arm and 51% (96/190) in the standard arm, indicating a risk difference of 13% (3%–33%) and a crude relative risk of 1.26 (1.05–1.50).10.1371/journal.pmed.1002015.t002Table 2ART initiation, 10-mo retention in care, and 10-mo viral suppression.OutcomeStandard arm(%)n = 190Rapid arm(%)n = 187Crude risk difference(95% CI)Crude relative risk(95% CI)Initiated ≤ 90 d and suppressed by 10 mo (primary outcome)96 (51%)119 (64%)13% (3%–23%)1.26 (1.05–1.50)\xa0\xa0\xa0\xa0Of those\nnot\ninitiated ≤ 90 d and suppressed by 10 mo\n\n94 (49%)\n\n68 (36%)\n\n\xa0\xa0\xa0\xa0\xa0\xa0Not initiated\n\n54 (28%)\n\n5 (3%)\n\n\xa0\xa0\xa0\xa0\xa0\xa0Initiated but not suppressed\n\n40 (21%)\n\n63 (34%)\n\n\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0Of those initiated but not suppressed:\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0Retained, unsuppressed viral load test reported\n\n11 (6%)\n\n17 (9%)\n\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0Retained, no viral load test reported\n\n14 (7%)\n\n16 (9%)\n\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0Transferred to another clinic\n\n1 (1%)\n\n6 (3%)\n\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0Died\n\n3 (2%)\n\n0 (0%)\n\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0\xa0Lost to follow-up\n\n11 (6%)\n\n24 (13%)\nInitiated ≤ 90 d136 (72%)182 (97%)25% (19%–33%)1.36 (1.24–1.49)Initiated ≤ 90 d and retained at 10 mo (secondary outcome)121 (64%)151 (81%)17% (5%–23%)1.27 (1.12–1.44)\xa0\xa0\xa0\xa0Of those not initiated ≤ 90 d and retained at 10 mo:\n69 (36%)\n\n36 (19%)\n\xa0\xa0\xa0\xa0\xa0\xa0Initiated but not retained\n\n15 (8%)\n\n31 (17%)\n\xa0\xa0\xa0\xa0\xa0\xa0Not initiated\n\n54 (28%)\n\n5 (3%)\nBy 90 d after study enrollment, 97% (182/187) of participants in the rapid arm and 72% (136/190) of participants in the standard arm had initiated ART, equating to a risk difference of 25% (95% CI 19%–33%) and a crude relative risk of 1.36 (1.24–1.49) (Table 2). In adjusted analysis (S1 Table), neither age, sex, nor baseline CD4 count affected these values. By 180 d, one additional patient in the rapid arm and two in the standard arm had initiated, leaving four patients in the rapid arm and 52 in the standard arm who did not initiate within the period of validity of their CD4 count results. In the rapid arm, all four were referred to a clinic nurse or doctor for clinical confirmation of TB and did not return for ART initiation. In the standard arm, 73% (38/52) of the patients who did not initiate within 180 d made no further visits to the site after the visit in which they were enrolled in the study.\nFig 3 shows the cumulative incidence of treatment initiation in each study arm over the 180 d following enrollment. In the rapid arm, 72% (135/187) of patients started ART on the same day as study enrollment, an additional 7% (13/187) on the next day, and 96% (179/187) within 1 mo. In the standard arm, 58% of patients initiated within one month. The median (IQR) time to initiation in the standard arm for the subset who did initiate within 90 d (n = 136) was 17 (11–26) d. For rapid arm patients who did not initiate on the same day (n = 48), the reasons for delay were the need for clinical confirmation of TB or a Stage 3 or 4 condition or for TB treatment (25/48, 52%), insufficient time to complete all steps on the same day (6/48, 13%), patient preferences (5/48, 10%), lack of electricity in the clinic (2/48, 4%), and unknown reasons (10/48, 21%). Time to treatment initiation in the standard arm was shorter for patients who already had CD4 count results available upon study enrollment (median days 16, [IQR 11–22]) compared to those who enrolled in the study at the time of having an HIV test (22 [IQR 10–35]); the median for both types of patients in the rapid arm was 0 d (i.e., same-day initiation).10.1371/journal.pmed.1002015.g003Fig 3Time to ART initiation, by study arm.Cumulative incidence of ART initiation in each study arm, by number of days since study enrollment.All patients in the rapid arm had the opportunity to initiate treatment on the day of study enrollment (same-day initiation) unless one of the reasons for delay listed above pertained to them. To explore whether a delay in initiation was associated with different post-initiation outcomes, we compared patients who did initiate on the same day to those who delayed for any reason. There were no differences in either the primary outcome of viral suppression or the secondary outcome of retention in care between these two groups of patients (S3 Table). Because this analysis was limited to rapid arm patients, however, it is not a randomized comparison and should be interpreted with caution.Retention in care, defined as making a clinic visit between months 5 and 10 after study enrollment, was 81% (151/187) in the rapid arm and 64% (121/190) in the standard arm, for a risk difference of 17% (5%–23%) and a crude relative risk of 1.27 (1.12–1.44). Table 2 also indicates that 86% (31/36) of patients in the rapid arm who were not retained were lost from care after ART initiation, compared to just 22% (15/69) in the standard arm; the fall-off in the standard arm, in contrast, was mainly among those who never initiated (54/69, 78%). Although there was less loss to follow-up after initiation in the standard arm (15/190, 8% versus 31/187, 17%), this was more than offset by the higher pre-initiation loss in the standard arm (54/190, 28% versus 5/187, 3%), resulting in an overall increase in retention of 17%. Among the patients lost to care after initiation (15 in the standard arm and 31 in the rapid arm), a large majority of patients who initiated ART but were not retained in care either never came back after their initiation visit (40% of patients in the standard arm (6/15) and 45% in the rapid arm (14/31)) or came back just once (47% (7/15) and 35% (11/31), respectively), suggesting that most of these patients were never “established” on ART.To explore further the rate of loss to care, we estimated attrition from care within the first 10 mo after initiation among the subsample of 318 patients who did initiate ART within 90 d. In the standard arm, during 1,250 mo of total person-time, 22/136 (16%) dropped out of care after ART initiation, for an attrition rate of 1.8 per 100 person-months. In the rapid arm, during 1,626 mo of total person-time, 30/182 (16%) dropped out of care, for a rate of 1.8 per 100 person-months. The hazard of attrition within the first 10 mo after ART initiation among those who initiated within 90 d did not differ between the treatment arms (HR 1.06; 95% CI 0.61–1.84). We note that this result is subject to selection bias and confounding, however, due to the exclusion of those who did not start treatment within 90 d.In pooled analysis of both study arms, none of the variables presented in Table 1 predicted any of the outcomes reported above, with three exceptions (S2 Table). A slightly higher proportion of patients with baseline CD4 counts below 100 cells/mm3 initiated ART, but this difference did not persist through retention or viral suppression at 10 mo. As might be expected, patients who enrolled in the study at the time of receiving their CD4 count results (thus their second HIV-related clinic visit overall), rather than at the time of having an HIV test, were slightly more likely to achieve all three outcomes, though only for retention in care was this difference statistically significant. Finally, patients who reported being employed at the time of study enrollment, while no more likely to initiate ART, had significantly better retention in care and viral suppression than did those who reported being unemployed.In stratified analysis (S4 Table) we observed non-significant differences in effect sizes for the primary outcome (viral suppression at 10 mo) by sex, age group, and study site. A larger effect was seen among men aged <35 y (risk difference [95% CI] 34% [12%–55%]), while little effect was seen among men or women ≥35 (5% [-9%–19%]). The effect size was also greater at the primary health clinic (21% [8%–34%]), while little effect was seen at the hospital-based HIV clinic (2% [-12%–17%]). As noted, these differences were not statistically significant, and the study was not powered to detect differences among subgroups.In the rapid arm, for which TB diagnostic data were available, 29/187 patients (16%) presented with TB symptoms and were tested for TB using Xpert MTB/RIF. Four patients (17% of those with symptoms and 2% of all rapid arm patients) had a confirmed TB diagnosis. All four initiated ART within the 90-d outcome defined above, with a range of 11–54 d between study enrollment and ART initiation.The results of the sensitivity analysis incorporating the six patients who were excluded after randomization for reasons other than ART eligibility or prior CD4 count, and assigning each a negative outcome, did not differ substantively from the findings presented above, with a relative risk of viral suppression by 10 mo of 1.22 [1.02–1.46].Rapid initiation, using the procedures described above and as implemented by the study, appeared acceptable to patients at the time it was offered and feasible to implement at both study sites. We were not able to assess acceptability after patients received the intervention, as the study had no post-initiation interaction with those enrolled, and thus can surmise acceptability only on the basis of acceptance of the intervention. The study refusal rate was very low (31/603, 5%); nearly four out of five (148/187, 79%) patients offered the intervention accepted initiation on the same day or the next day, and rapid arm patients consistently expressed appreciation for the opportunity to start immediately.All steps in the rapid initiation process were completed on the same day as study enrollment for 72% (135/187) of those in the rapid arm, demonstrating the feasibility of the intervention, at least within the context of the study. From provision of informed consent (study enrollment) to dispensing of the first supply of ARV medications, rapid initiation took a median of 2.4 (IQR 2.1–2.8) hours for those who initiated on the same day as study enrollment. This interval was shorter for patients who already had CD4 count results in hand at study enrollment (median 2.25 hours). It was longer (median 4.5 hours) for those who required a TB test and did initiate ART on the same day, but 15/20 patients requiring TB tests did not initiate on the same day. The only obstacle encountered in implementing rapid procedures was fairly frequent power outages, a common occurrence in South Africa, at Site 1, which did not have a generator for backup power supply. Most rapid instrument tests could not be performed during power outages. The rapid test instruments otherwise performed well throughout the study, and no major delays or problems arose in the acceleration of clinic procedures.DiscussionIn this randomized controlled trial, we evaluated the effectiveness of an accelerated ART initiation algorithm that combined compressed and accelerated clinic procedures with point-of-care laboratory testing technologies that allowed eligible patients to initiate ART in a single clinic visit. This intervention increased the proportion of patients eligible for ART at study enrollment who initiated ART within 90 d by 25%, to 97% of all eligible patients and 100% of patients who were not delayed for TB treatment. By 10 mo after study enrollment, the intervention increased viral suppression among all treatment-eligible patients by 13% and retention in care by 17%. It was feasible and appeared acceptable at both study sites.The trial demonstrated that it is possible to initiate nearly all eligible patients on ART, and to do so in a much shorter time interval than previously required. The net benefit for overall viral suppression was clinically meaningful and may underestimate the true benefits of the intervention. Both the study sites were relatively well-managed, public sector clinics, resulting in a higher rate of ART initiation in the standard arm (72%) than is found elsewhere in the country, for example in rural KwaZulu Natal Province where the rate was 59% [2]. In addition, we observed a larger effect at Site 1, the primary health clinic, than at Site 2, the hospital-based HIV clinic. Primary health clinics, which have fewer resources than hospital-based clinics but treat 85% of HIV patients in South Africa, may struggle more with loss to follow-up before treatment initiation than do hospital-based clinics, creating a greater opportunity for a service delivery intervention like RapIT to be effective. The potential for reaching younger men, who have been among the least likely to access ART under standard care [22], is another important potential benefit of rapid initiation. Additional research is needed to explore further the non-significant differences in effect that we observed in our study.The patients who likely benefited most from RapIT were those who would not otherwise have initiated treatment at all, or who would have waited until they were sick enough to compromise their prognosis on treatment. In the standard arm, most patients who did not start treatment did not return to the study clinics for even one more visit, underscoring the importance of taking full advantage of the first visit to get as many patients started on treatment as possible. For those who would have initiated treatment, just not as soon, there is some evidence that even relatively short delays may be harmful. A recent modeling exercise using South African data estimated that compared to immediate initiation, a delay in initiating ART of 70 d would lead to a 34% increase in 12-mo mortality [22]. Delaying treatment initiation thus both deters some patients from starting at all and jeopardizes outcomes for those who do start.We hypothesize that the delays and multiple visits patients must endure before starting ART directly deter treatment initiation. Patients who cannot afford transport fare for multiple visits, have childcare obligations at home, or risk job or wage loss if they miss too many days of work may be directly deterred from returning. Others may simply grow impatient or lose their courage or motivation, particularly if they are asymptomatic when diagnosed. These patients are likely to drift away and only return when their CD4 counts are lower and symptoms have started, or to die before treatment can be started. Our results suggest that offering the opportunity to start treatment on the spot, without delay, overcomes these barriers, without risking poorer outcomes later on.Among patients who did initiate ART, post-initiation loss to care was higher in the rapid arm than the standard arm. This difference disappeared in the survival analysis, which controlled for number of months on ART but does not reflect the benefits of randomization. We speculate that some patients who did not want or were not ready for treatment chose to accept immediate initiation simply because it was offered or they wanted to participate in the study. For these patients, attrition from care was simply shifted from before ART initiation to after. While the intervention was successful in increasing the overall proportion of treatment-eligible patients with successful outcomes (viral suppression and/or retention in care), the rate of post-initiation attrition is a reminder that early retention in care and adherence support once patients start treatment remain high priorities for further research and intervention.Other studies have gauged the impact on treatment uptake of a single POC technology [23] or changes in service delivery [24], but we found only one prior report of a “single-visit initiation” intervention that was similar, to some degree, to RapIT. That study enrolled pregnant women initiating ART for prevention of mother-to-child transmission in South Africa and found very high uptake of ART among women offered rapid initiation, but it did not have a comparison arm to allow an effect to be estimated [25]. A study in Tanzania and Zambia compared the effect of community support on a two-visit algorithm and reported 99% uptake of ART in both study arms [26]. Taken together, these studies imply that accelerating ART initiation is effective in a wide range of settings.Nothing in the rapid initiation procedures used in this study differed fundamentally from existing clinic procedures. The intervention was delivered by study nurses and counselors with the same qualifications as existing clinic staff, though with study-specific training and supervision. The intervention imposed no major burdens on site management, though managerial acquiescence to the study and operational flexibility were needed to adjust the schedule and content of patient visits, staff responsibilities, and record keeping to allow for rapid initiation [27]. The main technical training required was in the use of the POC test instruments, which also required a secure location within the clinic, temperature control, and electricity.Although South Africa has better clinic infrastructure than do many other countries in the region, the RapIT intervention does not require anything that most urban and many rural clinics cannot provide. We speculate that the RapIT intervention would be feasible and potentially even more effective in other high HIV prevalence areas, where patients travel farther to reach clinics and results from centralized laboratories take even longer to return. As the new WHO guidelines are adopted, moreover, laboratory test results may not be required prior to ART initiation for patients who are asymptomatic, reducing the need for POC technology.The generalizability of our results is limited in several ways. The study was conducted in only two clinics in one province of one country. The trial intervention was delivered by study staff; it is uncertain if clinic staff delivering the same intervention will achieve the same outcomes (and whether their outcomes will be better or worse than those observed in the trial). As is typical in individually randomized trials of service delivery interventions, the possibility exists that quality of care in the standard arm was improved by the presence of the study, as clinic staff providing care for the standard arm may have been motivated by the study to make treatment initiation more efficient. If this occurred, the effect reported here would understate the true improvement in ART initiation that could be expected under routine implementation. As with many studies in which retention in care is an endpoint, we do not know the true outcomes of study patients who were not retained nor whether rapid arm patients who were not retained and who agreed to start treatment solely due to the presence of the study, and would otherwise not have done so, are at increased risk of developing ARV resistance. Finally, as reported above, rapid initiation under the study algorithm took 2–3 hours to complete, making same-day initiation impractical for patients who arrive late in the day (and for clinics with large numbers of such patients).We also do not know how clinic and patient characteristics will affect the net cost and cost-effectiveness of the intervention. Most of the changes introduced in the RapIT intervention entailed only adjustments in schedules and staff time, and we speculate that these will not result in a major net change to service delivery costs. The POC instruments used in the trial require an up-front investment, but it may be possible to initiate ART in a single visit without any POC instruments if there is no CD4 count threshold for initiation, patients with TB symptoms are identified and managed separately, and ARV regimen adjustments are routinely made at the first refill visit, rather than before initiation. Costs saved by patients, who must make just one clinic visit rather than four or five, should also be taken into account.The RapIT intervention as designed and implemented showed clinically meaningful improvements in ART uptake and viral suppression, providing “proof of principle” for a single-visit treatment initiation algorithm. Follow-on studies are needed to evaluate effectiveness and cost-effectiveness in routine practice in a variety of settings, and variations on the algorithm could also be considered. The RapIT trial has demonstrated that accelerating ART initiation can be effective and feasible in this setting and appeared acceptable to patients to whom it was offered; the next challenge will be adapting it to the range of settings and conditions found in clinics throughout Africa.Supporting InformationS1 TableStudy outcomes adjusted for baseline CD4 count, age, and sex.(DOCX)Click here for additional data file.S2 TableCrude patient-level predictors of treatment uptake, viral suppression, and retention in care.(DOCX)Click here for additional data file.S3 TableStudy outcomes stratified by immediate versus delayed initiation (rapid arm patients initiating ≤90 d only).(DOCX)Click here for additional data file.S4 TableAbsolute and relative effect measure modification of primary outcome (initiated ≤90 d and suppressed by 10 mo).(DOCX)Click here for additional data file.S1 TextResearch protocol.(PDF)Click here for additional data file.S2 TextCONSORT statement.(PDF)Click here for additional data file.AbbreviationsALTalanine aminotransferaseaRRadjusted risk ratioARTantiretroviral therapyARVantiretroviralIQRinterquartile rangeCIconfidence intervalHRhazard ratioPHCprimary health clinicPOCpoint-of-careRapITRapid Initiation of TreatmentRDrisk differenceRRrelative riskTBtuberculosisReferences1\nSiednerMJ, NgCK, Bassett IV, KatzIT, BangsbergDR, TsaiAC. 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Trop Med Int Heal. 2011; 16:1384–1391. 10.1111/j.1365-3156.2011.02842.x\n14\nGousN, ScottL, PotgieterJ, NtabeniL, EnslinS, NewmanR, et al\nFeasibility of performing multiple point of care testing for HIV anti-retroviral treatment initiation and monitoring from multiple or single fingersticks. PLoS ONE. 2013; 8: e85265\n10.1371/journal.pone.0085265\n2437687315\nJani IV, SitoeNE, ChongoPL, AlfaiER, QuevedoJI, TobaiwaO, et al\nAccurate CD4 T-cell enumeration and antiretroviral drug toxicity monitoring in primary healthcare clinics using point-of-care testing. AIDS. 2011; 25:807–812. 10.1097/QAD.0b013e328344f424\n2137853516\nMnyaniCN, McIntyreJA, MyerL. The reliability of point-of-care CD4 testing in identifying HIV-infected pregnant women eligible for antiretroviral therapy. J Acquir Immune Defic Syndr. 2012; 60: 260–264. 10.1097/QAI.0b013e318256b651\n2248758917\nWadeD, DaneauG, AboudS, VercauterenGH, UrassaWSK, KestensL, et al\nWHO multicenter evaluation of FACSCount CD4 and Pima CD4 t-cell count systems\u202f: instrument performance and misclassification of HIV-infected patients. J Acquir Immune Defic Syndr. 2014; 66:98–107.18\nScottLE, CampbellJ, WestermanL, KestensL, VojnovL, KohastsuL, et al\nA meta-analysis of the performance of the Pima CD4 for point of care testing. BMC Med. 2015; 13:168\n10.1186/s12916-015-0396-2\n2620886719\nMeyer-RathG, SchnippelK, LongL, MacleodW, SanneI, StevensW, et al\nThe impact and cost of scaling up GeneXpert MTB/RIF in South Africa. PLoS ONE. 2012; 7:e36966\n10.1371/journal.pone.0036966. 10.1371/journal.pone.0036966\n2269356120\nUNITAID. Tuberculosis diagnostics technology and market landscape\nGeneva: UNITAID; 2013.21\nFoxMP, MaskewM, MacPhailA. Cohort profile: the Themba Lethu Clinical Cohort, Johannesburg, South Africa. International Journal of Epidemiology. 2013; 42:430–439. 10.1093/ije/dys029\n2243486022\nHoffmannCJ, LewisJJ, DowdyDW, FieldingKL, GrantAD, MartinsonN, et al\nMortality associated with delays between clinic entry and ART initiation in resource-limited settings: results of a transition-state model. J Acquir Immune Defic Syndr. 2013; 63:105–111. 10.1097/QAI.0b013e3182893fb4\n2339245723\nJani IV, SitoeNE, AlfaiER, ChongoPL, QuevedoJI, RochaBM, et al\nEffect of point-of-care CD4 cell count tests on retention of patients and rates of antiretroviral therapy initiation in primary health clinics: An observational cohort study. Lancet. 2011; 378:1572–1579. 10.1016/S0140-6736(11)61052-0\n2195165624\nBurtleD, WelfareW, EldenS, MamvuraC, VandelanotteJ, PetherickE, et al\nIntroduction and evaluation of a “pre-ART care” service in Swaziland: an operational research study. BMJ Open. 2012; 2:e000195\n10.1136/bmjopen-2011-000195\n25\nBlackS, ZulligerR, MyerL, MarcusR, JenekerS, HonsBA, et al\nSafety, feasibility and efficacy of a rapid ART initiation in pregnancy pilot programme in Cape Town, South Africa. S Afr Med J. 2013; 103:557–562. 10.7196/SAMJ.6565\n2388573926\nMfinangaS, ChandaD, KivuyoSL, GuinnessL, BottomleyC, SimmsV, et al\nCryptococcal meningitis screening and community-based early adherence support in people with advanced HIV infection starting antiretroviral therapy in Tanzania and Zambia: an open-label, randomised controlled trial. Lancet. 2015; 385:2173–2182. 10.1016/S0140-6736(15)60164-7\n2576569827\nClouseK, Page-ShippL, DanseyH, MoatlhodiB, ScottL, BassettJ, et al\nImplementation of Xpert MTB/RIF for routine point-of-care diagnosis of tuberculosis at the primary care level. S Afr Med J. 2012; 102:805–807. 10.7196/SAMJ.5851\n23034211', 'title': "Initiating Antiretroviral Therapy for HIV at a Patient's First Clinic Visit: The RapIT Randomized Controlled Trial.", 'date': '2016-05-11'}}
| 0.75
|
Public Health, Epidemiology & Health Systems
|
23
|
Is the rate of hypotension higher, lower, or the same when comparing capnography to standard monitoring?
|
no difference
|
moderate
|
no
|
['27006732']
| 28,334,427
| 2,017
|
{'27006732': {'article_id': '27006732', 'content': 'This prospective, randomized trial was undertaken to evaluate the utility of adding end-tidal capnometry (ETC) to pulse oximetry (PO) in patients undergoing procedural sedation and analgesia (PSA) in the emergency department (ED).\nThe patients were randomized to monitoring with or without ETC in addition to the current standard of care. Primary endpoints included respiratory adverse events, with secondary endpoints of level of sedation, hypotension, other PSA-related adverse events and patient satisfaction.\nOf 986 patients, 501 were randomized to usual care and 485 to additional ETC monitoring. In this series, 48% of the patients were female, with a mean age of 46 years. Orthopedic manipulations (71%), cardioversion (12%) and abscess incision and drainage (12%) were the most common procedures, and propofol and fentanyl were the sedative/analgesic combination used for most patients. There was no difference in patients experiencing de-saturation (SaO2<90%) between the two groups; however, patients in the ETC group were more likely to require airway repositioning (12.9% vs. 9.3%, P=0.003). Hypotension (SBP<100 mmHg or <85 mmHg if baseline <100 mmHg) was observed in 16 (3.3%) patients in the ETC group and 7 (1.4%) in the control group (P=0.048).\nThe addition of ETC does not appear to change any clinically significant outcomes. We found an increased incidence of the use of airway repositioning maneuvers and hypotension in cases where ETC was used. We do not believe that ETC should be recommended as a standard of care for the monitoring of patients undergoing PSA.', 'title': 'End-tidal capnometry during emergency department procedural sedation and analgesia: a randomized, controlled study.', 'date': '2016-03-24'}}
| 0
|
Surgery
|
24
|
Is the risk of HIV transmission at 12 months higher, lower, or the same when comparing triple antiretroviral prophylaxis during pregnancy and breastfeeding to short antiretroviral prophylaxis?
|
lower
|
low
|
no
|
['21237718']
| 25,280,769
| 2,014
|
{'21237718': {'article_id': '21237718', 'content': "Breastfeeding is essential for child health and development in low-resource settings but carries a significant risk of transmission of HIV-1, especially in late stages of maternal disease. We aimed to assess the efficacy and safety of triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis in pregnant women infected with HIV.\nPregnant women with WHO stage 1, 2, or 3 HIV-1 infection who had CD4 cell counts of 200-500 cells per μL were enrolled at five study sites in Burkina Faso, Kenya, and South Africa to start study treatment at 28-36 weeks' gestation. Women were randomly assigned (1:1) by a computer generated random sequence to either triple antiretroviral prophylaxis (a combination of 300 mg zidovudine, 150 mg lamivudine, and 400 mg lopinavir plus 100 mg ritonavir twice daily until cessation of breastfeeding to a maximum of 6·5 months post partum) or zidovudine and single-dose nevirapine (300 mg zidovudine twice daily until delivery and a dose of 600 mg zidovudine plus 200 mg nevirapine at the onset of labour and, after a protocol amendment in December, 2006, 1 week post-partum zidovudine 300 mg twice daily and lamivudine 150 mg twice daily). All infants received a 0·6 mL dose of nevirapine at birth and, from December, 2006, 4 mg/kg twice daily of zidovudine for 1 week after birth. Patients and investigators were not masked to treatment. The primary endpoints were HIV-free infant survival at 6 weeks and 12 months; HIV-free survival at 12 months in infants who were ever breastfed; AIDS-free survival in mothers at 18 months; and serious adverse events in mothers and babies. Analysis was by intention to treat. This trial is registered with Current Controlled Trials, ISRCTN71468401.\nFrom June, 2005, to August, 2008, 882 women were enrolled, 824 of whom were randomised and gave birth to 805 singleton or first, liveborn infants. The cumulative rate of HIV transmission at 6 weeks was 3·3% (95% CI 1·9-5·6%) in the triple antiretroviral group compared with 5·0% (3·3-7·7%) in the zidovudine and single-dose nevirapine group, and at 12 months was 5·4% (3·6-8·1%) in the triple antiretroviral group compared with 9·5% (7·0-12·9%) in the zidovudine and single-dose nevirapine group (p=0·029). The cumulative rate of HIV transmission or death at 12 months was 10·2% (95% CI 7·6-13·6%) in the triple antiretroviral group compared with 16·0% (12·7-20·0%) in the zidovudine and single-dose nevirapine group (p=0·017). In infants whose mothers declared they intended to breastfeed, the cumulative rate of HIV transmission at 12 months was 5·6% (95% CI 3·4-8·9%) in the triple antiretroviral group compared with 10·7% (7·6-14·8%) in the zidovudine and single-dose nevirapine group (p=0·02). AIDS-free survival in mothers at 18 months will be reported in a different publication. The incidence of laboratory and clinical serious adverse events in both mothers and their babies was similar between groups.\nTriple antiretroviral prophylaxis during pregnancy and breastfeeding is safe and reduces the risk of HIV transmission to infants. Revised WHO guidelines now recommend antiretroviral prophylaxis (either to the mother or to the baby) during breastfeeding if the mother is not already receiving antiretroviral treatment for her own health.\nAgence nationale de recherches sur le sida et les hépatites virales, Department for International Development, European and Developing Countries Clinical Trials Partnership, Thrasher Research Fund, Belgian Directorate General for International Cooperation, Centers for Disease Control and Prevention, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and UNDP/UNFPA/World Bank/WHO Special Programme of Research, Development and Research Training in Human Reproduction.", 'title': 'Triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis during pregnancy and breastfeeding for prevention of mother-to-child transmission of HIV-1 (Kesho Bora study): a randomised controlled trial.', 'date': '2011-01-18'}}
| 1
|
Obstetrics & Gynecology
|
25
|
Is the risk of infant HIV infection higher, lower, or the same when comparing zidovudine, lamivudine, and lopinavir/ritonavir to zidovudine, lamivudine, and abacavir from 26‐34 weeks gestation through six months of breastfeeding?
|
no difference
| null |
no
|
['20554983']
| 25,280,769
| 2,014
|
{'20554983': {'article_id': '20554983', 'content': "The most effective highly active antiretroviral therapy (HAART) to prevent mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) in pregnancy and its efficacy during breast-feeding are unknown.\nWe randomly assigned 560 HIV-1-infected pregnant women (CD4+ count, > or = 200 cells per cubic millimeter) to receive coformulated abacavir, zidovudine, and lamivudine (the nucleoside reverse-transcriptase inhibitor [NRTI] group) or lopinavir-ritonavir plus zidovudine-lamivudine (the protease-inhibitor group) from 26 to 34 weeks' gestation through planned weaning by 6 months post partum. A total of 170 women with CD4+ counts of less than 200 cells per cubic millimeter received nevirapine plus zidovudine-lamivudine (the observational group). Infants received single-dose nevirapine and 4 weeks of zidovudine.\nThe rate of virologic suppression to less than 400 copies per milliliter was high and did not differ significantly among the three groups at delivery (96% in the NRTI group, 93% in the protease-inhibitor group, and 94% in the observational group) or throughout the breast-feeding period (92% in the NRTI group, 93% in the protease-inhibitor group, and 95% in the observational group). By 6 months of age, 8 of 709 live-born infants (1.1%) were infected (95% confidence interval [CI], 0.5 to 2.2): 6 were infected in utero (4 in the NRTI group, 1 in the protease-inhibitor group, and 1 in the observational group), and 2 were infected during the breast-feeding period (in the NRTI group). Treatment-limiting adverse events occurred in 2% of women in the NRTI group, 2% of women in the protease-inhibitor group, and 11% of women in the observational group.\nAll regimens of HAART from pregnancy through 6 months post partum resulted in high rates of virologic suppression, with an overall rate of mother-to-child transmission of 1.1%. (ClinicalTrials.gov number, NCT00270296.)", 'title': 'Antiretroviral regimens in pregnancy and breast-feeding in Botswana.', 'date': '2010-06-18'}}
| 1
|
Pediatrics & Neonatology
|
26
|
Is the risk of infant mortality after 12 months higher, lower, or the same when comparing six weeks of infant nevirapine to single dose infant nevirapine?
|
lower
|
moderate
|
no
|
['21330912']
| 25,280,769
| 2,014
|
{'21330912': {'article_id': '21330912', 'content': 'We previously reported combined analysis of 6-week and 6-month endpoints of three randomized controlled trials [Six Week Extended Dose Nevirapine (SWEN) trials] that compared extended-dose nevirapine through 6 weeks of age to single-dose nevirapine to prevent HIV transmission via breastfeeding and mortality. We now present endpoints through 12 months of age.\nInfants in Ethiopia, India, and Uganda born to HIV-infected women who chose to breastfeed were randomized to receive single-dose or extended-dose nevirapine.\nHIV transmission, mortality, HIV transmission or death.\nPrimary analysis included 987 and 903 infants in the single-dose and the extended-dose arms, respectively. HIV transmission was 8.9% in the extended-dose group compared to 10.4% in the single-dose group, but the difference was not significant [risk ratio: 0.87, 95% confidence interval (CI): 0.65-1.15]. Cumulative mortality at 12 months was half in the extended-dose group compared to the single-dose group (risk ratio: 0.53, 95% CI: 0.32-0.85). The impact of extended-dose nevirapine was highest in infants of mothers with CD4 cell count more than 350 cells/μl. Risk ratios for death (risk ratio: 0.38, 95% CI: 0.17-0.84) and HIV transmission or death (risk ratio: 0.54, 95% CI: 0.35-0.85) were statistically significant for the CD4 cell counts more than 350 cells/μl category, whereas none of the risk ratios were significant for the CD4 cell counts 200 cells/μl or less and CD4 cell counts 201-350 cells/μl categories.\nFor populations with limited access to HAART, our results provide evidence for the use of extended-dose regimens to prevent infant deaths and increase HIV-free survival in infants of HIV-infected breastfeeding women, particularly for infants of women with CD4 cell counts more than 350 cells/μl.', 'title': 'Twelve-month follow-up of Six Week Extended Dose Nevirapine randomized controlled trials: differential impact of extended-dose nevirapine on mother-to-child transmission and infant death by maternal CD4 cell count.', 'date': '2011-02-19'}}
| 1
|
Pediatrics & Neonatology
|
33
|
Is the risk of infant HIV infection or death after 12 months higher, lower, or the same when comparing six weeks of infant nevirapine to single dose infant nevirapine?
|
no difference
|
moderate
|
no
|
['21330912']
| 25,280,769
| 2,014
|
{'21330912': {'article_id': '21330912', 'content': 'We previously reported combined analysis of 6-week and 6-month endpoints of three randomized controlled trials [Six Week Extended Dose Nevirapine (SWEN) trials] that compared extended-dose nevirapine through 6 weeks of age to single-dose nevirapine to prevent HIV transmission via breastfeeding and mortality. We now present endpoints through 12 months of age.\nInfants in Ethiopia, India, and Uganda born to HIV-infected women who chose to breastfeed were randomized to receive single-dose or extended-dose nevirapine.\nHIV transmission, mortality, HIV transmission or death.\nPrimary analysis included 987 and 903 infants in the single-dose and the extended-dose arms, respectively. HIV transmission was 8.9% in the extended-dose group compared to 10.4% in the single-dose group, but the difference was not significant [risk ratio: 0.87, 95% confidence interval (CI): 0.65-1.15]. Cumulative mortality at 12 months was half in the extended-dose group compared to the single-dose group (risk ratio: 0.53, 95% CI: 0.32-0.85). The impact of extended-dose nevirapine was highest in infants of mothers with CD4 cell count more than 350 cells/μl. Risk ratios for death (risk ratio: 0.38, 95% CI: 0.17-0.84) and HIV transmission or death (risk ratio: 0.54, 95% CI: 0.35-0.85) were statistically significant for the CD4 cell counts more than 350 cells/μl category, whereas none of the risk ratios were significant for the CD4 cell counts 200 cells/μl or less and CD4 cell counts 201-350 cells/μl categories.\nFor populations with limited access to HAART, our results provide evidence for the use of extended-dose regimens to prevent infant deaths and increase HIV-free survival in infants of HIV-infected breastfeeding women, particularly for infants of women with CD4 cell counts more than 350 cells/μl.', 'title': 'Twelve-month follow-up of Six Week Extended Dose Nevirapine randomized controlled trials: differential impact of extended-dose nevirapine on mother-to-child transmission and infant death by maternal CD4 cell count.', 'date': '2011-02-19'}}
| 0
|
Pediatrics & Neonatology
|
34
|
Is the risk of infant HIV infection after 12 months higher, lower, or the same when comparing six weeks of infant nevirapine to single dose infant nevirapine?
|
no difference
|
moderate
|
no
|
['21330912']
| 25,280,769
| 2,014
|
{'21330912': {'article_id': '21330912', 'content': 'We previously reported combined analysis of 6-week and 6-month endpoints of three randomized controlled trials [Six Week Extended Dose Nevirapine (SWEN) trials] that compared extended-dose nevirapine through 6 weeks of age to single-dose nevirapine to prevent HIV transmission via breastfeeding and mortality. We now present endpoints through 12 months of age.\nInfants in Ethiopia, India, and Uganda born to HIV-infected women who chose to breastfeed were randomized to receive single-dose or extended-dose nevirapine.\nHIV transmission, mortality, HIV transmission or death.\nPrimary analysis included 987 and 903 infants in the single-dose and the extended-dose arms, respectively. HIV transmission was 8.9% in the extended-dose group compared to 10.4% in the single-dose group, but the difference was not significant [risk ratio: 0.87, 95% confidence interval (CI): 0.65-1.15]. Cumulative mortality at 12 months was half in the extended-dose group compared to the single-dose group (risk ratio: 0.53, 95% CI: 0.32-0.85). The impact of extended-dose nevirapine was highest in infants of mothers with CD4 cell count more than 350 cells/μl. Risk ratios for death (risk ratio: 0.38, 95% CI: 0.17-0.84) and HIV transmission or death (risk ratio: 0.54, 95% CI: 0.35-0.85) were statistically significant for the CD4 cell counts more than 350 cells/μl category, whereas none of the risk ratios were significant for the CD4 cell counts 200 cells/μl or less and CD4 cell counts 201-350 cells/μl categories.\nFor populations with limited access to HAART, our results provide evidence for the use of extended-dose regimens to prevent infant deaths and increase HIV-free survival in infants of HIV-infected breastfeeding women, particularly for infants of women with CD4 cell counts more than 350 cells/μl.', 'title': 'Twelve-month follow-up of Six Week Extended Dose Nevirapine randomized controlled trials: differential impact of extended-dose nevirapine on mother-to-child transmission and infant death by maternal CD4 cell count.', 'date': '2011-02-19'}}
| 1
|
Pediatrics & Neonatology
|
35
|
Is the risk of HIV transmission at 24 months higher, lower, or the same when comparing nevirapine up to 14 weeks plus one week zidovudine to only single dose nevirapine plus one week zidovudine?
|
lower
|
moderate
|
no
|
['21423025']
| 25,280,769
| 2,014
|
{'21423025': {'article_id': '21423025', 'content': 'This analysis updates and extends efficacy estimates of the PEPI-Malawi trial through age 24 months at study completion in September 2009.\nInfants of breastfeeding HIV-infected women were randomized at birth to the following: (1) single-dose nevirapine (NVP) + 1-week zidovudine (ZDV) (control); (2) control + extended daily NVP (ExtNVP) through 14 weeks; (3) control + extended daily NVP + ZDV (ExtNVP/ZDV) through 14 weeks. We estimated rates of HIV infection, death and HIV infection, or death using Kaplan-Meier analysis.\nThis analysis includes 3126 infants uninfected at birth as follows: 1004 control, 1071 ExtNVP, and 1051 ExtNVP/ZDV. By 9 months, HIV infection rates were 5.0% in ExtNVP, 6.0% in ExtNVP/ZDV, and 11.1% in control (P < 0.001 comparing extended regimens with control). At age 24 months, HIV infection rates had risen to ~11% in the extended arms compared with 15.6% in the controls (P < 0.05). The rates of HIV infection or death were also significantly lower in extended arms. There were no differences in severe adverse events with the exception of higher possibly related events in the ExtNVP/ZDV arm.\nDaily infant antiretroviral prophylaxis reduces postnatal HIV infection by ~70% during the period of prophylaxis. But continued HIV transmission after prophylaxis stops suggests more prolonged infant prophylaxis is needed.', 'title': 'Postexposure prophylaxis of breastfeeding HIV-exposed infants with antiretroviral drugs to age 14 weeks: updated efficacy results of the PEPI-Malawi trial.', 'date': '2011-03-23'}}
| 1
|
Pediatrics & Neonatology
|
36
|
Is the risk of HIV transmission or death at 24 months higher, lower, or the same when comparing nevirapine up to 14 weeks plus one week zidovudine to only single dose nevirapine plus one week zidovudine?
|
lower
|
moderate
|
no
|
['21423025']
| 25,280,769
| 2,014
|
{'21423025': {'article_id': '21423025', 'content': 'This analysis updates and extends efficacy estimates of the PEPI-Malawi trial through age 24 months at study completion in September 2009.\nInfants of breastfeeding HIV-infected women were randomized at birth to the following: (1) single-dose nevirapine (NVP) + 1-week zidovudine (ZDV) (control); (2) control + extended daily NVP (ExtNVP) through 14 weeks; (3) control + extended daily NVP + ZDV (ExtNVP/ZDV) through 14 weeks. We estimated rates of HIV infection, death and HIV infection, or death using Kaplan-Meier analysis.\nThis analysis includes 3126 infants uninfected at birth as follows: 1004 control, 1071 ExtNVP, and 1051 ExtNVP/ZDV. By 9 months, HIV infection rates were 5.0% in ExtNVP, 6.0% in ExtNVP/ZDV, and 11.1% in control (P < 0.001 comparing extended regimens with control). At age 24 months, HIV infection rates had risen to ~11% in the extended arms compared with 15.6% in the controls (P < 0.05). The rates of HIV infection or death were also significantly lower in extended arms. There were no differences in severe adverse events with the exception of higher possibly related events in the ExtNVP/ZDV arm.\nDaily infant antiretroviral prophylaxis reduces postnatal HIV infection by ~70% during the period of prophylaxis. But continued HIV transmission after prophylaxis stops suggests more prolonged infant prophylaxis is needed.', 'title': 'Postexposure prophylaxis of breastfeeding HIV-exposed infants with antiretroviral drugs to age 14 weeks: updated efficacy results of the PEPI-Malawi trial.', 'date': '2011-03-23'}}
| 1
|
Pediatrics & Neonatology
|
37
|
Is the risk of HIV transmission or death at 24 months higher, lower, or the same when comparing nevirapine plus zidovudine with dual prophylaxis up to 14 weeks to only single dose nevirapine plus one week zidovudine?
|
lower
|
moderate
|
no
|
['21423025']
| 25,280,769
| 2,014
|
{'21423025': {'article_id': '21423025', 'content': 'This analysis updates and extends efficacy estimates of the PEPI-Malawi trial through age 24 months at study completion in September 2009.\nInfants of breastfeeding HIV-infected women were randomized at birth to the following: (1) single-dose nevirapine (NVP) + 1-week zidovudine (ZDV) (control); (2) control + extended daily NVP (ExtNVP) through 14 weeks; (3) control + extended daily NVP + ZDV (ExtNVP/ZDV) through 14 weeks. We estimated rates of HIV infection, death and HIV infection, or death using Kaplan-Meier analysis.\nThis analysis includes 3126 infants uninfected at birth as follows: 1004 control, 1071 ExtNVP, and 1051 ExtNVP/ZDV. By 9 months, HIV infection rates were 5.0% in ExtNVP, 6.0% in ExtNVP/ZDV, and 11.1% in control (P < 0.001 comparing extended regimens with control). At age 24 months, HIV infection rates had risen to ~11% in the extended arms compared with 15.6% in the controls (P < 0.05). The rates of HIV infection or death were also significantly lower in extended arms. There were no differences in severe adverse events with the exception of higher possibly related events in the ExtNVP/ZDV arm.\nDaily infant antiretroviral prophylaxis reduces postnatal HIV infection by ~70% during the period of prophylaxis. But continued HIV transmission after prophylaxis stops suggests more prolonged infant prophylaxis is needed.', 'title': 'Postexposure prophylaxis of breastfeeding HIV-exposed infants with antiretroviral drugs to age 14 weeks: updated efficacy results of the PEPI-Malawi trial.', 'date': '2011-03-23'}}
| 1
|
Pediatrics & Neonatology
|
38
|
Is the risk of HIV transmission at 24 months higher, lower, or the same when comparing nevirapine plus zidovudine with dual prophylaxis up to 14 weeks to only single dose nevirapine plus one week zidovudine?
|
lower
|
moderate
|
no
|
['21423025']
| 25,280,769
| 2,014
|
{'21423025': {'article_id': '21423025', 'content': 'This analysis updates and extends efficacy estimates of the PEPI-Malawi trial through age 24 months at study completion in September 2009.\nInfants of breastfeeding HIV-infected women were randomized at birth to the following: (1) single-dose nevirapine (NVP) + 1-week zidovudine (ZDV) (control); (2) control + extended daily NVP (ExtNVP) through 14 weeks; (3) control + extended daily NVP + ZDV (ExtNVP/ZDV) through 14 weeks. We estimated rates of HIV infection, death and HIV infection, or death using Kaplan-Meier analysis.\nThis analysis includes 3126 infants uninfected at birth as follows: 1004 control, 1071 ExtNVP, and 1051 ExtNVP/ZDV. By 9 months, HIV infection rates were 5.0% in ExtNVP, 6.0% in ExtNVP/ZDV, and 11.1% in control (P < 0.001 comparing extended regimens with control). At age 24 months, HIV infection rates had risen to ~11% in the extended arms compared with 15.6% in the controls (P < 0.05). The rates of HIV infection or death were also significantly lower in extended arms. There were no differences in severe adverse events with the exception of higher possibly related events in the ExtNVP/ZDV arm.\nDaily infant antiretroviral prophylaxis reduces postnatal HIV infection by ~70% during the period of prophylaxis. But continued HIV transmission after prophylaxis stops suggests more prolonged infant prophylaxis is needed.', 'title': 'Postexposure prophylaxis of breastfeeding HIV-exposed infants with antiretroviral drugs to age 14 weeks: updated efficacy results of the PEPI-Malawi trial.', 'date': '2011-03-23'}}
| 1
|
Obstetrics & Gynecology
|
39
|
Is the risk of HIV infection or death higher, lower, or the same when comparing a maternal extended triple‐drug antiretroviral regimen to no extended postnatal antiretroviral regimen?
|
lower
|
moderate
|
no
|
['20554982']
| 25,280,769
| 2,014
|
{'20554982': {'article_id': '20554982', 'content': 'We evaluated the efficacy of a maternal triple-drug antiretroviral regimen or infant nevirapine prophylaxis for 28 weeks during breast-feeding to reduce postnatal transmission of human immunodeficiency virus type 1 (HIV-1) in Malawi.\nWe randomly assigned 2369 HIV-1-positive, breast-feeding mothers with a CD4+ lymphocyte count of at least 250 cells per cubic millimeter and their infants to receive a maternal antiretroviral regimen, infant nevirapine, or no extended postnatal antiretroviral regimen (control group). All mothers and infants received perinatal prophylaxis with single-dose nevirapine and 1 week of zidovudine plus lamivudine. We used the Kaplan-Meier method to estimate the cumulative risk of HIV-1 transmission or death by 28 weeks among infants who were HIV-1-negative 2 weeks after birth. Rates were compared with the use of the log-rank test.\nAmong mother-infant pairs, 5.0% of infants were HIV-1-positive at 2 weeks of life. The estimated risk of HIV-1 transmission between 2 and 28 weeks was higher in the control group (5.7%) than in either the maternal-regimen group (2.9%, P=0.009) or the infant-regimen group (1.7%, P<0.001). The estimated risk of infant HIV-1 infection or death between 2 and 28 weeks was 7.0% in the control group, 4.1% in the maternal-regimen group (P=0.02), and 2.6% in the infant-regimen group (P<0.001). The proportion of women with neutropenia was higher among those receiving the antiretroviral regimen (6.2%) than among those in either the nevirapine group (2.6%) or the control group (2.3%). Among infants receiving nevirapine, 1.9% had a hypersensitivity reaction.\nThe use of either a maternal antiretroviral regimen or infant nevirapine for 28 weeks was effective in reducing HIV-1 transmission during breast-feeding. (ClinicalTrials.gov number, NCT00164736.)', 'title': 'Maternal or infant antiretroviral drugs to reduce HIV-1 transmission.', 'date': '2010-06-18'}}
| 1
|
Obstetrics & Gynecology
|
40
|
Is the risk of HIV infection higher, lower, or the same when comparing a maternal extended triple‐drug antiretroviral regimen to no extended postnatal antiretroviral regimen?
|
lower
|
moderate
|
no
|
['20554982']
| 25,280,769
| 2,014
|
{'20554982': {'article_id': '20554982', 'content': 'We evaluated the efficacy of a maternal triple-drug antiretroviral regimen or infant nevirapine prophylaxis for 28 weeks during breast-feeding to reduce postnatal transmission of human immunodeficiency virus type 1 (HIV-1) in Malawi.\nWe randomly assigned 2369 HIV-1-positive, breast-feeding mothers with a CD4+ lymphocyte count of at least 250 cells per cubic millimeter and their infants to receive a maternal antiretroviral regimen, infant nevirapine, or no extended postnatal antiretroviral regimen (control group). All mothers and infants received perinatal prophylaxis with single-dose nevirapine and 1 week of zidovudine plus lamivudine. We used the Kaplan-Meier method to estimate the cumulative risk of HIV-1 transmission or death by 28 weeks among infants who were HIV-1-negative 2 weeks after birth. Rates were compared with the use of the log-rank test.\nAmong mother-infant pairs, 5.0% of infants were HIV-1-positive at 2 weeks of life. The estimated risk of HIV-1 transmission between 2 and 28 weeks was higher in the control group (5.7%) than in either the maternal-regimen group (2.9%, P=0.009) or the infant-regimen group (1.7%, P<0.001). The estimated risk of infant HIV-1 infection or death between 2 and 28 weeks was 7.0% in the control group, 4.1% in the maternal-regimen group (P=0.02), and 2.6% in the infant-regimen group (P<0.001). The proportion of women with neutropenia was higher among those receiving the antiretroviral regimen (6.2%) than among those in either the nevirapine group (2.6%) or the control group (2.3%). Among infants receiving nevirapine, 1.9% had a hypersensitivity reaction.\nThe use of either a maternal antiretroviral regimen or infant nevirapine for 28 weeks was effective in reducing HIV-1 transmission during breast-feeding. (ClinicalTrials.gov number, NCT00164736.)', 'title': 'Maternal or infant antiretroviral drugs to reduce HIV-1 transmission.', 'date': '2010-06-18'}}
| 1
|
Pediatrics & Neonatology
|
41
|
Is the risk of HIV infection higher, lower, or the same when comparing an extended infant nevirapine regimen to no extended postnatal antiretroviral regimen?
|
lower
|
low
|
no
|
['20554982']
| 25,280,769
| 2,014
|
{'20554982': {'article_id': '20554982', 'content': 'We evaluated the efficacy of a maternal triple-drug antiretroviral regimen or infant nevirapine prophylaxis for 28 weeks during breast-feeding to reduce postnatal transmission of human immunodeficiency virus type 1 (HIV-1) in Malawi.\nWe randomly assigned 2369 HIV-1-positive, breast-feeding mothers with a CD4+ lymphocyte count of at least 250 cells per cubic millimeter and their infants to receive a maternal antiretroviral regimen, infant nevirapine, or no extended postnatal antiretroviral regimen (control group). All mothers and infants received perinatal prophylaxis with single-dose nevirapine and 1 week of zidovudine plus lamivudine. We used the Kaplan-Meier method to estimate the cumulative risk of HIV-1 transmission or death by 28 weeks among infants who were HIV-1-negative 2 weeks after birth. Rates were compared with the use of the log-rank test.\nAmong mother-infant pairs, 5.0% of infants were HIV-1-positive at 2 weeks of life. The estimated risk of HIV-1 transmission between 2 and 28 weeks was higher in the control group (5.7%) than in either the maternal-regimen group (2.9%, P=0.009) or the infant-regimen group (1.7%, P<0.001). The estimated risk of infant HIV-1 infection or death between 2 and 28 weeks was 7.0% in the control group, 4.1% in the maternal-regimen group (P=0.02), and 2.6% in the infant-regimen group (P<0.001). The proportion of women with neutropenia was higher among those receiving the antiretroviral regimen (6.2%) than among those in either the nevirapine group (2.6%) or the control group (2.3%). Among infants receiving nevirapine, 1.9% had a hypersensitivity reaction.\nThe use of either a maternal antiretroviral regimen or infant nevirapine for 28 weeks was effective in reducing HIV-1 transmission during breast-feeding. (ClinicalTrials.gov number, NCT00164736.)', 'title': 'Maternal or infant antiretroviral drugs to reduce HIV-1 transmission.', 'date': '2010-06-18'}}
| 1
|
Pediatrics & Neonatology
|
42
|
Is the risk of HIV infection or death higher, lower, or the same when comparing an extended infant nevirapine regimen to no extended postnatal antiretroviral regimen?
|
lower
|
moderate
|
no
|
['20554982']
| 25,280,769
| 2,014
|
{'20554982': {'article_id': '20554982', 'content': 'We evaluated the efficacy of a maternal triple-drug antiretroviral regimen or infant nevirapine prophylaxis for 28 weeks during breast-feeding to reduce postnatal transmission of human immunodeficiency virus type 1 (HIV-1) in Malawi.\nWe randomly assigned 2369 HIV-1-positive, breast-feeding mothers with a CD4+ lymphocyte count of at least 250 cells per cubic millimeter and their infants to receive a maternal antiretroviral regimen, infant nevirapine, or no extended postnatal antiretroviral regimen (control group). All mothers and infants received perinatal prophylaxis with single-dose nevirapine and 1 week of zidovudine plus lamivudine. We used the Kaplan-Meier method to estimate the cumulative risk of HIV-1 transmission or death by 28 weeks among infants who were HIV-1-negative 2 weeks after birth. Rates were compared with the use of the log-rank test.\nAmong mother-infant pairs, 5.0% of infants were HIV-1-positive at 2 weeks of life. The estimated risk of HIV-1 transmission between 2 and 28 weeks was higher in the control group (5.7%) than in either the maternal-regimen group (2.9%, P=0.009) or the infant-regimen group (1.7%, P<0.001). The estimated risk of infant HIV-1 infection or death between 2 and 28 weeks was 7.0% in the control group, 4.1% in the maternal-regimen group (P=0.02), and 2.6% in the infant-regimen group (P<0.001). The proportion of women with neutropenia was higher among those receiving the antiretroviral regimen (6.2%) than among those in either the nevirapine group (2.6%) or the control group (2.3%). Among infants receiving nevirapine, 1.9% had a hypersensitivity reaction.\nThe use of either a maternal antiretroviral regimen or infant nevirapine for 28 weeks was effective in reducing HIV-1 transmission during breast-feeding. (ClinicalTrials.gov number, NCT00164736.)', 'title': 'Maternal or infant antiretroviral drugs to reduce HIV-1 transmission.', 'date': '2010-06-18'}}
| 1
|
Pediatrics & Neonatology
|
43
|
Is the risk of HIV infection higher, lower, or the same when comparing an extended infant nevirapine regimen to a maternal extended triple‐drug antiretroviral regimen?
|
no difference
|
moderate
|
no
|
['20554982']
| 25,280,769
| 2,014
|
{'20554982': {'article_id': '20554982', 'content': 'We evaluated the efficacy of a maternal triple-drug antiretroviral regimen or infant nevirapine prophylaxis for 28 weeks during breast-feeding to reduce postnatal transmission of human immunodeficiency virus type 1 (HIV-1) in Malawi.\nWe randomly assigned 2369 HIV-1-positive, breast-feeding mothers with a CD4+ lymphocyte count of at least 250 cells per cubic millimeter and their infants to receive a maternal antiretroviral regimen, infant nevirapine, or no extended postnatal antiretroviral regimen (control group). All mothers and infants received perinatal prophylaxis with single-dose nevirapine and 1 week of zidovudine plus lamivudine. We used the Kaplan-Meier method to estimate the cumulative risk of HIV-1 transmission or death by 28 weeks among infants who were HIV-1-negative 2 weeks after birth. Rates were compared with the use of the log-rank test.\nAmong mother-infant pairs, 5.0% of infants were HIV-1-positive at 2 weeks of life. The estimated risk of HIV-1 transmission between 2 and 28 weeks was higher in the control group (5.7%) than in either the maternal-regimen group (2.9%, P=0.009) or the infant-regimen group (1.7%, P<0.001). The estimated risk of infant HIV-1 infection or death between 2 and 28 weeks was 7.0% in the control group, 4.1% in the maternal-regimen group (P=0.02), and 2.6% in the infant-regimen group (P<0.001). The proportion of women with neutropenia was higher among those receiving the antiretroviral regimen (6.2%) than among those in either the nevirapine group (2.6%) or the control group (2.3%). Among infants receiving nevirapine, 1.9% had a hypersensitivity reaction.\nThe use of either a maternal antiretroviral regimen or infant nevirapine for 28 weeks was effective in reducing HIV-1 transmission during breast-feeding. (ClinicalTrials.gov number, NCT00164736.)', 'title': 'Maternal or infant antiretroviral drugs to reduce HIV-1 transmission.', 'date': '2010-06-18'}}
| 0
|
Pediatrics & Neonatology
|
44
|
Is the risk of HIV infection or death higher, lower, or the same when comparing an extended infant nevirapine regimen to a maternal extended triple‐drug antiretroviral regimen?
|
no difference
|
moderate
|
no
|
['20554982']
| 25,280,769
| 2,014
|
{'20554982': {'article_id': '20554982', 'content': 'We evaluated the efficacy of a maternal triple-drug antiretroviral regimen or infant nevirapine prophylaxis for 28 weeks during breast-feeding to reduce postnatal transmission of human immunodeficiency virus type 1 (HIV-1) in Malawi.\nWe randomly assigned 2369 HIV-1-positive, breast-feeding mothers with a CD4+ lymphocyte count of at least 250 cells per cubic millimeter and their infants to receive a maternal antiretroviral regimen, infant nevirapine, or no extended postnatal antiretroviral regimen (control group). All mothers and infants received perinatal prophylaxis with single-dose nevirapine and 1 week of zidovudine plus lamivudine. We used the Kaplan-Meier method to estimate the cumulative risk of HIV-1 transmission or death by 28 weeks among infants who were HIV-1-negative 2 weeks after birth. Rates were compared with the use of the log-rank test.\nAmong mother-infant pairs, 5.0% of infants were HIV-1-positive at 2 weeks of life. The estimated risk of HIV-1 transmission between 2 and 28 weeks was higher in the control group (5.7%) than in either the maternal-regimen group (2.9%, P=0.009) or the infant-regimen group (1.7%, P<0.001). The estimated risk of infant HIV-1 infection or death between 2 and 28 weeks was 7.0% in the control group, 4.1% in the maternal-regimen group (P=0.02), and 2.6% in the infant-regimen group (P<0.001). The proportion of women with neutropenia was higher among those receiving the antiretroviral regimen (6.2%) than among those in either the nevirapine group (2.6%) or the control group (2.3%). Among infants receiving nevirapine, 1.9% had a hypersensitivity reaction.\nThe use of either a maternal antiretroviral regimen or infant nevirapine for 28 weeks was effective in reducing HIV-1 transmission during breast-feeding. (ClinicalTrials.gov number, NCT00164736.)', 'title': 'Maternal or infant antiretroviral drugs to reduce HIV-1 transmission.', 'date': '2010-06-18'}}
| 0
|
Pediatrics & Neonatology
|
27
|
Is fatigue severity higher, lower, or the same when comparing doxepin to placebo?
|
insufficient data
|
low
|
no
|
['23561946']
| 26,447,539
| 2,015
|
{'23561946': {'article_id': '23561946', 'content': "Although a variety of pharmacologic and non-pharmacologic treatments are effective for insomnia in the general population, insomnia in Parkinson's disease differs in important ways and may need different treatments. No studies have conclusively demonstrated effective insomnia treatments in Parkinson's disease.\nWe conducted a three-arm six-week randomized pilot study assessing non-pharmacologic treatment (cognitive behavioural therapy with bright light therapy) or doxepin (10 mg daily), compared to an inactive placebo in Parkinson's patients with insomnia. Sleep outcomes included insomnia scales, clinical global impression, sleep diaries and actigraphy. Secondary outcomes included motor severity, fatigue, depression and quality of life.\n18 patients were randomized, 6 to each group. Compared to placebo, doxepin improved the Insomnia Severity Index (-9 ± 5.4 vs. -2 ± 3.9, p = 0.03), the SCOPA-night score (-5.2 ± 1.5 vs. -2.3 ± 2.8, p = 0.049), the Pittsburgh Sleep Quality Index-sleep disturbances subscale (-0.5 ± 0.5 vs 0.2 ± 0.4, p = 0.02), and both patient and examiner-rated clinical global impression of change (1.7 ± 0.8 vs. 0.5 ± 0.8, p = 0.03 and 1.4 ± 0.5 vs. 0.3 ± 0.5, p = 0.003). On secondary outcomes doxepin reduced the fatigue severity scale (p = 0.02) and improved scores on the Montreal Cognitive Assessment (p = 0.007). Non-pharmacological treatment reduced the Insomnia Severity Index (-7.8 ± 3.8 vs. -2.0 ± 3.9, p = 0.03), and the examiner-reported clinical global impression of change (p = 0.006), but was associated with decline in Parkinson Disease Questionnaire-39. There were no changes in other primary and secondary outcomes, including actigraphy outcomes. Adverse events were comparable in all groups.\nDoxepin and non-pharmacologic treatment substantially improved insomnia in Parkinson's disease. These potential benefits must be replicated in a full confirmatory randomized controlled trial.", 'title': "Doxepin and cognitive behavioural therapy for insomnia in patients with Parkinson's disease -- a randomized study.", 'date': '2013-04-09'}}
| 0
|
Psychiatry & Neurology
|
28
|
Is the progression of physical aspects of fatigue higher, lower, or the same when comparing rasagiline to placebo?
|
lower
|
high
|
no
|
['21482191']
| 26,447,539
| 2,015
|
{'21482191': {'article_id': '21482191', 'content': "The ADAGIO study investigated whether rasagiline has disease-modifying effects in Parkinson's disease. Rasagiline 1 mg per day, but not 2 mg per day, was shown to be efficacious in the primary analysis. Here, we report additional secondary and post-hoc analyses of the ADAGIO study.\nADAGIO was a placebo-controlled, double-blind, multicentre, delayed-start study, in which 1176 patients with untreated early Parkinson's disease were randomly assigned to receive rasagiline 1 mg or 2 mg per day for 72 weeks (early-start groups) or placebo for 36 weeks followed by rasagiline 1 mg or 2 mg per day for 36 weeks (delayed-start groups). We assessed the need for additional antiparkinsonian therapy and changes in non-motor experiences of daily living and fatigue scales (prespecified outcomes) and changes in unified Parkinson's disease rating scale (UPDRS) scores and subscores in placebo and active groups (post-hoc outcomes). The ADAGIO study is registered with ClinicalTrials.gov, number NCT00256204.\nThe need for additional antiparkinsonian therapy was reduced with rasagiline 1 mg (25 of 288 [9%] patients) and 2 mg (26 of 293 [9%]) versus placebo (108 of 593 [18%]; odds ratio for 1 mg rasagiline vs placebo 0·41, 95% CI 0·25-0·65, p=0·0002; 2 mg rasagiline vs placebo 0·41, 0·26-0·64, p=0·0001). At week 36, both doses significantly improved UPDRS motor subscores compared with placebo (1 mg rasagiline mean difference -1·88 [SE 0·35]; 2 mg rasagiline -2·18 [0·35]; both p<0·0001) and activities of daily living subscores (ADL; 1 mg rasagiline -0·86 [0·18]; 2 mg rasagiline -0·88 [0·18]; both p<0·0001), and 1 mg rasagiline significantly improved UPDRS mentation subscore (-0·22 [0·08]; p=0·004). At week 72, the only significant difference between early-start and delayed-start groups was for ADL subscore with the 1 mg dose (-0·62 [0·29]; p=0·035). When assessed for the effect on non-motor symptoms at week 36, both doses showed benefits on the Parkinson fatigue scale versus placebo (1 mg rasagiline mean difference -0·14 [SE 0·05], p=0·0032; 2 mg rasagiline -0·19 [0·05], p<0·0001), and the 1 mg dose showed benefits on the scale for non-motor experiences of daily living compared with placebo (mean difference -0·33 [0·17]; p=0·049). The rate of progression of total UPDRS score for patients in the placebo group was 4·3 points [SE 0·3] over 36 weeks, with extrapolation to about 6 units per year. In the placebo group, patients with the lowest quartile of baseline UPDRS scores (≤14; n=160) progressed more slowly than did those with highest scores (>25·5; n=145; mean difference -3·46 [SE 0·77]; p<0·0001).\nThese findings show that rasagiline delayed the need for symptomatic antiparkinsonian drugs and emphasise the contribution of the UPDRS ADL in the response of the rasagiline 1 mg per day early-start versus delayed-start group. The rate of UPDRS deterioration was less than was anticipated from previous studies and correlated with baseline severity. Understanding of the pattern of UPDRS deterioration is essential to assess disease modification.\nTeva Pharmaceutical Industries and H Lundbeck A/S.", 'title': "A double-blind, delayed-start trial of rasagiline in Parkinson's disease (the ADAGIO study): prespecified and post-hoc analyses of the need for additional therapies, changes in UPDRS scores, and non-motor outcomes.", 'date': '2011-04-13'}}
| 1
|
Psychiatry & Neurology
|
29
|
Is subjective fatigue higher, lower, or the same when comparing modafinil to placebo?
|
no difference
| null |
no
|
['19620846', '16291885']
| 26,447,539
| 2,015
|
{'19620846': {'article_id': '19620846', 'content': 'Fatigue is a major nonmotor symptom in Parkinson disease(PD). It is associated with reduced activity and lower quality of life.\nTo determine if modafinil improves subjective fatigue and physical fatigability in PD.\nNineteen PD patients who reported significant fatigue in the Multidimensional Fatigue Inventory (MFI) participated in this 8-week study. Subjects took their regular medications and were randomly assigned to the treatment group (9 subjects, modafinil 100-mg capsule BID) or placebo group (10 subjects). We used the MFI to measure subjective fatigue and used finger tapping and intermittent force generation to evaluate physical fatigability. Subjects also completed the Epworth Sleepiness Scale (ESS) and the Center of Epidemiological Study-Depression Scale.\nThere were no significant differences at baseline and at 1 month in finger tapping and ESS between the modafinil and placebo groups. At 2 months, the modafinil group had a higher tapping frequency (P<0.05), shorter dwell time (P<0.05), and less fatigability in finger tapping and tended to have lower ESS scores (P<0.12) than the placebo group. However, there was no difference between groups over time for any dimension of the MFI .\nThis small study demonstrated that although modafinil may be effective in reducing physical fatigability in PD, it did not improve fatigue symptoms.', 'title': 'Using modafinil to treat fatigue in Parkinson disease: a double-blind, placebo-controlled pilot study.', 'date': '2009-07-22'}, '16291885': {'article_id': '16291885', 'content': "Excessive daytime somnolence (EDS) commonly complicates Parkinson's disease (PD). The aetiology of EDS is probably multifactorial but is probably exacerbated by dopaminergic medications. Modafinil is a wake-promoting agent approved for use in narcolepsy, but it is often used to treat a variety of somnolent conditions.\nA double blind, placebo controlled parallel design trial was conducted to assess the efficacy of modafinil (200-400 mg/day) for the treatment of EDS in PD. The primary efficacy measure was the Epworth Sleepiness (ES) scale score. Secondary efficacy points included the Unified Parkinson's Disease Rating Scale (UPDRS), the Fatigue Severity Scale, the Hamilton Depression Scale, and the multiple sleep latency test (MSLT).\nOf a total of 40 subjects (29 men, mean (SD) age 64.8 (11.3) years), randomised to modafinil or placebo, 37 completed the study. Modafinil failed to significantly improve ES scores compared with placebo (2.7 v 1.5 points improvement, respectively, p = 0.28). MSLT failed to improve with modafinil relative to placebo (-0.16 v -0.70, respectively, p = 0.14). UPDRS, global impressions, Fatigue Severity Scale, and Hamilton Depression Scale scores were unchanged. Adverse events were minimal.\nModafinil failed to significantly improve EDS in PD compared with placebo. The drug did not alter motor symptoms in PD and was well tolerated.", 'title': "Modafinil for daytime somnolence in Parkinson's disease: double blind, placebo controlled parallel trial.", 'date': '2005-11-18'}}
| 1
|
Psychiatry & Neurology
|
30
|
Is fatigue severity higher, lower, or the same when comparing exercise to usual care?
|
no difference
|
low
|
no
|
['22257506', '21953509']
| 26,447,539
| 2,015
|
{'22257506': {'article_id': '22257506', 'content': "To investigate the feasibility and effectiveness of six weeks of home-based treadmill training in people with mild Parkinson's disease.\nPilot randomized controlled trial of a six-week intervention followed by a further six weeks follow-up.\nHome-based treadmill training with outcome measures taken at a hospital clinic.\nTwenty cognitively intact participants with mild Parkinson's disease and gait disturbance. Two participants from the treadmill training group and one from the control group dropped out.\nThe treadmill training group undertook a semi-supervised home-based programme of treadmill walking for 20-40 minutes, four times a week for six weeks. The control group received usual care.\nThe feasibility of the intervention was assessed by recording exercise adherence and acceptability, exercise intensity, fatigue, muscle soreness and adverse events. The primary outcome measure of efficacy was walking capacity (6-minute walk test distance).\nHome-based treadmill training was feasible, acceptable and safe with participants completing 78% (SD 36) of the prescribed training sessions. The treadmill training group did not improve their walking capacity compared to the control group. The treadmill training group showed a greater improvement than the control group in fatigue at post test (P = 0.04) and in quality of life at six weeks follow-up testing (P = 0.02).\nSemi-supervised home-based treadmill training is a feasible and safe form of exercise for cognitively intact people with mild Parkinson's disease. Further investigation regarding the effectiveness of home-based treadmill training is warranted.", 'title': "Home-based treadmill training for individuals with Parkinson's disease: a randomized controlled pilot trial.", 'date': '2012-01-20'}, '21953509': {'article_id': '21953509', 'content': "Fatigue is one of the most disabling non-motor symptoms for people with Parkinson's disease. Exercise may modify fatigue. This study examines prescribed exercise effects on physical activity levels, well-being, and fatigue in Parkinson's disease.\nIn this single-blinded trial, participants were randomly assigned to either a 12 week community exercise program or control group. Primary outcome measures were fatigue (Fatigue Severity Scale) and physical activity.\nThirty-nine people with Parkinson's disease were included: 20 in exercise and 19 in control. Sixty-five percent of the study group were fatigued (n = 24, mean 4.02, SD 1.48). Increased fatigue was associated with lower mobility and activity (P < .05). Individuals participated in a mean of 15 (SD 10) exercise sessions with no significant change in fatigue, mobility, well-being, or physical activity after exercise (P ≥ .05).\nParticipation in weekly exercise did not improve fatigue in people with Parkinson's Disease.", 'title': "Weekly exercise does not improve fatigue levels in Parkinson's disease.", 'date': '2011-09-29'}}
| 0.5
|
Psychiatry & Neurology
|
31
|
Is subjective fatigue higher, lower, or the same when comparing memantine to placebo?
|
no difference
|
moderate
|
no
|
['21193343']
| 26,447,539
| 2,015
|
{'21193343': {'article_id': '21193343', 'content': 'To perform an exploratory study evaluating memantine for several common non-motor problems in Parkinson\'s disease.\nWe conducted a single center, double-blind, placebo controlled pilot trial of memantine, titrated to 20 mg/day, in PD subjects. Inclusion criteria were intentionally broad and included both fluctuating and non-fluctuating patients. After baseline assessments, subjects (N = 40) were randomized to drug and placebo groups. They received a battery of traditional and non-motor assessments. After a safety call (2 weeks after baseline) they returned for identical assessments at week 8. An 8-week open label extension was started if desired.\nSubject demographics (age 69.1 ± 7.8; 24 males), were similar in the drug and placebo groups. Four dropped from the study while on drug vs. none on placebo. Two of 36 remaining dropped out over the 8-week open label section. Of the 34 who completed the final open label visit, 24 elected to be prescribed memantine after the study. During the controlled trial, there was no significant change in UPDRS section I or II, Epworth sleepiness scale, fatigue severity scale, Hamilton depression scale, Conner adult inventory, PD Quality of Life-39, or clinical global impressions. UPDRS "on" motor scores tended to improved, p = 0.19.\nMemantine was well tolerated in PD; however, specific measures of sleepiness, fatigue, depression, and attention did not significantly improve. The majority of subjects elected to stay on the drug after the open label extension suggesting some unassessed benefit.', 'title': "Memantine for non-motor features of Parkinson's disease: a double-blind placebo controlled exploratory pilot trial.", 'date': '2011-01-05'}}
| 1
|
Psychiatry & Neurology
|
32
|
Is subjective fatigue higher, lower, or the same when comparing methylphenidate to placebo?
|
no difference
|
moderate
|
no
|
['17674415']
| 26,447,539
| 2,015
|
{'17674415': {'article_id': '17674415', 'content': 'Fatigue is a common nonmotor symptom in idiopathic Parkinson disease (IPD) that can prominently affect everyday function. This study was a randomized, double-blind, placebo-controlled trial evaluating methylphenidate for the treatment of fatigue in patients with IPD maintained on their regular medications. Thirty-six patients were randomized to receive either methylphenidate (10 mg three times per day; n = 17) or placebo (n = 19) for 6 weeks. Primary outcomes were the change from baseline on two separate self-report fatigue questionnaires: the Fatigue Severity Scale (FSS) and the Multidimensional Fatigue Inventory (MFI). Secondary outcomes included the Unified Parkinson Disease Rating Scale (UPDRS) motor score and the five individual domains of the MFI. Fourteen patients in the methylphenidate group and 16 patients in the control group remained on the intervention for the entire study period. In the treatment arm, mean FSS score was reduced by 6.5 points (from a baseline of 43.8) and mean MFI score was reduced by 8.4 points (from a baseline of 51.0). Both these reductions were significant (P < 0.04). Smaller reductions in the placebo group were nonsignificant. Mean UPDRS motor score did not change significantly in either group. Analysis of MFI subscores showed a significant reduction in General Fatigue in the methylphenidate group (P < 0.001). Overall, adverse effects of medication were more frequent in the placebo group. In conclusion, methylphenidate was effective in lowering fatigue scores in patients with IPD following a 6-week treatment period.', 'title': 'Methylphenidate improves fatigue scores in Parkinson disease: a randomized controlled trial.', 'date': '2007-08-04'}}
| 0
|
Psychiatry & Neurology
|
45
|
Is the coverage of appropriate treatment from an appropriate provider for any iCCM illness higher, lower, or the same when comparing iCCM to usual facility services plus CCM for malaria?
|
uncertain effect
|
very low
|
yes
|
['26787147']
| 33,565,123
| 2,021
|
{'26787147': {'article_id': '26787147', 'content': "Am J Trop Med HygAm. J. Trop. Med. HygtpmdThe American Journal of Tropical Medicine and Hygiene0002-96371476-1645The American Society of Tropical Medicine and Hygiene26787147477589510.4269/ajtmh.15-0585ArticlesIndependent Evaluation of the Rapid Scale-Up Program to Reduce Under-Five Mortality in Burkina FasoMUNOS AND OTHERSEVALUATION OF RAPID SCALE-UP IN BURKINA FASOMunosMelinda*GuiellaGeorgesRobertonTimothyMaïgaAbdoulayeTiendrebeogoAdamaTamYvonneBryceJenniferBayaBanzaInstitute for International Programs, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; Institut Supérieur des Sciences de la Population, University of Ouagadougou, Ouagadougou, Burkina Faso; Université catholique de Louvain, Louvain-la-Neuve, Belgium; Institut National de la Statistique et de la Démographie, Ouagadougou, Burkina Faso*Address correspondence to Melinda Munos, Institute for International Programs, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205. E-mail: mmunos1@jhu.edu0232016023201694358459511820152992015©The American Society of Tropical Medicine and Hygiene2016This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.We conducted a prospective evaluation of the “Rapid Scale-Up” (RSU) program in Burkina Faso, focusing on the integrated community case management (iCCM) component of the program. We used a quasi-experimental design in which nine RSU districts were compared with seven districts without the program. The evaluation included documentation of program implementation, assessments of implementation and quality of care, baseline and endline coverage surveys, and estimation of mortality changes using the Lives Saved Tool. Although the program trained large numbers of community health workers, there were implementation shortcomings related to training, supervision, and drug stockouts. The quality of care provided to sick children was poor, and utilization of community health workers was low. Changes in intervention coverage were comparable in RSU and comparison areas. Estimated under-five mortality declined by 6.2% (from 110 to 103 deaths per 1,000 live births) in the RSU area and 4.2% (from 114 to 109 per 1,000 live births) in the comparison area. The RSU did not result in coverage increases or mortality reductions in Burkina Faso, but we cannot draw conclusions about the effectiveness of the iCCM strategy, given implementation shortcomings. The evaluation results highlight the need for greater attention to implementation of iCCM programs.IntroductionOver the course of the previous decade, there has been rapid and increasing investment in community case management (CCM) at country and global levels, prompted in part by the issuance of several World Health Organization (WHO)/United Nations Children's Fund (UNICEF) joint statements promoting CCM as a way to reduce mortality in children under five and increase equity.1,2 Donors have funded this scale-up through large initiatives like the Catalytic Initiative to Save a Million Lives3 and the Rapid Access Expansion Program,4 as well as smaller-scale projects, and many countries have now adopted policies allowing community health workers to treat conditions such as malaria, diarrhea, and suspected pneumonia.5From 2008 to 2010, the Catalytic Initiative funded “proof of concept” evaluations in three countries (Burkina Faso, Malawi, and Mozambique; Mozambique was later dropped due to implementation challenges and Ethiopia was added instead) to show that proven interventions could be scaled up rapidly to reduce maternal, newborn, and child mortality. In each country, the Ministry of Health (MoH), together with a UN agency, planned and implemented a “Rapid Scale-Up” (RSU) of high-impact interventions that was evaluated prospectively by Johns Hopkins University together with in-country research partners.Burkina Faso, which is ranked 181st of 187 countries on the Human Development Index,6 has declining but still high levels of mortality. The under-five mortality rate decreased from 186 per 1,000 live births in 2000 to 114 per 1,000 in 20107; the maternal mortality ratio has fallen from 580 per 100,000 live births to 400 per 100,000 in 2013.8 The major causes of under-five deaths in Burkina in 2010 were infectious diseases for which effective treatments exist: malaria (23%), pneumonia (13%), and diarrhea (11%).9 Neonatal causes of death including infections, prematurity, and asphyxia together accounted for another 26% of under-five deaths in 2010.9 With RSU funding from the Catalytic Initiative and technical assistance from UNICEF, the MoH in Burkina Faso implemented a set of community- and facility-based interventions from 2009 to 2013 with the objectives of reducing the under-five mortality rate in the RSU area by 25% relative to baseline and of reaching specified targets for maternal, newborn, and child health (MNCH) intervention coverage in RSU areas (Table 1).10 No targets were established for maternal and neonatal mortality.This article, focusing on the RSU in Burkina Faso, is one of three reports of full prospective evaluations of the implementation of the RSU. The objectives of the evaluation in Burkina Faso were to assess whether the program objectives10 were met and to assess the impact of the RSU strategy relative to ongoing activities in the rest of the country. The evaluation was conducted by an independent team of researchers from Johns Hopkins University as well as the Institut Supérieur des Sciences de la Population at the University of Ouagadougou, with assistance from the National Institute of Statistics and Demography (INSD) in Burkina Faso.MethodsProgram design and setting.Setting.The RSU in Burkina Faso was implemented in nine health districts comprising the Nord and Centre-Nord regions of the country (Figure 1\nFigure 1.Program and comparison areas for the Rapid Scale-Up evaluation.). These regions were selected purposively by the MoH on the basis of high under-five mortality levels, capacity to absorb the project funds, and relative lack of investment by health and development partners.10 The independent evaluation team had no input in the selection of the program regions.Program description.The RSU in Burkina Faso included both community and facility components.10 The main aspect of the community component was the implementation of integrated community case management (iCCM) for diarrhea and malaria in seven program districts, and the implementation of iCCM for pneumonia, diarrhea, and malaria in two program districts. To enable implementation of this component, the MoH had to change its policy to allow community-based case management of diarrhea and malaria and to allow community-based treatment of pneumonia on a pilot basis in two districts.11 Other community-based activities included detection and referral of cases of acute malnutrition and promotion of healthy practices by community-based workers (called “Agents de santé à base communautaire” or ASBCs). A parallel national effort to implement malaria CCM, funded by the Global Fund and managed by Plan Burkina, was not integrated with the RSU.The ASBCs who were responsible for the community-based component of the RSU were part of an existing cadre of lay volunteers in Burkina Faso.11 ASBCs were selected by the community in which they worked (two per village, one male and one female), were often illiterate, and received little to no preservice training upon being selected as ASBCs.12 iCCM-trained nurses at the local health center were responsible for supervising ASBCs in their catchment area; the number of ASBCs in a health facility catchment area in the program districts ranged from 2 to 48.12 The RSU planned to train all ASBCs within the program districts in iCCM and equip them with drug kits.10 Nurses were to supervise ASBCs in iCCM bimonthly (monthly in the areas implementing pneumonia CCM).12 ASBCs providing iCCM services were responsible for visiting the local health facility to restock their drug kits; they then could sell these drugs to community members at a markup to provide a small financial “motivation” for their work.12 Over the course of program implementation, the MoH made a number of policy changes affecting community health. These included the creation of a Directorate of Community Health (later absorbed into the Directorate of Health Promotion) and the development of a comprehensive policy on community health workers.13The facility component of the RSU used project funds to support activities such as integrated management of childhood illness (IMCI); emergency obstetric and newborn care; emergency triage and treatment training for clinicians; and acquisition of commodities, such as delivery tables and bag and mask kits for hospitals, which were expected to reduce maternal, newborn, and under-five mortality.10 Funds were also used to support outreach activities such as child health days and insecticide-treated bednet (ITN) distribution campaigns.10 Because similar activities were ongoing throughout the country, the evaluation focused primarily on the implementation of iCCM, which was the one novel aspect of the project that might be expected to accelerate changes in coverage and mortality in the project districts, relative to other areas of the country.Evaluation design and conceptual framework.Design.Because the program districts were not randomly selected, the evaluation design was restricted to a quasi-experimental approach with both pre-post and difference in differences analyses. The evaluation was guided by the common evaluation framework (Figure 2\nFigure 2.Framework for Rapid Scale-Up evaluation in Burkina Faso.).14 The evaluation timeline is shown in Figure 3\nFigure 3.Evaluation timeline.. The primary outcome for the evaluation was changes in intervention coverage in RSU and comparison areas, measured through baseline and endline coverage surveys. We did not measure mortality directly but rather modeled it based on changes in coverage using the Lives Saved Tool (LiST). We used measures of program strength and quality of care to inform our interpretation of changes in intervention coverage and mortality.District-level documentation, baseline and endline coverage surveys, and mortality estimation with LiST were conducted in both project and comparison areas. The assessments of implementation strength and quality of care for iCCM were conducted only in the program area, primarily because there were no iCCM activities in comparison areas at the time of the assessments. Although comparison areas did have ASBCs, they were primarily responsible for health education and promotion activities, as well as some CCM of malaria through a Global Fund grant. The quality of care assessment for health facilities was funded and implemented separately by WHO with no input from the Independent Evaluation Team, and was conducted in the program area only.Selection of comparison area.A set of seven health districts was matched to the nine intervention districts using the following approach. The Independent Evaluation Team limited the pool of potential comparison districts to 25 districts, on the basis of ecological and cultural similarities to the project area. We defined matching criteria for six demographic and health systems indicators (Supplemental Web Annex 1, Table 1.1). We then identified 61,652 combinations of 7 districts from the pool of 25 candidate districts that satisfied our matching criteria. Of these, one set of seven districts was selected at random.15Data sources.Documentation.The evaluation's documentation system was separate from the program monitoring conducted by the MoH and was based on the abstraction of routine data in each district. Documentation data were collected prospectively from the third quarter of 2010 to the third quarter of 2013, and retrospectively for 2009 and the first and second quarters of 2010. We designed data abstraction forms covering facility and community-based activities, as well as outreach campaigns. Data were abstracted quarterly in each district in the program and comparison areas. Data were entered with CSPro 4.016 (United States Census Bureau, Suitland, MD) and analyzed with SPSS version 17 (SPSS Inc., Chicago, IL).17Qualitative interviews were conducted in each district every 6–12 months to collect data on contextual factors, including natural disasters, new projects, agricultural or economic development, and other factors that could affect MNCH in the districts. Interviews were conducted by two trained interviewers using a short interview guide and were recorded and transcribed. Transcriptions were coded using NVivo software18 and analyzed to look at prespecified themes.We supplemented the collection of documentation data with the use of publicly available annual statistical handbooks produced by government ministries.19–22Implementation strength and quality of care assessments.Because districts had few data on iCCM available at district level, we conducted an assessment of the implementation of iCCM and quality of care provided by ASBCs in the program districts in February–May 2013.12 The methods used were based on an earlier study in Ethiopia,23 except that we provided ASBCs with a fully stocked drug kit to use during observations of sick child consultations, and we conducted in-depth interviews and focus groups with ASBCs and their supervisors as well as community members.Briefly, the Independent Evaluation Team sampled 420 ASBCs across the nine program districts (30 in each of the districts without pneumonia CCM and 105 in each of the districts with pneumonia CCM) using systematic random sampling, of which 385 were found and agreed to participate. Data collectors interviewed each participating ASBC and inspected their drug kit and register. ASBC supervisors at the local health facility were also interviewed. Data collectors then observed up to two sick child consultations (for children aged 2–59 months) for each ASBC and recorded their observations in a questionnaire. They then conducted an exit interview with the caregiver accompanying the child. Finally, the sick children were reexamined by study team members who were experienced IMCI-trained clinicians, and the gold standard diagnoses and treatments for the child were recorded. Data were collected on Samsung Galaxy 2 and 3 smartphones (Samsung Electronics Co., Ltd., Seoul, Seoul Capital Area, South Korea) using Pendragon Forms software (Pendragon Software Corp., Chicago, IL).24 Data analysis was conducted in Stata, version 13 (StataCorp LP, College Station, TX).25An assessment of the quality of care provided to sick children in health facilities was conducted in 2011 in the project districts. This assessment was funded and carried out separately by WHO in collaboration with the Institut pour la Recherche en Sciences de la Santé without involvement from the Independent Evaluation Team. The methods of this assessment were consistent with the WHO guidelines for quality of care assessments at health facilities,26 and the results have been published as a report.27 Briefly, 50 first-level health facilities were sampled across the nine RSU districts. Sampling was stratified by district with the number of facilities sampled in each district proportional to the number of first-level facilities in the district. Within each district, facilities were randomly sampled from a list of all first-level facilities. At each facility, the first five sick children aged less than 5 years presenting for care were enrolled. Data collectors observed the consultations of these children, and then interviewed the caregiver accompanying them. Children were then reexamined by a study team member who was a clinician to obtain the gold standard diagnosis and treatment. Data collectors also recorded information on training and supervision of health workers at the facility and on stocks of drugs and commodities. Results from the study report are presented in this article in support of the evaluation of the RSU program.Coverage surveys.Household coverage surveys were conducted in August 2010 to January 2011 (baseline) and November 2013 to March 2014 (endline) in both program and comparison areas. These surveys collected data on coverage of MNCH interventions, as well as on water, sanitation, and hygiene indicators.For both surveys, two-stage cluster sampling was used, stratified by district. In each district, rural census enumeration areas (EAs) were sampled with probability proportional to size, with data on EA size provided by INSD based on the 2006 national census.28 Within each district, sampling was implicitly stratified by commune. Maps of the sampled EAs were updated and the households enumerated, and in each sampled EA, 30 households were selected using systematic sampling. All women aged 15–49 years and children aged less than 5 years in the sampled households were eligible for the survey.The baseline survey sampled 2,000 households in each of the districts implementing pneumonia CCM, and 1,000 households in each of the remaining districts, for a total of 18,000 households. The endline survey sampled 3,000 households in each of the districts implementing pneumonia CCM, and 840 households in each of the remaining districts, for a total of 17,760 households. We oversampled in the districts implementing pneumonia CCM to provide sufficient power to detect the effect of this intervention on careseeking and treatment of pneumonia in these two districts relative to the comparison districts. These samples sizes were selected to provide 80% power to detect a difference of differences of 10–15 percentage points (pp) or better in intervention coverage levels between program and comparison areas. With these sample sizes, the evaluation also had 80% power to detect a difference in differences of at least 15 pp in pneumonia treatment coverage levels between the two districts implementing pneumonia CCM and the comparison districts.Baseline data were collected on paper questionnaires, which were checked in the field. Questionnaires were double-entered using CSPro 4.016 at the central Independent Evaluation Team office, data entry errors were reconciled, and logic checks were conducted. Endline data were collected on Samsung Galaxy S2 and S3 smartphones using Pendragon Forms VI software.24 Data were synchronized nightly with a secure Amazon webserver. Data were cleaned and logic checks run on a daily basis in Stata version 13,25 and any inconsistencies in the data were verified with field staff.Analysis.Implementation and quality of care data.Analysis of iCCM implementation and quality of care data was conducted in Stata versions 12 and 13.25,29 Data were weighted for unequal probability of sampling and for nonresponse. The Taylor linearization method was used to adjust standard errors for the effects of clustering.30We calculated point estimates and 95% confidence intervals (CIs) using standard indicators where possible. Indicators were calculated for the RSU area as a whole, for districts without pneumonia CCM, and for districts with pneumonia CCM. For utilization, we had incomplete register data as only 70% of ASBCs could produce a register, and ASBC self-reports of the number of sick children seen were contradictory. We therefore calculated a range of possible utilization rates from these different data sources. We multiplied the mean number of sick children treated per ASBC per month based on register data by 12 months and by the estimated number of ASBCs providing iCCM services and divided the result by the estimated number of under-fives in the program area21 to produce an estimate of the mean number of contacts with an ASBC per child per year. We then did the same using the self-reported utilization data from ASBCs and reported both numbers.We used the implementation and quality of care results to inform our interpretation of the data on changes in intervention coverage and mortality.Coverage data.We used standard coverage indicator definitions from the Multiple Indicator Cluster Surveys and the Commission on Information and Accountability in Women's and Children's Health.31,32 Point estimates and 95% CIs were calculated at baseline and endline for the program area (including districts with and without pneumonia CCM), comparison area, and each region and district within the program and comparison areas. We weighted data for unequal probability of sampling and for nonresponse, and used the Taylor series expansion method,30 which accounts for the effects of cluster sampling, to estimate the variance around point estimates.Pre-post analysis.For each coverage indicator, the percentage point change in coverage from baseline to endline was calculated by subtracting the baseline coverage value from the endline coverage value and calculating the 95% CI for the difference.Difference in differences analysis.The differences in differences analysis compared changes in intervention coverage in RSU areas and comparison areas. For indicators of careseeking for children with suspected pneumonia, and treatment of suspected pneumonia with antibiotics, we compared coverage changes in comparison areas to coverage changes in the two RSU districts implementing CCM for pneumonia. This analysis does not require that coverage levels in intervention and comparison areas be the same at baseline, but assumes that the RSU program is the only factor that could lead to changes in coverage in the RSU area. As we were evaluating the effectiveness of the RSU approach relative to the status quo, we also assumed that there were no major programs with the potential to affect MNCH intervention coverage in comparison areas. These assumptions are examined in the section on contextual factors.The difference in differences in intervention coverage between program and comparison areas from baseline to endline was calculated by first computing the point estimates and standard errors for coverage indicators at baseline and endline in RSU and comparison areas, as described above. We then computed the point estimate and 95% CI for the linear combination of these indicators, subtracting the coverage change from baseline to endline in the comparison area from the coverage change from baseline to endline in the RSU area. We made no adjustments for multiple comparisons.Mortality analysis.We estimated changes in mortality using LiST.33 LiST is a module within the Spectrum software application that brings demographic, cause of death, and intervention coverage data together with the best available estimates of intervention effectiveness to estimate the effect on mortality produced by changes in coverage. LiST analyses make the assumption that changes in intervention coverage drive changes in mortality, and that the effects of more distal factors such as education or poverty on mortality are mediated by changes in intervention coverage.We used LiST to produce four models of mortality change (overall program area, program districts with pneumonia CCM, program districts without pneumonia CCM, and comparison area) from 2010 to 2013. Demographic data for each district were taken from the MoH's annual statistical handbook,20,21 which provides population projections from the most recent census. Baseline mortality levels and cause of death data were estimated for each area by adjusting the national mortality and cause of death data9 using the baseline levels of intervention coverage in each area. Coverage data were taken from the baseline and endline coverage surveys.At present, there is no agreed-upon approach for computing uncertainty bounds around LiST mortality estimates because of challenges in determining the extent to which errors and biases in the many different inputs are correlated. However, we conducted a sensitivity analysis by producing two additional projections, one using the upper bounds of the 95% CIs around the LiST intervention effectiveness estimates and one using the lower bounds. This produced a range of possible mortality reductions, which we report in the results. A similar approach was used by Bhutta and others34 in the recent Every Newborn Series.Ethical review.Ethical approval for the evaluation was obtained from the Johns Hopkins Bloomberg School of Public Health Institutional Review Board (IRB) (IRB2590 and IRB3909) and from the Burkina Faso National Ethics Committee for Health Research (DELIBERATION No. 2009-67 and DELIBERATION No. 2012-10-69).Role of the funding source.The evaluation sponsor had no role in the design of the evaluation; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the article for publication.ResultsBaseline values for key variables for each arm of the evaluation are shown in Supplemental Web Annex 1, Table 2.1. There were no significant differences between the RSU and comparison districts at baseline, except that coverage of oral rehydration solution (ORS) for diarrhea was significantly higher in RSU districts relative to comparison districts.Intensity and quality of program implementation.Initial program implementation appeared strong, with 3,399 ASBCs trained in 2010 (5.94 per 1,000 children under 5 years), increasing to 4,012 by 2013 (7.39 per 1,000 children under 5 years). In addition, 99% of ASBCs providing iCCM services in 2013 reported receiving an initial drug kit (Table 2). However, there were weaknesses in iCCM training: written training materials were used even for illiterate ASBCs, only 52% of ASBCs providing iCCM services were trained with clinical practice, the reported size of the training groups ranged from 1 to 150 (median 20), and a cascade training approach was used in which central-level staff trained district staff, and district staff then either conducted training themselves, or more frequently trained nurses in health facilities to conduct the training of CHWs. Training of district staff and nurses was conducted in 2009–10, while training of ASBCs was primarily conducted in 2010 (and in one district in 2011).With respect to ongoing implementation, we observed that in 2013, only 64% of ASBCs having received iCCM training reported providing iCCM services in the previous 12 months. Further, only 38% of ASBCs providing iCCM services had been supervised in the past 3 months and only 9% had a fully stocked drug kit. A frequent problem in health facilities was the absence of IMCI-trained personnel: During the health facility assessment, only 62% of health facilities had at least one IMCI-trained health worker in the facility on the day of the assessment. Further, only 18% of health facilities had all essential oral medications in stock on the day of the visit.We observed poor quality of care for sick children in both health facilities and the community (Tables 2 and 3). At community level, all aspects of case management, including assessment, classification, treatment, and counseling were poor, with only 36% of sick children correctly treated by ASBCs. Although health workers in facilities correctly managed 91% of children with uncomplicated malaria, only 18% of children with diarrhea and 34% of children with pneumonia were correctly managed.Based on data from ASBC registers (which were available for 70% of ASBCs), mean utilization was two sick children/ASBC/month. Based on ASBC self-reports of utilization, the median time since the ASBC's last sick child consultation was 1 week, and mean utilization was 12 sick children/ASBC/month. Assuming 4,012 ASBCs in 2013, of which 64% were providing iCCM services and 572,238 under-fives,21 we estimated a utilization range of 0.11–0.65 ASBC contacts per child per year.Coverage changes.We observed shifts in the coverage of careseeking for fever and the sources from which care was sought (Table 4 and Supplemental Web Annex 2 [Tables 2.9, 2.10, 2.12, 2.13, 2.15, 2.16]). Careseeking for fever from health facilities decreased by 9.7 pp (95% CI: −14.1 to −5.2) from baseline to endline, while careseeking from ASBCs increased by 2.6 pp (95% CI: 0.7–4.6). Careseeking for suspected pneumonia from ASBCs increased from 5.5 to 10.2%, a 4.6 pp increase (95% CI: −3.0 to 12.3), but the CIs were very wide. We saw little change in careseeking for diarrhea.In program areas, we observed coverage increases from baseline to endline for a number of interventions targeted by the RSU in Burkina Faso (Figure 4\nFigure 4.Changes in coverage in the program and comparison areas, from baseline to endline. and Supplemental Web Annex 2). With the exception of ITN ownership, these coverage increases were relatively small (< 10 pp) and similar in magnitude to coverage increases in comparison areas. Coverage of key iCCM interventions, including antimalarials for fever, antibiotics for pneumonia, and ORS for diarrhea, decreased in program and comparison districts. We did observe a small but statistically significant increase in the treatment of diarrhea with zinc in the program area (from 4.0% [95% CI: 2.8–5.8] to 8.3% [95% CI: 6.2–11.0]) but not in the comparison area. Only two RSU targets for intervention coverage were achieved (intermittent preventive treatment of malaria in pregnancy and vitamin A supplementation) (Table 1). For four other interventions (skilled birth attendance, cesarean section, oral rehydration therapy [ORT] with continued feeding, and exclusive breast-feeding), the program targets, which were set based on data from 2003 and 2006, had already been reached at baseline.The difference in differences analysis showed relatively small differences of differences between RSU and comparison areas (< 10 pp), with the exception of intermittent preventive treatment of malaria in pregnancy (IPTp) (14.9 pp [95% CI: 9.2–20.6], postpartum vitamin A (10.2 pp [95% CI: 4.7–15.8]), and antibiotics for pneumonia (14.2 pp [95% CI: −1.7 to 30.1]), all of which increased more (or decreased less) in RSU areas than in comparison areas (Table 5 and Supplemental Web Annex 2).Mortality changes.Projecting these coverage changes in LiST showed an estimated mortality reduction of 6.2% (range: 5–8.4%] in intervention areas (from 110 deaths per 1,000 live births to 103 [range: 100–104] per 1,000) versus 4.2% (range: 3.6–6.0%) in comparison areas (from 114 per 1,000 to 109 [range: 107–110] per 1,000) from 2010 to 2013 (Figure 5\nFigure 5.Modeled under-five mortality reductions in program and comparison areas, 2010–2013.). Mortality rates for mothers and newborns showed similar reductions in program and comparison areas, with the maternal mortality ratio declining by 2.5% [range: 1.9–3.5%] (from 416 per 100,000 to 405 [range: 402–408]) in program areas and 3.3% in comparison areas (from 434 per 100,000 to 419 [range: 415–423]), and neonatal mortality declining by 5.8% in program areas (from 26 per 1,000 to 24 [range: 24–25]) and 5.1% in comparison areas (from 27 per 1,000 to 26 [range: 26–26]).Most of the estimated mortality reduction in both program and comparison areas was attributable to household ownership of ITNs. Increases in the coverage of this intervention accounted for 71% of the mortality reduction in program areas and 63% in comparison areas (Supplemental Web Annex 3, Figures 1.3 and 2.3).Contextual factors.A quantitative description of key contextual variables is shown in Supplemental Web Annex 4, Table 1.4. The proportion of women of reproductive age with any formal education increased in both program and comparison areas from 2010 to 2013, and these increases were of similar magnitude (6.1 pp versus 5.1 pp). We observed significantly greater in-migration in comparison districts relative to program districts from 2010 to 2013 (comparison: 4.8% [95% CI: 4.2–5.3%]; RSU: 2.8% [95% CI: 2.5–3.3%]). Access to health facilities, as reported by the MoH,20,21 increased slightly in program areas while decreasing in comparison areas over the same time period.In-depth interviews with district health personnel in program and comparison areas revealed similar trends in contextual factors that could have had an impact on MNCH over the program period. All districts reported poor harvests in 2011, but improved harvests and food security in 2012 and 2013. Gold mining activity and migration due to that activity was also a concern of health authorities across the program and comparison areas. Industrial gold mines are located in Kongoussi, Boulsa, and Ouahigouya districts in the program area and in Tenkodogo district in the comparison area, and smaller-scale “artisanal” gold mining is ongoing throughout the country, with the exception of the central region. Regional data on the number of gold mining sites in each region (province and district level data were not available) from 2010 to 2012 shows reductions in the overall number of gold mining sites in RSU regions during this period, but no overall change in the number of gold mining sites in regions containing comparison districts (Supplemental Web Annex 4, Table 2.4).22A major contextual factor was the Global Fund-supported ITN distribution campaign and training of ASBCs to provide case management of malaria for children and adults. This program was implemented nationally, but the component providing CCM for malaria largely ended in 2012, and the endline coverage data show very low careseeking from ASBCs for children with fever in comparison areas (2.6%). No other major programs likely to have affected MNCH coverage indicators were identified in program or comparison areas.DiscussionThis full prospective evaluation of the effectiveness of the RSU program in Burkina Faso included in-depth assessments of program implementation, quality of care, utilization, and intervention coverage changes, as well as modeled changes in mortality. We found important shortcomings in each of these areas and were unable to attribute any change in under-five, maternal, or neonatal mortality to the program. In this section, we discuss these findings and their implications as responses to a series of questions.To what extent was the program implemented? Were implementation, quality of care, and utilization sufficient to achieve population-level coverage changes?Although initial iCCM implementation appeared to be strong, with over 3,000 ASBCs trained in 2010–2011, there were important shortcomings in both initial and ongoing implementation. In terms of the initial training, there were quality concerns including the use of nurses trained months before on iCCM to deliver the training, the failure to adapt training materials for illiterate ASBCs, the relatively large size of some training groups, and the lack of clinical practice for half of ASBCs. Thus, we would not expect this training to produce community workers able to provide high-quality care for sick children. In addition, in 2013, only 64% of the ASBCs who received initial iCCM training were providing iCCM services, suggesting an inefficient approach to training and deployment of ASBCs.Ongoing iCCM implementation suffered from difficulties including infrequent supervision and lack of observation of case management during supervision. In addition, drug stockouts at the ASBC level were very common. Provision of clinical IMCI services suffered from some of the same difficulties, notably widespread stockouts of essential drugs and the fact that many first-level facilities did not have an IMCI-trained clinician present.The implementation difficulties for both iCCM and clinical IMCI would be expected to lead to unsatisfactory quality of care for sick children, and this is what the evaluation found. All aspects of case management were poor at facility and community levels, with the exception of malaria case management in health facilities, which was quite good. Because the facility-level assessment was conducted in 2011, it is possible that facility-based care improved in program areas in 2012–2013. The community-based assessment, however, was conducted in 2013 and thus is a good representation of the quality of care provided by ASBCs at the end of the program.Both quality of health services and utilization of these services must be high to produce population-level changes in coverage and mortality. We found that at community level, in addition to poor quality of care, utilization of ASBCs was very low. Low levels of utilization were likely attributable to the practice of charging for drugs, the fact that careseeking from facilities for sick children was relatively high at baseline, and the lack of a strong strategy to generate demand for iCCM. Given implementation challenges, poor quality of care at facility and community levels, and low utilization of ASBCs, there was no clear way for the RSU program to achieve significant changes in population-level coverage of interventions for sick children, and therefore few pathways to reducing under-five mortality, which was the program's overall objective.Were changes in coverage or mortality greater in the program area than in the comparison area?Of the interventions targeted by the RSU program, there were only three for which coverage increased significantly more in the program area than in the comparison area: one antenatal (IPTp), one postnatal (postpartum vitamin A), and one for sick children (zinc treatment of diarrhea). Most program interventions, including zinc for diarrhea, saw only small coverage increases or even decreases from 2010 to 2013.Because we modeled mortality change in program and comparison areas using LiST, a model in which mortality change is driven by intervention coverage change, it is not surprising that we saw small and similar levels of mortality reduction in both program and comparison areas. Without uncertainty bounds, we cannot determine whether the mortality reductions in program and comparison areas (−6.2% and −4.2%, respectively) were significantly different. However, we note that these reductions are qualitatively similar, that the sensitivity analysis produced overlapping ranges of possible mortality reductions in RSU and comparison areas, and that the reductions are very far from the 25% under-five mortality reduction targeted by the program.Could contextual factors have played a role in these findings?Much of the estimated mortality reduction from LiST was attributable to increases in ITN coverage in program and comparison areas. Increases in ITN coverage were similar in program and comparison areas and were likely largely attributable to the Global Fund-supported ITN distribution campaigns. Although the RSU used program funds to pay for some of the ITNs distributed in the program areas, it seems likely that if these funds had not been available, an alternative source would have been found. Thus, our modeled mortality reductions are partially attributable to the Global Fund's activities.We did not observe major differences in contextual factors between program and comparison areas that could have confounded the association (or lack thereof) between the program and intervention coverage. This does not exclude the possibility of unmeasured confounding, which is always a risk, particularly in nonrandomized evaluations. However, we believe that our findings with regard to intermediate factors (program implementation, quality of care, and utilization) sufficiently explain the coverage and mortality results. We note, however, that contextual factors, and particularly gold mining, may have acted as effect modifiers, in that they may have led to some attrition and dissatisfaction of ASBCs who may have seen gold mining as a more profitable occupation than community health work.12Implications for efforts to deliver iCCM at scale in Burkina Faso and similar contexts.Based on the results of this evaluation, we cannot draw conclusions regarding whether iCCM as a strategy “works” in Burkina Faso, as the implementation of the strategy was flawed, perhaps because of pressure to implement quickly. Evaluators in other settings have also noted that attempts to rapidly scale up a complex intervention such as IMCI resulted in poor implementation and no impact.35 However, we can draw preliminary lessons regarding how to improve the implementation and results of such programs going forward. One important lesson is that when planning for training of health workers, quality matters. ASBC training was completed on a large scale and quite quickly, and, perhaps as a result, the quality of training appears to have been insufficient. A better approach might have been to scale up training more slowly, using trainers from the central MoH, small training groups, clinical practice, and training tools adapted for illiterate ASBCs.A second lesson is the importance of the cadre delivering the program. Burkina Faso used an existing cadre of community health workers (ASBCs) to implement iCCM, and while their long-standing ties with their communities may have been an asset in program implementation, their low level of education and volunteer status may have impeded program success. Commendably, the MoH and partners have developed a new policy on ASBCs13 that aims to address many of the issues identified in the evaluation, although it is not yet clear how this policy will be operationalized.A final lesson is the importance of taking into account drug supply systems and demand generation in the design of an iCCM program. Widespread stockouts at community level made it difficult for ASBCs to provide adequate case management, and the low level of utilization of ASBCs likely limited the impact of the iCCM program. In addition, stockouts were not systematically monitored by the program and therefore were not identified as a problem until the Independent Evaluation Team's survey of ASBCs in 2013.The findings regarding utilization and careseeking point to the need for programs to develop, before implementation, a clear strategy regarding the population to be targeted by a particular program, and regarding how to increase demand in the target population. An equity analysis to assess the types of households that sought care from different sources is underway and will be published separately. This analysis may provide the basis for recommendations on how to reach those sick children who are taken neither to a health facility nor to an ASBC.Limitations.This evaluation had a number of limitations. Due to delays in inviting the evaluation team to Burkina Faso and initial funding delays, the baseline survey was conducted in 2010, although some health facility activities had started in 2009. While this should not affect our assessment of the impact of iCCM, it means that we may not have captured the full effect of facility-based activities. There were also timing issues with respect to the endline survey: Because the transfer of funds for the survey was delayed by the primary grantee, the endline was conducted in a slightly different season than the baseline (November–March versus August–January). A previous study on seasonal differences in careseeking in Burkina Faso,36 as well as a reanalysis of 2010 Demographic and Health Survey data by season (Supplemental Web Annex 5, Tables 1.15 and 2.5), suggests that this difference should have favored the program (i.e., careseeking for childhood illness is expected to be higher after the rainy season than during the rainy season). In addition, we would expect the seasonal effect to be similar in both intervention and comparison areas. However, we cannot exclude the possibility that this seasonal difference in baseline and endline surveys affected our difference in differences analysis.The evaluation included one round of facility-level quality of care assessments and one round of community-level implementation and quality of care assessments. To better capture changes in program implementation and quality of care, it would have been preferable to conduct two rounds of assessments and to conduct the facility assessments in both program and comparison areas. An economic assessment was also planned as a part of the original design, but could not be completed because the facility quality of care assessment was conducted only in the program areas, and there was therefore no basis for cost comparisons.This evaluation focused primarily on assessing whether the program achieved its targets, which were formulated in terms of intervention coverage and under-five mortality. We did not conduct an in-depth assessment of policy inputs and effects of the program, although we tried to document these as we learned about them through meetings with implementing partners.One of the RSU program indicators was the proportion of children with suspected pneumonia who received antibiotics. Validation studies published in 201337 concluded that this indicator has poor validity when measured in household surveys, as respondents cannot report accurately on the numerator or denominator. The evaluation still measured this indicator and observed a large decrease, but we put little weight on that decrease because of the concerns regarding the validity of the indicator. In addition to this indicator, we also reported on careseeking for children with symptoms of pneumonia, which has fewer validity concerns (and which also decreased over the program period).Finally, this evaluation used a nonrandomized design by necessity, as the program districts had already been selected by the time the evaluation team was invited to Burkina Faso and randomization was not an option. We instead used a group-matched design and found that our program and comparison areas were very similar at baseline. We also attempted to measure contextual factors to account for potential confounding. However, unmeasured confounding cannot be ruled out with this type of design.ConclusionsAlthough the RSU did result in a number of policy changes at program outset and later on in response to evaluation findings, implementation of the RSU program itself and in particular the iCCM component was not strong enough to achieve population-level changes in coverage or mortality. Encouragingly, the Burkina Faso MoH and partners have indicated that they will incorporate evaluation findings in future MNCH programming. These results should not be interpreted as evidence that iCCM cannot result in coverage or mortality changes, but rather that it did not result in changes in this setting given weak implementation, poor quality of care, and low utilization. It is notable, however, that very few settings have been able to implement CCM at scale with strong enough intensity and quality to achieve mortality and coverage impacts.38 More attention to the implementation and quality of these programs is needed, with perhaps a longer timeframe for design and scale-up to ensure that implementation challenges are adequately addressed.Supplementary MaterialSupplemental Datas.ACKNOWLEDGMENTSWe thank the Ministry of Health of Burkina Faso and its partners for their support of the independent evaluation team and their willingness to share their insights and perspectives. We especially want to thank Djeneba Sanon from the Ministry of Health; Awa Seck, Assiatta Kaboré, Maurice Hours, and Salvator Nibitanga from UNICEF; and Bernadette Daelmans and Samira Aboubaker from the World Health Organization. We also thank the district health staff, the agents de santé communautaire, and the mothers and children who participated in the various evaluation activities. We thank Salamata Ouédraogo, Moussa Zan, Fiacre Bazié, Issa Zongo, Robert Zoma, Hervé Guéné, and many other current and former staff of the Institut Supérieur des Sciences de la Population and the Institut National de la Statistique et de la Démographie for their help in conducting the studies that make up this evaluation. We also thank the interviewers, supervisors, and other field staff for the evaluation studies. A number of current and former John Hopkins University faculty members and students also contributed to the evaluation in various ways, including Marjorie Opuni-Akuamoa, Damian Walker, Ben Johns, and Anastasia Coutinho. We also thank Adrienne Clermont for her help in preparing the manuscript for submission.Financial support: This evaluation was funded by the Bill and Melinda Gates Foundation through a grant to the World Health Organization. Additional funding for the coverage surveys came from UNICEF and from Johns Hopkins University through the Bill and Melinda Gates Foundation grant to support the Lives Saved Tool. Foreign Affairs, Trade and Development Canada supported open-access publication and printing charges through the Real-Time Results Tracking Grant to Johns Hopkins University.Authors' addresses: Melinda Munos, Timothy Roberton, Yvonne Tam, and Jennifer Bryce, Institute for International Programs, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, E-mails: mmunos1@jhu.edu, timroberton@gmail.com, yvonneyotam@jhu.edu, and jbryce1@jhu.edu. Georges Guiella, Institut Supérieur des Sciences de la Population, University of Ouagadougou, Ouagadougou, Burkina Faso, E-mail: guiella@yahoo.com. Abdoulaye Maïga, Institut Supérieur des Sciences de la Population, University of Ouagadougou, Ouagadougou, Burkina Faso, and Université Catholique de Louvain, Louvain-la-Neuve, Belgium, E-mail: mailayebf@yahoo.fr. Adama Tiendrebeogo and Banza Baya, Institut National de la Statistique et de la Démographie, Ouagadougou, Burkina Faso, E-mails: adamatiendre@gmail.com and bayabanza@yahoo.fr.1.\nWorld Health Organization, UNICEF\n2009\nWHO/UNICEF Joint Statement: Home Visits for the Newborn Child: A Strategy to Improve Survival\nGeneva, Switzerland\nWorld Health Organization2.\nWorld Health Organization, UNICEF\n2012\nWHO/UNICEF Joint Statement: Integrated Community Case Management\nGeneva, Switzerland\nWorld Health Organization3.\nDepartment of Foreign Affairs, Trade and Development Canada\n2007\nThe Initiative to Save a Million Lives\nAvailable athttp://www.pm.gc.ca/eng/news/2007/11/26/initiative-save-million-lives\nAccessed May 3, 20144.\nWorld Health Organization\n2015\nRapid Access Expansion 2015 Programme (RAcE 2015)\nAvailable athttp://www.who.int/malaria/areas/rapid_access_expansion_2015/en/\nAccessed July 25, 20155.\nde SousaATiedjeKERechtJBjelicIHamerDH\n2012\nCommunity case management of childhood illnesses: policy and implementation in Countdown to 2015 countries\nBull World Health Organ\n90\n183\n190224617136.\nUnited Nations Development Programme\n2014\nHuman Development Report 2014: Sustaining Human Progress: Reducing Vulnerabilities and Building Resilience\nNew York, NY\nUnited Nations Development Programme7.\nUnited Nations Inter-Agency Group on Mortality Estimation\n2015\nChild Mortality Estimates, Burkina Faso\nAvailable athttp://www.childmortality.org/index.php?r=site/graph#ID=BFA_Burkina Faso\nAccessed July 25, 20158.\nWorld Health Organization\n2014\nTrends in Maternal Mortality: 1990 to 2013. Estimates by WHO, UNICEF, UNFPA, The World Bank and the United Nations Population Division\nGeneva, Switzerland\nWorld Health Organization9.\nLiuLJohnsonHLCousensSPerinJScottSLawnJERudanICampbellHCibulskisRLiMMathersCBlackREFor the Child Health Epidemiology Reference Group of WHO and UNICEF\n2012\nGlobal, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000\nLancet\n379\n2151\n21612257912510.\nMinistère de la Santé du Burkina Faso\n2008\nRequête du Burkina Faso auprès du partenariat pour la santé de la mère, du nouveau né et de l'enfant\nOuagadougou, Burkina Faso\nGovernment of Burkina Faso11.\nBennettSGeorgeARodriguezDShearerJDialloBKonateMDalglishSJumaPNamakhomaIBandaHChilundoBMarianoACliffJ\n2014\nPolicy challenges facing integrated community case management in sub-Saharan Africa\nTrop Med Int Health\n19\n872\n8822475051612.\nInstitut Supérieur des Sciences de la Population, Institute for International Programs, Johns Hopkins University\n2014\nEvaluation independante du projet d'accélération de la réduction de la mortalité maternelle, néonatale et infanto-juvénile dans les régions sanitaires du Nord et Centre-Nord au Burkina Faso: Enquête communautaire\nOuagadougou, Burkina Faso\nISSP and IIP-JHU13.\nMinistère de la Santé du Burkina Faso\n2014\nProfil de l'agent de santé à base communautaire\nOuagadougou, Burkina Faso\nGovernment of Burkina Faso14.\nBryceJVictoraCGBoermaTPetersDHBlackRE\n2011\nEvaluating the scale-up for maternal and child survival: a common framework\nInt Health\n3\n139\n1462403836215.\nHayesRJMoultonLH\n2010\nCluster Randomized Trials\nBoca Raton, FL\nChapman and Hall/CRC16.\nUnited States Census Bureau\n2010\nCensus and Survey Processing System (CSPro) 4.0\nAvailable athttp://www.census.gov/ipc/www/cspro/\nAccessed July 27, 201517.\nSPSS Inc\n2009\nSPSS, Version 17\nChicago, IL\nSPSS Inc.18.\nQSR International Pty Ltd\n2012\nNVivo Qualitative Data Analysis Software, Version 10\nDoncaster, Victoria\nQSR International Pty Ltd.19.\nDirection générale de l'information et des statistiques sanitaires du Ministère de la Santé\n2009\nAnnuaire Statistique 2008\nOuagadougou, Burkina Faso\nGovernment of Burkina Faso20.\nDirection générale de l'information et des statistiques sanitaires du Ministère de la Santé\n2011\nAnnuaire Statistique 2010\nOuagadougou, Burkina Faso\nGovernment of Burkina Faso21.\nDirection générale de l'information et des statistiques sanitaires du Ministère de la Santé\n2014\nAnnuaire Statistique 2013\nOuagadougou, Burkina Faso\nGovernment of Burkina Faso22.\nBurkina Faso Ministry of Mines and Energy\n2014\n2012 Statistical Handbook for the Ministry of Mines and Energy\nOuagadougou, Burkina Faso\nGovernment of Burkina Faso23.\nMillerNPAmouzouATafesseMHazelELegesseHDegefieTVictoraCGBlackREBryceJ\n2014\nIntegrated community case management of childhood illness in Ethiopia: implementation strength and quality of care\nAm J Trop Med Hyg\n91\n424\n4342479936924.\nPendragon Software Corporation\n2011\nPendragon Forms VI\nBuffalo Grove, IL\nPendragon Software Corporation25.\nStataCorp\n2013\nStata Statistical Software, Version 13\nCollege Station, TX\nStataCorp LP26.\nDepartment of Child and Adolescent Health and Development, World Health Organization\n2003\nHealth Facility Survey: Tool to Evaluate the Quality of Care Delivered to Sick Children Attending Outpatient Facilities\nGeneva, Switzerland\nWorld Health Organization27.\nInstitut pour la Recherche en Sciences de la Santé\n2012\nEvaluation de la qualité des soins prodigués aux enfants de moins de 5 ans dans les formations sanitaires des régions du Nord et du Centre-Nord du Burkina Faso\nOuagadougou, Burkina Faso\nGovernment of Burkina Faso28.\nInstitut National de la Statistiqe et de la Démographie\n2008\nRecensement General de la Population et de l'Habitation de 2006, Résultats Définitifs\nOuagadougou\nBurkina Faso29.\nStataCorp\n2011\nStata Statistical Software, Version 12\nCollege Station, TX\nStataCorp LP30.\nBinderDA\n1983\nOn the variances of asymptotically normal estimators from complex surveys\nInt Stat Rev\n51\n279\n29231.\nUN Commission on Information and Accountability for Women's and Children's Health\n2014\nAvailable athttp://www.everywomaneverychild.org/accountability/coia\nAccessed April 23, 201532.\nUNICEF\n2014\nUNICEF Statistics and Monitoring: Multiple Indicator Cluster Survey\nAvailable athttp://www.unicef.org/statistics/index_24302.html\nAccessed May 3, 201433.\nWalkerNTamYFribergIK\n2013\nOverview of the Lives Saved Tool (LiST)\nBMC Public Health\n13\n(Suppl 3)\nS12456443834.\nBhuttaZADasJKBahlRLawnJESalamRAPaulVKSankarJMBlencoweHRizviAChouABWalkerN\nfor the Lancet Newborn Interventions Review Group and the Lancet Every Newborn Study Group\n2014\nCan available interventions end preventable deaths in mothers, newborn babies, and stillbirths, and at what cost?\nLancet\n383\n1333\n13542426324935.\nNsungwa-SabiitiJBurnhamGPariyoG\nUganda IMCI Documentation Team\n2004\nImplementation of a National Integrated Management of Childhood Illness (IMCI) Program in Uganda\nJ Health Popul Dev Ctries\ndoi: 10.12927/whp.2004.1764336.\nSauerbornRNougtaraAHienMDiesfeldHJ\n1996\nSeasonal variations of household costs of illness in Burkina Faso\nSoc Sci Med\n43\n281\n290884493137.\nHazirTBegumKEl ArifeenSKhanAMHuqueMHKazmiNRoySAbbasiSRahmanQSTheodoratouEKhorshedMSRahmanKMBariSKaiserMMSahaSKAhmedASRudanIBryceJQaziSACampbellH\n2013\nMeasuring coverage in MNCH: a prospective validation study in Pakistan and Bangladesh on measuring correct treatment of childhood pneumonia\nPLoS Med\n10\ne10014222366733938.\nAmouzouAMorrisSMoultonLHMukangaD\n2014\nAssessing the impact of integrated community case management (iCCM) programs on child mortality: review of early results and lessons learned in sub-Saharan Africa\nJ Glob Health\n4\n02041125520801Table 1Program targets and baseline and endline levels of mortality and coverageIndicatorTargetBaseline (2010)Endline (2013)Under-five mortality rate25% reduction from baseline to endline (82.5 deaths per 1,000)110 deaths per 1,000103 deaths per 1,000Antenatal care - 4 or more visits (ANC4+)80%44%45%IPTp70%39%44%Skilled birth attendance60%73%80%Cesarean section2%2%3%Early initiation of breast-feeding40%25%26%Postpartum vitamin A60%50%57%ACT for fever70%27%23%Antibiotics for pneumonia60%30%16%ORT + continued feeding60%65%64%ITNs70%51%92%Exclusive breast-feeding20%35%42%Vitamin A supplementation90%89%93%ACT = artemisinin combination therapy; IPTp = intermittent preventive treatment of malaria in pregnancy; ITNs = insecticide-treated bednets; ORT = oral rehydration therapy.Table 2Implementation and quality of iCCM in program areas, 2013n/N%95% CIImplementation\u2003ASBCs providing iCCM services who received CCM training380/38598.695.8–99.5\u2003ASBCs providing iCCM services who received CCM training with clinical practice201/38552.245.9–58.4\u2003ASBCs providing iCCM services who received at least one CCM supervision304/38578.972.7–84.0\u2003Time since last supervision\u2003\u20030–2 months147/38538.132.3–44.2\u2003\u20033+ months/never supervised239/38561.955.8–67.8\u2003Activities during supervision\u2003\u2003Supervisor observed sick child consultation90/30429.623.3–36.9\u2003\u2003Supervisor gave case scenarios46/30415.311.2–20.5\u2003\u2003ASBCs providing iCCM services who received initial CCM drug kit380/38598.895.4–99.7\u2003\u2003ASBCs providing iCCM services who had all essential drugs in stock on the day of the visit34/3858.86.0–12.7Quality of care\u2003Child assessed for four danger signs78/724118.2–14.1\u2003Child checked for cough/difficult breathing, diarrhea, and fever248/7243429.0–40.1\u2003Child correctly classified for diarrhea and fever (and for pneumonia in pneumonia CCM districts)*472/7186660.5–70.5\u2003Child with uncomplicated illness correctly managed for diarrhea and fever (and for pneumonia in pneumonia CCM districts)*240/6683631.3–40.9\u2003Child not needing an antibiotic did not receive an antibiotic (in pneumonia CCM districts)*58/728174.7–85.2\u2003Child needing referral was referred51/1772920.0–939.0ASBCs = Agents de santé à base communautaires; CI = confidence interval; iCCM = integrated community case management.*Excludes six children with danger signs who were immediately referred.Table 3Quality of care for sick children in health facilities in program areas, 2011\u2009n/N%Child assessed for three danger signs70/25028.0Child checked for cough/difficult breathing, diarrhea, and fever206/25082.4Children for whom health worker's classification matches gold standard classification21/13615.4Children with uncomplicated malaria for whom ACTs were correctly prescribed168/18590.8Children with pneumonia for whom antibiotics were correctly prescribed13/3834.2Children with diarrhea for whom ORS and zinc were correctly prescribed21/11618.1Children with diarrhea for whom ORS was correctly prescribed35/11630.2Children needing referral were referred8/2040.0ACTs = artemisinin combination therapies; ORS = oral rehydration solution.Table 4Careseeking in program and comparison districts, at baseline (August 2010 to January 2011) and endline (November 2013 to March 2014)ASBCFacilityBaselineEndlineBaselineEndline%95% CI%95% CI%95% CI%95% CICareseeking for fever, diarrhea, or suspected pneumonia\u2003Program4.73.7–6.06.75.5–8.256.553.6–59.347.244.3–50.3\u2003Comparison1.91.4–2.72.31.4–3.750.647.3–53.943.440.1–46.7Careseeking for fever\u2003Program4.53.5–5.87.25.7–8.958.455.5–61.248.745.4–52.0\u2003Comparison2.11.5–3.02.61.6–4.253.550.1–56.845.842.1–49.5Careseeking for suspected pneumonia\u2003Program districts with pneumonia CCM5.52.0–14.510.26.0–16.755.745.6–65.352.144.1–59.9\u2003Comparison0.70.1–4.61.90.6–5.362.152.6–70.754.746.9–61.4Careseeking for diarrhea\u2003Program3.52.3–5.14.23.0–6.043.139.3–47.044.340.4–48.2\u2003Comparison0.60.2–1.60.50.2–1.433.229.0–37.730.727.3–34.3ASBC = Agents de santé à base communautaire; CCM = community case management; CI = confidence interval.Table 5Difference in differences analysis for coverage of key program interventionsInterventionDifference in differences in intervention coverage between program and comparison areas, 2010–2013Percentage points95% CIAntenatal care - 4 or more visits (ANC4+)−9.3†−14.8 to −3.8IPTp14.9‡9.2 to 20.6Skilled birth attendance−1.2−8.7 to 6.3Cesarean section0.2−1.4 to 1.8Postpartum vitamin A10.2‡4.7 to 15.8Early breast-feeding initiation−6.2−11.1 to 1.2Exclusive breast-feeding−2.6−11.4 to 6.1Vitamin A supplementation0.9−2.0 to 3.8ACTs for malaria−1.4−6.2 to 3.5Antibiotics for pneumonia*14.2−1.7 to 30.1ORS for diarrhea6.2−0.3 to 12.8Zinc for diarrhea6.6‡3.2 to 9.9ITN ownership4.4−0.6 to 9.5ACTs = artemisinin combination therapies; CI = confidence interval; IPTp = intermittent preventive treatment of malaria in pregnancy; ITN = insecticide-treated bednet; ORS = oral rehydration solution.*Program districts with pneumonia CCM relative to comparison districts.†Coverage increased significantly more in comparison areas relative to program areas, P < 0.05.‡Coverage increased significantly more in program areas relative to comparison areas, P < 0.05.", 'title': 'Independent Evaluation of the Rapid Scale-Up Program to Reduce Under-Five Mortality in Burkina Faso.', 'date': '2016-01-21'}}
| 0
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Public Health, Epidemiology & Health Systems
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46
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Is the coverage of careseeking to an appropriate provider for any iCCM illness higher, lower, or the same when comparing iCCM to usual facility services plus CCM for malaria?
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no difference
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low
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yes
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['23136276']
| 33,565,123
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{'23136276': {'article_id': '23136276', 'content': "Am J Trop Med HygAm. J. Trop. Med. HygtpmdThe American Journal of Tropical Medicine and Hygiene0002-96371476-1645The American Society of Tropical Medicine and Hygiene23136276374852010.4269/ajtmh.2012.11-0733ArticlesIncreased Use of Community Medicine Distributors and Rational Use of Drugs in Children Less than Five Years of Age in Uganda Caused by Integrated Community Case Management of FeverKALYANGO AND OTHERSCOMMUNITY MEDICINE DISTRIBUTORS AND RATIONAL USE OF DRUGSKalyangoJoan N.*LindstrandAnnRutebemberwaElizeusSsaliSarahKadoberaDanielKaramagiCharlesPetersonStefanAlfvenTobiasClinical Epidemiology Unit, Department of Pharmacy, Department of Health Policy, Planning and Management, and Department of Paediatrics and Child Health, School of Public Health, Makerere University College of Health Sciences, Kampala, Uganda; Department of Public Health Sciences, Division of Global Health, Karolinska Institutet, Stockholm, Sweden; Sach's Children's Hospital, Stockholm, Sweden; Department of Gender and Women Studies, Makerere University, Kampala, Uganda; Iganga-Mayuge Health and Demographic Surveillance Site, Iganga, Uganda; International Maternal and Child Health, Department of Women and Children's Health, Uppsala University, Uppsala, Sweden*Address correspondence to Joan N. Kalyango, Department of Public Health Sciences, Division of Global Health, Karolinska Institutet, Stockholm, Sweden. E-mail: nakayaga2001@yahoo.com0711201207112012875 Suppl3645251120112212012©The American Society of Tropical Medicine and Hygiene2012This is an Open Access article distributed under the terms of the American Society of Tropical Medicine and Hygiene's Re-use License which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.We compared use of community medicine distributors (CMDs) and drug use under integrated community case management and home-based management strategies in children 6–59 months of age in eastern Uganda. A cross-sectional study with 1,095 children was nested in a cluster randomized trial with integrated community case management (CMDs treating malaria and pneumonia) as the intervention and home-based management (CMDs treating only malaria) as the control. Care-seeking from CMDs was higher in intervention areas (31%) than in control areas (22%; P = 0.01). Prompt and appropriate treatment of malaria was higher in intervention areas (18%) than in control areas (12%; P = 0.03) and among CMD users (37%) than other health providers (9%). The mean number of drugs among CMD users compared with other health providers was 1.6 versus 2.4 in intervention areas and 1.4 versus 2.3 in control areas. Use of CMDs was low. However, integrated community case management of childhood illnesses increased use of CMDs and rational drug use.Disclaimer: The findings and conclusions in this article are those of the authors and do not necessarily represent the views of Swedish International Development Cooperation Agency or the United Nations Children's Fund/ United Nations Development Program/World Bank/World Health Organization Special Program for Research and Training in Tropical Diseases.IntroductionApproximately 1.4 million children in Africa die of malaria and pneumonia each year.1 Effective drugs for treatment of these two illnesses are available, but they should be administered promptly, i.e., within 24 hours, to minimize the adverse outcomes of the illnesses.2,3 However, caregivers experience several barriers and children do not always receive timely and effective treatment.4–9Efforts to overcome some of these barriers were made through the introduction of the so called home-based management of fever strategy (HBMF) in regions with endemic malaria. Uganda was one of the first countries to implement this strategy in 2002. In this strategy, community medicine distributors (CMDs), also known as community drug distributors or community health workers, treat children with fever in the community with antimalarial drugs.10–12 The CMDs lacked formal medical training but were trained for at least five days in management of fever as a symptom of malaria. The proportion of children receiving prompt and appropriate treatment increased with this strategy, but was nevertheless below the 2000 Abuja targets of 60%13 and its use was low.7,9,14,15 Furthermore, some children with other illnesses (e.g., pneumonia) were treated with antimalarial drugs16 because of symptom overlap or co-infection.17Integrated community case management of childhood illnesses (ICCM) was recommended in 2004 and has been adopted by some countries, including Uganda. In ICCM, CMDs use an evidence-based algorithm to treat children at the community level with antimalarial drugs, antibiotics, and oral rehydration salts. More drugs are accessible to the community under ICCM than under HBMF and this increased acccessibility may improve treatment patterns of children. However, easy access to drugs could also promote drug misuse, leading to wasting of resources and development of resistance to antibiotics. In Zambia, ICCM improved pneumonia treatment of children treated by CHWs.18 However, it remains unclear whether this new strategy will improve use and appropriateness of treatment compared with what has been achieved with the HBMF strategy in other settings with different care-seeking and treatment practices. Therefore, the aim of this study was to compare the effect of ICCM and HBMF strategies on use of CMDs and community drug use patterns in children 6–59 months of age.MethodsStudy design and setting.A cross-sectional study was conducted during January–February 2011 in Iganga-Mayuge Health and Demographic Surveillance Site in eastern Uganda. The population in the area is approximately 70,000 persons living in 13,000 households in 65 villages, where approximately 90% live in rural areas. Malaria is endemic to the area, and there are two main transmission seasons (March and September). The population of children less than five years is approximately 11,000 and the mortality rate in children less than five years of age is 128 per 1,000 live births.19 The study area has 10 government and 3 non-governmental organization health facilities, 122 drug shops and private clinics, and 132 CMDs. A cluster randomized trial to evaluate the impact of integrated presumptive management of malaria and pneumonia with antimalarial drugs and antibiotics on mortality in children less than five years of age has been ongoing in the area since 2009 (trial registration no. ISRCTN52966230).Description of cluster randomized trial.The 65 villages in the area were aggregated into 8 urban and 18 rural clusters, which were then randomized to either intervention arm or control arm. Each village has two CMDs that treat children less than five years of age. The basic criteria for working as a CMD are that one is able to read and write, is chosen by the community, and has received short-term training in treatment of children. The CMDs were all trained initially for one week in the management of malaria. In the intervention arm, the CMDs received additional training in the management of pneumonia for one week. Finally, CMDs in both arms receive monthly refresher training. In the intervention arm, CMDs treat children with fever using antimalarial drugs (artemether–lumefantrine [AL]). Children with non-severe respiratory symptoms according to Integrated Management of Childhood Illnesses guidelines20 are also treated with antibiotics (amoxicillin). In the control arm, CMDs treat children with fever using antimalarial drugs (AL), and those with respiratory symptoms of any severity are referred to health facilities. In both arms, children with severe respiratory or severe malaria symptoms20 are referred to health facilities (Figure 1). The medicines used by the CMDs were pre-packaged in age-specific doses. Health workers from the nearest health center or hospital conduct monthly support supervision of CMDs in both arms to assess drug storage, treatment practices, and record keeping. Before the start of the study, community sensitization seminars about the intervention, recognition of illness in children, and prompt care seeking were conducted.Figure 1.Algorithm for treatment of children by Community Medicines Distributors in Iganga-Mayuge health and demographic surveillance site. + Cough or difficult breathing with fast breathing (i.e. ≥ 50 breaths per minute for child aged 4-12 months; ≥ 40 breaths per minute for child aged 12--59 months). * Cough or difficult breathing with chest indrawing or noisy breathing.Participants and sampling.We sampled 1,400 children 6–59 months of age from the health and demographic surveillance site database by using random sampling stratified by intervention and control villages to obtain equal numbers from each arm of the cluster randomized trial. We assumed that with expected non-response rate of 25% based on a previous study in the area,21 this would give us 1,094 children (547 in each arm) that we needed to answer the objectives. The sample size was estimated by using the formula for comparison of two proportions with adjustment for clustering.22 Assumptions used were 5% level of significance, 80% power, design effect of 1.9, 54% of children ill in previous 2 weeks,23 and a change in proportion of children receiving prompt and appropriate treatment of malaria equivalent to what was observed under HBMF (i.e., 7.4–13.5%),9 giving a change rate of 13.5–24.3%. This sample size was also adequate to detect a 30% difference in use of CMDs in the intervention and control areas. All children whose caregivers were available at home and consented to participate in the study were enrolled.Data collection.Eight experienced and trained interviewers used a pre-tested questionnaire to interview the caregivers. The interviewers were supervised by a pharmacist (Joan N. Kalyango) and a pediatrician (Ann Lindstrand). Data were collected on knowledge about fever, malaria, and pneumonia; perceptions of quality of care; availability of health providers; illness in the previous two weeks; care-seeking patterns; and treatment received including the dose, frequency, duration, timeliness, and source.Medicine posters showing drugs commonly used in the area for treatment of children were used to help the caregivers to identify which treatment children had received. Medicine packages, when available, were also checked to confirm the drug and dose prescribed. Data on child and caregiver demographics, distances of the households from the nearest CMD (using global positioning system coordinates), and the wealth index of the household were extracted from the health and demographic surveillance site data base. The wealth index was computed by using principal components analysis on the basis of household characteristics and assets similar to those used by the Uganda Bureau of Statistics,19 and categorized into five quintiles of relative wealth (poorest to least poor) as described elsewhere.24Variable definitions.A child was considered as having had malaria if the caregiver reported fever in the previous two weeks.25 Self-reported pneumonia symptoms were defined as caregiver report of cough and fast breathing with or without fever; cough and difficult breathing with or without fever; difficult and fast breathing with or without fever; and fever and difficult breathing.2We categorized treatment as appropriate if the child used the recommended drug, dose, frequency, and duration. In addition, if the child used appropriate treatment promptly, i.e., if it was administered on the day of onset of symptoms or the next day,14,23 it was categorized as prompt and appropriate.9 Assessment for appropriateness of treatment was conducted for the first treatment given to the child (i.e., first treatment action) and for the second treatment given to the child if they needed further treatment (i.e., second treatment action).We based assessment of appropriateness of medicines used on national26 and CMD treatment guidelines,27 and treatment recommendations of the British National Formulary,28 which is widely used in Uganda. The medicines considered appropriate for treatment of malaria and pneumonia are shown in Appendix 1.Use of CMDs was defined as care seeking from a CMD for the first or second treatment action for illness in the previous two weeks.We classified a respondent as having knowledge of transmission of malaria if they could identify mosquito bites as the method by which malaria is transmitted from person to person. A score was generated for each of the other knowledge dimensions, i.e., knowledge of malaria and pneumonia prevention, symptoms, and danger signs of illness in children. The respondent obtained one mark on knowledge for each correct answer they gave.29Data management and analysis.Data were double-entered in a FoxPro computer package and exported to STATA version 10 (StataCorp LP, College Station, TX) for analysis. Descriptive statistics were used for description of participants, estimation of the proportions of persons receiving appropriate treatment, and CMD use. Chi-square or Fisher's exact tests were used for comparison of proportions. Logistic regression was used to assess the relationship between various independent variables and prompt and appropriate treatment and CMD use. Unadjusted analysis was performed and on the basis of this analysis, factors that had P values < 0.2 were carried forward for multivariate analysis. Interaction was assessed by comparing log likelihoods of reduced and full models. All analyses were adjusted for the loss in variation because of use of stratified sampling with svy commands in STATA. A P value of 5% was considered statistically significant.Ethical issues.Ethical clearance was obtained from the Makerere University School of Public Health Higher Degrees Research and Ethics Committee, the Uganda National Council of Science and Technology and the Regional Ethics Committee of Karolinska Institutet, Sweden. Permission to conduct the study in the area was also obtained from the local administration of Iganga and Mayuge Districts and the demographic surveillance site. Written informed consent was obtained from the participants.ResultsDemographic and illness characteristics of participants.We enrolled 1,095 (78%) of the 1,400 sampled children in the study (547 in the control arm and 548 in the intervention arm). Households where either the child or caregiver was not available at the first visit were visited a second time. Approximately half (49.3%) of the children were females and the mean (SD) age was 34.9 (20.3) months (Table 1). Households were mostly within the poorer to less poor wealth quintiles. The median distance to the nearest CMD was 422 meters (range = 5.6–1,635 meters). There was no difference in demographic characteristics of the children, respondents and household heads in the two arms of the cluster randomized trial. There was also no difference in their knowledge of malaria, pneumonia, and danger signs.Approximately 74% of the children were reported to have been ill in the two weeks before the study. Of these children, 96% were treated with some type of medication and 87% sought care outside the home. More children in the control arm reported malaria symptoms (i.e., fever) than in the intervention arm (95% vs. 91%), and more children in the intervention arm reported pneumonia symptoms (32% vs. 26%). Runny nose and fever were the most common symptoms (both reported by 93%), followed by cough (80%) (Table 1).Use of CMDs.Of the children that sought care outside home 27% (95% confidence interval [CI] = 23–30%) sought care from a CMD, and there was a higher proportion in the intervention arm than in the control arm (31% vs. 22%; P = 0.01). Approximately 70% had used the services of CMDs, and 97% of these persons were willing to take their children to CMDs again. The most common source of initial treatment was private clinics (32%), followed by CMDs (Table 2). The most common reasons for seeking care from CMDs were not having to pay for treatment (60%), services were nearby (60%), and services were good (10%).Factors associated with use of CMDs by multivariate analysis were being in the intervention arm of the cluster randomized trial (odds ratio [OR] = 1.60, 95% CI = 1.09–2.35), being in the poorest to less poor wealth quintiles compared with the least poor quintiles (OR = 1.92, 95% CI = 0.99–3.71), increased knowledge of malaria prevention strategies (OR = 1.39, 95% CI = 1.12–1.73), increased knowledge of danger signs of illness (OR = 1.22, 95% CI = 1.03–1.43), and not having fever (OR = 2.55, 95% CI = 1.26–5.16). Distance of the household from the nearest CMD of more than 500 meters was negatively associated with use of CMDs by unadjusted analysis (OR = 0.68, 95% CI = 0.47–0.96) but not by multivariate analysis.Approximately 80% of caregivers that sought care from CMDs rated the service as good and 20% rated it as fair. None of them rated the quality of care received as poor. Respondents whose children sought care from the government health unit, private clinics, and drug shops rated the care received as poor in 4.8%, 1.3%, and 0.6%, respectively.Treatment practices.Medicines used.Antipyretics were the most commonly used drugs in self (home) treatment, and antimalarial drugs were the most commonly used by those who sought care outside the home. More children in the intervention arm (92%) who were ill received at least one drug than children in the control arm (88%). The proportion of children that received any antibiotic was higher in the intervention arm than in the control arm (45% versus 34%; P = 0.007). The mean (SD) number of medicines per child was 2 (1.1), and there were no difference between arms. Overall, 5% of the children used unidentified crushed medicines (medicines mixed and crushed by the health worker and given to the caregiver in powder form with directions on how to estimate the dose), and 2% were treated with herbs (Table 3).Antibiotic use was lower among children that sought care from CMDs than in those that sought care from elsewhere in the intervention arm (44% versus 49%; P = 0.003) (CMDs in the control arm did not have antibiotics). The mean number of drugs was lower among children that had sought care from CMDs than in those that sought care from elsewhere in the control arm (1.4 versus 2.3; P < 0.001) and in the intervention arm (1.6 versus 2.4; P < 0.001).Treatment of malaria symptoms.More than 90% of the children with malaria symptoms (i.e., fever) received prompt treatment. However, only 61% received an antimalarial drug and 51% received a recommended antimalarial drug. Overall, only 15% received prompt and appropriate treatment of malaria symptoms, and this proportion was higher in the intervention arm than in the control arm (18% versus 12%; P = 0.03) (Figure 2).Figure 2.Malaria symptoms treatment practices in intervention and control arms in Iganga-Mayuge demographic surveillance site, Uganda.A higher proportion of children received prompt and appropriate treatment for malaria among CMD users than among other health providers (37% versus 9%; P < 0.001). All children who received care from CMDs were treated with the recommended drug, compared with only 38% among the children who received care from other health care providers. There were also significant differences in children receiving recommended dose, frequency, and duration (Figure 3).Figure 3.Malaria symptoms and treatment practices among community medicine distributor (CMD) and non-CMD users in Iganga-Mayuge demographic surveillance site, Uganda.Multivariate analysis showed that the factors associated with prompt and appropriate treatment of malaria were CMD use (OR = 7.27, 95% CI = 4.47–11.82), age of the household head (OR = 1.02, 95% CI = 1.00–1.04), younger children (OR = 0.98, 95% CI = 0.96–0.99), knowledge of malaria transmission (OR = 2.05, 95% CI = 1.23–3.41), and increasing knowledge of signs of pneumonia (OR = 1.40, 95% CI = 1.14–1.72). Being in the intervention arm of the cluster randomized trial was significantly associated with prompt and appropriate treatment of malaria symptoms by unadjusted analysis (OR = 1.52, 95% CI = 1.01–2.28) but not by multivariate analysis.Treatment of pneumonia symptoms.Approximately 42% of children with self-reported pneumonia symptoms received a correct antibiotic, but with no significant difference observed between the intervention and control arms (45% versus 37%; P = 0.44). However, only 9% received prompt and appropriate antibiotics, but there was no significant difference between the intervention and control arms (11% versus 5%; P = 0.10) (Figure 4).Figure 4.Self-reported pneumonia symptoms and treatment practices in intervention and control arms in Iganga-Mayuge demographic surveillance site, Uganda.Approximately 48% of children treated with antibiotics received cotrimoxazole, and only 39% were treated with amoxicillin. A higher proportion of children treated with antibiotics for self-reported pneumonia symptoms in the intervention arm received amoxicillin than those in the control arm (49% versus 21%; P = 0.007). Approximately 47% of those treated with amoxicillin received it from CMDs. The proportion of children who received antibiotics for pneumonia symptoms did not differ between CMDs users and non-CMD users in the intervention arm (42% versus 45%; P = 0.39). There were also no differences in proportions of children that received the correct dose, frequency, and duration of antibiotics (Figure 5).Figure 5.Self reported pneumonia symptoms and treatment practices among community medicine distributor (CMD) and non-CMD users in the intervention arm in Iganga-Mayuge demographic surveillance site, Uganda.DiscussionCare-seeking from CMDs for sick children was higher in the intervention arm (31%) than in the control arm (22%), although it was quite low overall (27%). The CMDs were the second most preferred source of treatment after private clinics. Most caregivers highly rated the quality of care received from CMDs. The CMDs improved rational use of medicines through reduction of polypharmacy, better malaria treatment practices, and improved promptness of treatment.The level of use of CMDs in our study is within the range of 2–59%, which has been reported in other studies.9,14,21,30 Unlike in our study in which most CMDs were newly enrolled, Ajayi and others enrolled pre-existing CMDs, and this may have resulted in the much higher use rate of CMDs (59%).14 In contrast, Rutebemberwa and others reported a low level of use of CMDs (2%), which was probably caused by a recent change in the Uganda malaria policy to artemisinin-based combination therapy as first-line antimalarial drug, which had not been accompanied by provision of artemisinin-based combination therapy to CMDs.21The level of use of CMDs in Iganga-Mayuge was lower than could be expected given that the CMDs have been operational for approximately two years, and that the treatment was free and easily accessible. This finding may have been caused by caregiver preference for private clinics, which are perceived to have skilled health professionals and a wider range of services. Second, although there was community sensitization about the CMDs at the start of the program, there was no continued sensitization. Third, CMDs were affected by periodic drug shortages.Having CMDs who can only treat malaria has been cited as one of the possible reasons for low use of their services because many children have multiple illnesses.9 Our study suggests that CMDs with broader options, such as in the intervention arm of this study, have more clients. In our study, caregivers in the intervention arm were 1.6 times more likely to seek treatment for their children from CMDs than caregivers in the control arm.Caregivers with lower socioeconomic status were more likely to seek care for their children from CMDs compared with caregivers with higher socioeconomic status. This finding confirms the findings of a qualitative study from Uganda, which showed that persons from the poorest quintile were more likely to use free public health facilities.31 However, our findings contrast with those of a study in western Uganda in which children in the least poor quintile were more likely to receive medicines from CMDs.9 The differences in the study findings may be caused by differences in availability of other sources of health care, e.g., private clinics that the caregivers of higher socioeconomic status are more able to afford.Caregivers with more knowledge of malaria preventive strategies and danger signs of illness were more likely to seek care for their children from CMDs than those with less knowledge. This finding may reflect transmission of knowledge from CMDs to caregivers when the caregivers seek care for their children from CMDs. It could also be explained by caregivers having more knowledge about illness being more aware that they can get effective drugs for the illness from CMDs and therefore seek care from them. Knowledge has been shown to influence treatment practices in other studies.9,32,33The findings of rational use of medicines among CMDs in our study are similar to those of studies in western Uganda, rural Senegal, and Zambia.9,18,34 All children treated for malaria symptoms by CMDs received the recommended drug. However, only 37% of them received prompt and appropriate treatment. The children treated for malaria by CMDs had much better results than those treated by other health providers, for which only 38% received the correct drug and 9% received prompt and appropriate treatment. The main challenges of treatment for CMDs and other health providers were in dosing schedules and treatment duration. These challenges might be caused by dosing errors or inadequate information on drug administration given to caregivers by health providers, or misinterpretation of instructions by caregivers. In children treated by other health providers, there was an additional problem of prescription of ineffective medicines, which calls for stronger drug regulation to avoid having these drugs on the market. The proportion of children receiving prompt and appropriate treatment in our study was slightly higher than that found in a previous study in western Uganda under the HBMF strategy9 and in rural Senegal.34It is more difficult to interpret the results for the treatment of pneumonia symptoms from our study. We could only get self-reported pneumonia symptoms, and it is well known that not all children with self-reported pneumonia symptoms have objective signs of pneumonia and therefore should be treated with antibiotics. The CMDs have been trained to promote rational use of antibiotics through respiratory rate assessment before prescription. The proportion of children treated with recommended antibiotics did not differ between CMD users and non-CMD users in the intervention arm, which suggested that CMDs may perform as well in provision of appropriate medicines for pneumonia as other health care providers. Furthermore, the concern that CMDs may increase overuse of antibiotics does not seem to be correct. However, there is a need to ensure that their skills in respiratory assessment are adequate and that they are not failing to diagnose pneumonia in children. This finding is supported by findings from a study among CMDs in Uganda where classification of pneumonia was inadequate.35 Further studies of pneumonia treatment by CMDs are needed in which objective measurements of pneumonia are included.Surprisingly, the use of pre-packed antibiotics did not result in better dosing among children treated by CMDs for self-reported pneumonia symptoms. Pre-packaged drugs have been reported to result in better drug use.36 These findings may result from caregiver's non-adherence to dosing instructions either because of misunderstanding of the instructions or of wrong perceptions about how the medicines should be administered to children. The dosing range for the amoxicillin used by CMDs is 1–3 tablets. This number of tablets is quite high compared with what caregivers are used to for treatment of common conditions in these age groups. This finding may explain why many of the children not treated with recommended doses had used does that were too low. This hypothesis may need to be explored with further studies. However, we also cannot not rule out incorrect dosing by CMDs, or misreporting of how medicines were administered because of problems in recall because we used caregiver reports of medicines used for illness in the past two weeks.Having CMDs that provide amoxicillin increases the use of a more effective oral drug against pneumonia instead of cotrimoxazole, which most other health providers are prescribing but to which high levels of resistance have been demonstrated elsewhere.37 Approximately half of the children who were treated with antibiotics received cotrimoxazole. However, approximately half of those that received amoxicillin received it from CMDs.We had hypothesized that ICCM would improve drug use patterns for pneumonia because of the improved access to medicines, having pre-packaged medicines delivered by trained CMDs, and general improvement in practices especially of health workers that supervise the CMDs. However, our study did not find a significant difference in the proportions of children that received prompt and appropriate treatment for self-reported pneumonia symptoms in the intervention and control arms. Nevertheless, there were higher proportions of children in the intervention arm that received drugs in the correct frequency and duration. The non-significant difference in overall practices in the intervention and control arms may have been caused by insufficient power to detect differences because of the low numbers that were ill with pneumonia and subsequently the low numbers receiving appropriate treatment. It is likely that the influence of ICCM on the community drug use patterns may have been small, therefore requiring large sample sizes to detect it.We used caregivers reports of illness in children in the two weeks before the interview, which may have led to inclusion of illness that occurred earlier than the two weeks. This finding may explain the high illness rate (74%) reported in our study. In addition, we did not have sufficient power to detect differences in pneumonia treatment practices between study arms because of the small number of children with pneumonia symptoms who received prompt and appropriate treatment. Measurement bias may have occurred because of misreporting of symptoms or treatments in children by caregivers, and misinterpretation of fast breathing. However, we showed caregivers posters of commonly used drugs in the area to aid recall and also examined prescriptions and dispensed drugs when these were available.Use of CMDs increased in the intervention arm, suggesting that CMDs who can treat pneumonia, in addition to malaria, increase uptake of their services. However, overall CMD use is still quite low and private clinics and drug shops are still preferred. Nevertheless, CMDs may have greater effect in districts where private clinics and drug shops are less numerous. Because most children in our study sought care from other sources, especially private clinics, interventions to improve the management of malaria and pneumonia should be introduced in the private sector. Malaria treatment was much better among CMD users than non-CMD-users, whereas no difference could be seen in the treatment of self reported pneumonia symptoms. However, prompt and appropriate treatment of malaria and pneumonia is poor and mainly caused by inappropriate drug use. The CMDs are championing the use of effective antimalarial drugs and antibiotics in a situation in which children continue to receive ineffective medicines.ACKNOWLEDGMENTSWe thank the study participants and Iganga-Mayuge Health and Demographic Surveillance Site administration and staff, most notably Edward Galiwango, Judith Kaija, Jane Mirembe, and James Kalungi for making this study possible; and the research assistants and data entrants for their hard work during this research.Financial support: This study was supported by the Swedish International Development Cooperation Agency and the United Nations Children's Fund/ United Nations Development Program/World Bank/World Health Organization Special Program for Research and Training in Tropical Diseases.Authors' addresses: Joan N. Kalyango, Clinical Epidemiology Unit and Department of Pharmacy, Makerere University College of Health Sciences, Kampala, Uganda; and Department of Public Health Sciences, Division of Global Health, Karolinska Institutet, Stockholm, Sweden, E-mail: nakayaga2001@yahoo.com. Ann Lindstrand and Tobias Alfven, Department of Public Health Sciences, Division of Global Healthm, Karolinska Institutet, Stockholm, Sweden; and Sach's Children's Hospital, Stockholm, Sweden, E-mails: ann.lindstrand@sodersjukhuset.se and tobias.alfven@ki.se. Elizeus Rutebemberwa, Department of Health Policy, Planning and Management, School of Public Health, Makerere University College of Health Sciences, Kampala, Uganda, E-mail: ellie@musph.ac.ug. Sarah Ssali, Department of Gender and Women Studies, Makerere University, Kampala, Uganda, E-mail: sssalin@yahoo.com. Daniel Kadobera, Iganga-Mayuge Health and Demographic Surveillance Site, Iganga, Uganda, E-mail: dkadobera@gmail.com. Charles Karamagi, Clinical Epidemiology Unit, and Department of Paediatrics and Child Health, Makerere University College of Health Sciences, Kampala, Uganda, E-mail: ckaramagi2000@yahoo.com. Stefan Peterson, Department of Public Health Sciences, Division of Global Health, Karolinska Institutet, Stockholm, Sweden; and International Maternal and Child Health, Department of Women and Children's Health, Uppsala University, Uppsala, Sweden, E-mail: stefan.peterson@ki.se.1.\nBlackRECousensSJohnsonHLLawnJERudanIBassaniDGJhaPCampbellHWalkerCFCibulskisREiseleTLiuLMathersC\n2010\nGlobal, regional, and national causes of child mortality in 2008: a systematic analysis\nLancet\n375\n1969\n1987204664192.\nUNICEF, WHO\n2006\nPneumonia: The Forgotten Killer of Children\nGeneva\nUNICEF/WHO\n443.\nWHO\n2005\nMalaria Control Today: Current WHO Recommendations\nGeneva\nWHO4.\nChibwanaAMathangaDChinkhumbaJCampbellC\n2009\nSocio-cultural predictors of health-seeking behaviour for febrile under-five children in Mwanza-Neno district, Malawi\nMalar J\n8\n219197784335.\nWarsameMKimbuteOMachindaZRuddyPMelkisedickMPetoTRibeiroIKituaATomsonGGomesM\n2007\nRecognition, perceptions and treatment practices for severe malaria in rural Tanzania: implications for accessing rectal artesunate as a pre-referral\nPLoS ONE\n2\ne149172258546.\nMasloveDMnyusiwallaAMillsEMcGowanJAttaranAWilsonK\n2009\nBarriers to the effective treatment and prevention of malaria in Africa: a systematic review of qualitative studies\nBMC Int Health Hum Rights\n9\n26198528577.\nKembleSKDavisJCNalugwaTNjama-MeyaDHopkinsHDorseyGStaedkeSG\n2006\nPrevention and treatment strategies used for the community management of childhood fever in Kampala, Uganda\nAm J Trop Med Hyg\n74\n999\n1007167605108.\nNsungwa-SabiitiJTomsonGPariyoGOgwal-OkengJPetersonS\n2005\nCommunity effectiveness of malaria treatment in Uganda: a long way to Abuja targets\nAnn Trop Paediatr\n25\n91\n100159491979.\nNsungwa-SabiitiJPetersonSPariyoGOgwal-OkengJPetzoldMTomsonG\n2007\nHome-based management of fever and malaria treatment practices in Uganda\nTrans R Soc Trop Med Hyg\n101\n1199\n12071794532010.\nUganda Ministry of Health\n2010\nMalaria Case Management: Home Based Management of Fever\nKampala, Uganda\nUganda Ministry of Health11.\nRoll Back Malaria\n2002\nCommunity Involvement in Rolling Back Malaria\nGeneva\nWHO12.\nWHO\n2005\nThe Roll Back Malaria Strategy for Improving Access to Treatment through Home Management of Malaria\nGeneva\nWHO13.\nRoll Back Malaria /World Health Organization\n2003\nThe Abuja Declaration and the Plan of Action\nGeneva\nWorld Health Organization14.\nAjayiIOBrowneENGarshongBBateganyaFYusufBAgyei-BaffourPDoamekporLBalyekuAMungutiKCousensSPagnoniF\n2008\nFeasibility and acceptability of artemisinin-based combination therapy for the home management of malaria in four African sites\nMalar J\n7\n815.\nSirimaSBKonateATionoAConvelboNCousensSPagnoniF\n2003\nEarly treatment of childhood fevers with pre-packaged antimalarial drugs in the home reduces severe malaria morbidity in Burkina Faso\nTrop Med Int Health\n8\n133\n1391258143816.\nKällanderKHildenwallHWaiswaPGaliwangoEPetersonSPariyoG\n2008\nDelayed care seeking for fatal pneumonia in children aged under five years in Uganda: a case-series study\nBull World Health Organ\n86\n332\n3381854573417.\nKällanderKNsungwa-SabiitiJPetersonS\n2004\nSymptom overlap for malaria and pneumonia: policy implications for home management strategies\nActa Trop\n90\n211\n2141517714818.\nYeboah-AntwiKPilinganaPMacleodWBSemrauKSiazeeleKKaleshaPHamainzaBSeidenbergPMazimbaASabinLKamholzKTheaDMHamerDH\n2010\nCommunity case management of fever due to malaria and pneumonia in children under five in Zambia: a cluster randomized controlled trial\nPLoS Med\n7\ne10003402087771419.\nUganda Bureau of Statistics, Macro International Inc\n2007\nUganda Demographic and Health Survey 2006\nKampala, Uganda\nBureau of Statistics20.\nWHO, UNICEF\n2008\nIntegrated Management of Childhood Illness Chart Booklet\nGeneva\nWHO21.\nRutebemberwaEPariyoGPetersonSTomsonGKallanderK\n2009\nUtilization of public or private health care providers by febrile children after user fee removal in Uganda\nMalar J\n8\n451928467322.\nAdamchakSBondKMacLarenLMagnaniRNelsonKSeltzerJ\n2000\nA Guide to Monitoring and Evaluating Adolescent Reproductive Health Programs\nWashington, DC\nFocus on Young Adults23.\nRutebemberwaEPariyoGPetersonSTomsonGKallanderKA\n2009\nDeterminants of delay in care-seeking for febrile children in eastern Uganda\nTrop Med Int Health\n14\n472\n4791922282324.\nWaiswaPPetersonSTomsonGPariyoG\n2010\nPoor newborn care practices: a population based survey in eastern Uganda\nBMC Pregnancy Childbirth\n10\n92017862625.\nGoveS\n1997\nIntegrated management of childhood illness by outpatient health workers: technical basis and overview. The WHO Working Group on Guidelines for Integrated Management of the Sick Child\nBull World Health Organ\n75\n(Suppl 1)\n7\n24952971426.\nMinistry of Health, Uganda\n2010\nUganda Clinical Guidelines\nKampala, Uganda\nMinistry of Health, Uganda27.\nDepartment of Health Policy Planning and Management\n2010\nCommunity Medicine Distributor Training Guide on Integrated Management of Malaria and Pneumonia\nKampala, Uganda\nSchool of Public Health\n2428.\nJoint Formulary Committee\n2007\nBritish National Formulary\nLondon\nBritish Medical Association and Royal Pharmaceutical Society of Great Britain29.\nHwangJGravesPMJimaDReithingerRKachurSP\n2007\nKnowledge of malaria and its association with malaria-related behaviors: results from the Malaria Indicator Survey, Ethiopia\nPLoS ONE\n5\ne116922065778230.\nDasARavindranTS\n2010\nFactors affecting treatment-seeking for febrile illness in a malaria endemic block in Boudh District, Orissa, India: policy implications for malaria control\nMalar J\n9\n3772119282531.\nBakeeraSWamalaSGaleaSStateAPetersonSPariyoG\n2009\nCommunity perceptions and factors influencing utilization of health services in Uganda\nInt J Equity Health\n8\n251960224432.\nLindbladeKAO'NeillDBMathangaDPKatunguJWilsonML\n2000\nTreatment for clinical malaria is sought promptly during an epidemic in a highland region of Uganda\nTrop Med Int Health\n5\n865\n8751116927633.\nTsionATeferaBAyalewTAmareD\n2008\nMothers' health care seeking behavior for childhood illnesses in Derra District, Northshoa Zone, Oromia Regional State, Ethiopia Ethiop\nJ Health Sci\n18\n87\n9434.\nSmithLBruceJGueyeLHelouADialloRGueyeBJonesCWebsterJ\n2010\nFrom fever to anti-malarial: the treatment-seeking process in rural Senegal\nMalar J\n9\n3332109217635.\nMukangaDBabiryeRPetersonSPariyoGWOjiamboGTibenderanaJKNsubugaPKallanderK\n2011\nCan lay community health workers be trained to use diagnostics to distinguish and treat malaria and pneumonia in children? Lessons from rural Uganda\nTrop Med Int Health\n16\n1234\n12422175216336.\nYeboah-AntwiKGyapongJOAsareIKBarnishGEvansDBAdjeiS\n2001\nImpact of prepackaging antimalarial drugs on cost to patients and compliance with treatment\nBull World Health Organ\n79\n394\n3991141703437.\nHoaNTrungNLarssonMErikssonBPhucHChucNLundborgC\n2010\nDecreased Streptococcus pneumoniae susceptibility to oral antibiotics among children in rural Vietnam: a community study\nBMC Infect Dis\n10\n8520356399Appendix 1: Appropriate medicines for malaria and pneumonia treatmentMedicines were considered appropriate for malaria treatment if the child was treated with artemether–lumefantrine, 1 tablet twice a day for children less than 3 years of age or 2 tablets twice a day for children 3–5 years of age for 3 days; artesunate plus amodiaquine, 4 mg/kg and 10 mg/kg of body weight, respectively, per day for 3 days; dihydroartemisinin plus piperaquine, 2–4 mg/kg/day plus 16–18 mg/kg/day, respectively, for 3 days; quinine, 10 mg/kg, 3 times a day for 7–10 days.26 The weights of children used for evaluation of the doses were estimated according to age by using the Ugandan standard growth chart.26Medicines were considered appropriate for pneumonia treatment if the child received amoxicillin, 125 mg twice a day for children less than 12 months of age, 250 mg twice a day for children 12–35 months of age, 375 mg twice a day for children 36–59 months of age for 3 days if the treatment was from community medicine disteributors27 or 15–25 mg/kg every 8 hours for 5days if treatment was given by other health providers; erythromycin, 10–15 mg/kg every 6 hours for 5 days; azithromycin, 10 mg/kg/day for 3 days; ampicillin, 25–50 mg/kg plus cloxacillin, 25–50 mg/kg every 6 hours for at least 5 days; gentamicin at a dose of 2.5 mg/kg every 12 hours plus ampicillin at a dose of 25–50 mg/kg every 6 hours for at least 5 days; benzyl penicillin, 50,000 IU/kg every 6 hours, which could be changed to oral amoxicillin to complete 5 days of treatment with antibiotics; procaine penicillin fortified for at least 3 days plus amoxicillin to complete at least 5 days of treatment with antibiotics; chloramphenicol, 25 mg/kg every 6 hours for 5–10 days and cotrimoxazole, 24 mg/kg twice a day for 5 days;26 cefuroxime, 125–250 mg twice a day for 5 days; amoxicillin plus clavulanate, 15–25 mg/kg based on amoxicillin 2–3 times a day.28Table 1Demographic and illness characteristics of 1,095 children in Iganga-Mayuge demographic surveillance site, Uganda*CharacteristicOverallInterventionControlPNo. children1,095548547Female children, no. (%)540 (49.3)263 (48.0)277 (50.6)0.38Mean age of children, months (SD)34.9 (20.3)35.5 (24.4)34.4 (15.1)0.47Female respondent, no. (%)870 (80.1)444 (81.6)426 (78.6)0.21Mean age of respondents, years (SD)33.2 (10.8)32.9 (11.0)33.5 (10.8)0.22Male household heads, no. (%)941 (89.2)466 (88.4)475 (90.0)0.42Mean age of household head, years (SD)41.5 (12.3)41.4 (12.5)41.6 (12.3)0.85Wealth Index of household\u2003Poorest164 (17.5)86 (18.3)78 (16.8)0.48\u2003Poorer207 (22.1)106 (22.5)101 (21.7)\u2003Poor238 (25.4)108 (22.9)130 (28.0)\u2003Less poor212 (22.7)104 (22.1)108 (23.2)\u2003Least poor115 (12.3)67 (14.2)48 (10.3)Median distance from CMD, meters (range)422 (5.6–1,635)415 (12.0–1,466.9)425.3 (5.6–1,635.4)0.48Children ill, no. (%)811 (74.1)419 (76.5)392 (71.7)0.07Treated for illness, no. (%)780 (96.2)406 (96.9)374 (95.4)0.27Sought care outside home, no. (%)703 (86.7)358 (85.4)345 (88.0)0.09Malaria symptoms among the ill, no. (%)754 (93.0)381 (90.9)373 (95.2)0.02Pneumonia symptoms among the ill, no. (%)236 (29.1)134 (32.0)102 (26.0)0.06Mean knowledge score of malaria (SD)4.1 (1.8)4.1 (1.9)4.1 (1.9)0.66Mean knowledge score of pneumonia (SD)1.0 (1.3)1.0 (1.3)1.0 (1.3)0.70Mean knowledge score of danger signs (SD)2.3 (1.0)2.4 (1.2)2.3 (1.1)0.18Symptoms of children, no. (%) (n = 811)\u2003Runny nose755 (93.1)383 (91.4)372 (94.9)0.05\u2003Fever754 (93.0)381 (90.9)373 (95.2)0.02\u2003Cough652 (80.4)333 (79.5)319 (81.4)0.50\u2003Loss of appetite380 (46.9)192 (45.9)188 (48.0)0.55\u2003Headache302 (37.2)142 (33.9)160 (40.8)0.05\u2003Diarrhea244 (30.1)132 (31.5)112 (28.6)0.37\u2003Chills243 (30.0)118 (28.2)125 (31.9)0.26\u2003Vomiting211 (26.0)108 (25.8)103 (26.3)0.87\u2003Difficult breathing157 (19.4)86 (20.5)71 (18.1)0.39\u2003Fast breathing145 (17.9)83 (19.5)62 (15.8)0.15\u2003Convulsions32 (4.0)19 (4.5)13 (3.3)0.27\u2003Stomach pain22 (2.7)13 (2.4)9 (1.6)0.34\u2003Rash21 (2.6)6 (1.1)15 (2.7)0.23\u2003Other†32 (3.9)23 (4.2)9 (1.6)0.44*CMD = community medicine distributor.†Includes nose bleeding, weakness, yellowing of eyes, pallor, mouth sores, loss of consciousness, mumps, measles, painful eyes, chicken pox, itching, and excessive crying.Table 2Treatment-seeking characteristics for 734 children that sought care in Iganga-Mayuge demographic surveillance site, Uganda*CharacteristicOverallInterventionControlPSource of first treatmentPrivate clinic231 (31.5)120 (31.4)111 (31.5)0.97CMDs187 (25.5)112 (29.3)75 (21.3)0.01Drug shop180 (24.5)87 (22.8)93 (26.4)0.26Government unit126 (17.2)56 (14.7)70 (19.9)0.07NGO unit5 (0.7)4 (1.1)1 (0.3)0.21General shop3 (0.4)2 (0.5)1 (0.3)0.61Traditional healer2 (0.3)1 (0.3)1 (0.3)0.95CMD use\u2003Sought treatment from CMD as first or second action195 (26.6)117 (30.6)78 (22.2)0.01\u2003Ever used services of CMD (n = 1,095)765 (70.0)392 (71.7)373 (68.3)0.23\u2003Mention CMDs as one of the providers where can take child (n = 1,095)797 (73.0)415 (75.9)382 (70.1)0.04\u2003Willing to take child to CMD again (n = 700)678 (96.9)342 (96.3)336 (97.4)0.45\u2003CMD use among children with pneumonia symptoms (n = 213)†61 (28.6)43 (35.5)18 (19.6)0.01\u2003CMD use among children with malaria symptoms (n = 687)†175 (25.5)103 (29.5)72 (21.3)0.01*Values are no. (%). CMD = community medicine distributor; NGO = non-government organization.†Children with specific symptoms who sought care.Table 3Medicines received among 811 children that were ill in Iganga-Mayuge demographic surveillance site, UgandaDrug classOverallInterventionControlPDrugs used in home treatment, no. (mean)n = 77n = 48n = 29\u2003Antipyretics*48 (0.62)29 (0.60)19 (0.66)0.65\u2003Antimalarial drugs†22 (0.29)16 (0.55)6 (0.21)0.003\u2003Antibiotics‡16 (0.21)10 (0.21)6 (0.21)0.99\u2003Antihistamines§ 5 (0.06)4 (0.08)1 (0.03)0.40\u2003Other¶9 (0.11)4 (0.08)5 (0.17)0.24Drugs given by health providers, no. (mean)n = 734n = 381n = 353\u2003Antimalarial drugs#471 (0.64)249 (0.65)222 (0.63)0.83\u2003Antipyretics**459 (0.63)222 (0.58)237 (0.67)0.44\u2003Antibiotics††359 (0.49)207 (0.54)152 (0.43)0.34\u2003Antihistamines§80 (0.11)39 (0.10)41 (0.12)0.85\u2003Steroids‡‡56 (0.08)28 (0.07)28 (0.08)0.92\u2003Hematinics15 (0.02)8 (0.02)7 (0.02)0.98\u2003Vitamins14 (0.02)6 (0.02)8 (0.02)0.83\u2003Other§§14 (0.02)9 (0.02)5 (0.01)0.76\u2003Combination drugs for flu¶¶13 (0.02)8 (0.02)5 (0.01)0.82\u2003Dewormers9 (0.01)4 (0.01)5 (0.01)0.87\u2003Anticonvulsant (diazepam)8 (0.01)4 (0.01)4 (0.01)0.97Received at least one drug733 (90.4)387 (92.4)346 (88.3)0.05Received at least one antibiotic132 (33.7)187 (44.6)319 (39.3)0.007Overall mean number of medicines (SD)2.2 (1.1)2.3 (1.0)2.2 (1.1)0.94Unidentified crushed tablets,## no. (%)34 (4.6)12 (3.1)22 (6.2)0.05*Paracetamol, aspirin, and ibuprofen.†Artemether–lumefantrine and quinine.‡Amoxicillin, metronidazole, and cotrimoxazole.§Chlorphenramine and cetirizine.¶Combination drugs for influenza, vitamins, hematinics, diazepam, bronchodilators, steroids, and dewormers.#Artemether–lumefantrine, quinine, amodiaquin, sulfadoxine–pyrimethamine, chloroquine, and artemether.**Paracetamol, aspirin, ibuprofen, and diclofenac.††Amoxicillin, cotrimoxazole, metronidazole, erythromycin, azithromycin, benzyl penicillin, penicillin V tablets, chloramphenicol, ampicillin, ampicillin plus cloxacillin, and cloxacillin.‡‡Dexamethasone and prednisolone.§§Metoclopramide, antacids, bronchodilators, oral rehydration salts, nystatin oral suspension.¶¶Combinations of antihistamines, antipyretics, and systemic nasal decongestants.##Medicines mixed and crushed by health worker and given to caregiver in powder form.", 'title': 'Increased use of community medicine distributors and rational use of drugs in children less than five years of age in Uganda caused by integrated community case management of fever.', 'date': '2013-01-03'}}
| 0
|
Public Health, Epidemiology & Health Systems
|
47
|
Is the incidence of breast hematomas within 90 days of breast surgery higher, lower, or the same when comparing NSAIDs to placebo?
|
no difference
|
low
|
yes
|
['27935990']
| 34,753,201
| 2,021
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{'27935990': {'article_id': '27935990', 'content': "PLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of ScienceSan Francisco, CA USA27935990514783010.1371/journal.pone.0166601PONE-D-16-16213Research ArticleBiology and Life SciencesPhysiologySensory PhysiologySomatosensory SystemPain SensationMedicine and Health SciencesPhysiologySensory PhysiologySomatosensory SystemPain SensationBiology and Life SciencesNeuroscienceSensory SystemsSomatosensory SystemPain SensationMedicine and Health SciencesSurgical and Invasive Medical ProceduresMedicine and health sciencesPharmacologyDrugsAnalgesicsCOX-2 inhibitorsMedicine and health sciencesPain managementAnalgesicsCOX-2 inhibitorsMedicine and Health SciencesPain ManagementHyperalgesiaMedicine and Health SciencesOncologyCancer TreatmentSurgical OncologyMedicine and Health SciencesClinical MedicineClinical OncologySurgical OncologyMedicine and Health SciencesOncologyClinical OncologySurgical OncologyMedicine and Health SciencesOncologyCancers and NeoplasmsBreast TumorsBreast CancerMedicine and Health SciencesAnesthesiologyAnesthesiaLocal and Regional AnesthesiaParavertebral BlockMedicine and Health SciencesPharmaceuticsDrug TherapyAnesthesiaLocal and Regional AnesthesiaParavertebral BlockMedicine and Health SciencesHealth CareQuality of LifeHyperalgesia and Persistent Pain after Breast Cancer Surgery: A Prospective Randomized Controlled Trial with Perioperative COX-2 InhibitionHyperalgesia and Persistent Pain after Breast Cancer Surgeryvan HelmondNoud1*SteegersMonique A.1Filippini-de MoorGertie P.2VissersKris C.1Wilder-SmithOliver H.131\nDepartment of Anaesthesiology, Pain and Palliative Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands2\nDepartment of Anesthesiology, Bernhoven Hospital, Uden, The Netherlands3\nCenter for Sensory-Motor Interaction (SMI), Department of Health Science and Technology, Aalborg University, Aalborg, DenmarkDuboisLudwigEditorMaastricht University Medical Centre, NETHERLANDSCompeting Interests: The support from Pfizer does not alter our adherence to PLOS One policies on sharing data and materials.Conceptualization: OWS KV MS.Data curation: GF NVH.Formal analysis: OWS NVH.Funding acquisition: OWS KV.Investigation: GF MS.Methodology: OWS KV MS.Project administration: OWS GF MS.Resources: OWS KV.Software: OWS.Supervision: OWS KV MS.Visualization: NVH.Writing – original draft: NVH.Writing – review & editing: NVH GF OWS MS KV.\n* E-mail: Noud.vanHelmond@radboudumc.nl912201620161112e0166601205201629102016© 2016 van Helmond et al2016van Helmond et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.BackgroundPersistent pain is a challenging clinical problem after breast cancer treatment. After surgery, inflammatory pain and nociceptive input from nerve injury induce central sensitization which may play a role in the genesis of persistent pain. Using quantitative sensory testing, we tested the hypothesis that adding COX-2 inhibition to standard treatment reduces hyperalgesia after breast cancer surgery. A secondary hypothesis was that patients developing persistent pain would exhibit more postoperative hyperalgesia.Methods138 women scheduled for lumpectomy/mastectomy under general anesthesia with paravertebral block were randomized to COX-2 inhibition (2x40mg parecoxib on day of surgery, thereafter 2x200mg celecoxib/day until day five) or placebo. Preoperatively and 1, 5, 15 days and 1, 3, 6, 12 months postoperatively, we determined electric and pressure pain tolerance thresholds in dermatomes C6/T4/L1 and a 100mm VAS score for pain. We calculated the sum of pain tolerance thresholds and analyzed change in these versus preoperatively using mixed models analysis with factor medication. To assess hyperalgesia in persistent pain patients we performed an additional analysis on patients reporting VAS>30 at 12 months.Results48 COX-2 inhibition and 46 placebo patients were analyzed in a modified intention to treat analysis. Contrary to our primary hypothesis, change in the sum of tolerance thresholds in the COX-2 inhibition group was not different versus placebo. COX-2 inhibition had an effect on pain on movement at postoperative day 5 (p<0.01). Consistent with our secondary hypothesis, change in sum of pressure pain tolerance thresholds in 11 patients that developed persistent pain was negative versus patients without pain (p<0.01) from day 5 to 1 year postoperatively.ConclusionsPerioperative COX-2 inhibition has limited value in preventing sensitization and persistent pain after breast cancer surgery. Central sensitization may play a role in the genesis of persistent postsurgical pain.http://dx.doi.org/10.13039/100004319Pfizervan HelmondNoudThis study was supported by a grant from Pfizer. They had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Data AvailabilityAll relevant data are within the paper and its Supporting Information files. Additionally, data can be accessed at the following repository: http://dx.doi.org/10.17026/dans-xd7-g3z5Data AvailabilityAll relevant data are within the paper and its Supporting Information files. Additionally, data can be accessed at the following repository: http://dx.doi.org/10.17026/dans-xd7-g3z5IntroductionPersistent pain after surgery is a significant clinical problem which affects 10 to 50 percent of patients [1]. Chronic pain treatments are effective in reducing pain in only about 30 percent of patients with such persistent pain [2]. In breast cancer surgery similar outcomes are reported, with around 40 percent of patients suffering from persistent pain one year after surgery [3, 4]. These results are not surprising in view of the complexity of persistent pain and current empirical symptom-based pain management approaches. Further improvement in persistent and chronic pain management will likely depend on the development of more mechanism-based approaches [5, 6].A key insight from fundamental pain research is that ongoing nociceptive input alters subsequent sensory processing by the nervous system [7]. Surgical nociception results in postoperative hyperalgesia via pronociceptive changes in central nervous system processing. Such ‘central sensitization’ occurs via two mechanisms, namely damage to tissues and to nerves, with the former acting more via humoral biochemical products of tissue inflammation, and the latter more via neuronal mechanisms [7]. Postoperative central sensitization and hyperalgesia not only lead to increased acute pain, they have also been linked to subsequent development of chronic pain [8–13]. Preventing postoperative central sensitization may therefore provide an attractive mechanism based approach to prevent persistent pain development, e.g. by blocking nociceptive input or direct antihyperalgesic therapy [14–18].Regional anesthesia is currently the best therapy to block surgical nociceptive input and may protect partially against persistent pain development after surgery [19–21]. However, even with paravertebral block around twenty-two percent of women undergoing breast cancer surgery suffer from persistent pain six months after surgery [22, 23]. To further improve management of surgical pain it would be useful to understand the effect of adding inhibition of the inflammatory component of sensitization, e.g. by providing perioperative cyclooxygenase-2 (COX-2) inhibition [24–26] in addition to blockade of neuronal nociceptive input. COX-2 inhibitors interfere with prostaglandin production [27] and may counteract central sensitization development by inhibiting peripheral sensitization [27] and reducing nociceptive input. Additionally, COX-2 inhibitors may prevent central sensitization by a central mechanism [24, 27].The primary aim of this study was to assess the value of perioperatively inhibiting the inflammatory component of sensitization added to block of neuronal nociceptive input on central sensitization after surgery. A secondary aim was to assess the relationship between hyperalgesia and persistent pain development at 12 months postoperatively. We studied these aims in a randomized prospective controlled trial in women undergoing breast cancer surgery under paravertebral blockade combined with perioperative COX-2 inhibition or placebo. We hypothesized that:Adding COX-2 inhibition to standard maximal antinociceptive treatment (paravertabral blockade) perioperatively would result in less widespread hyperalgesia as a sign of central sensitization–and therefore less persistent pain–following surgery compared to a placebo-supplemented group.Patients who complained of persistent pain 12 months postoperatively would exhibit more widespread hyperalgesia following surgery, than patients not complaining of persisting pain.Materials and MethodsWe conducted a prospective, randomized, double blind, placebo-controlled, clinical trial at the Bernhoven Hospital in Uden, the Netherlands, approved by the Ethical Committee on March 16th 2005 (nr: 2004/239, CMO region Arnhem-Nijmegen, Nijmegen, The Netherlands). All participants provided written informed consent; the trial was registered with the Netherlands Trial Register (NTR1793). Trial registration was not complete when subject recruitment had begun. However, this was rectified and our trial was registered on May 3rd 2009. The authors confirm that all ongoing and related trials for this drug/intervention are registered. The protocol for this trial and supporting CONSORT checklist are available as supporting information; see S1 Checklist and S1 Protocol.PatientsWe included women scheduled for breast cancer surgery. Two dedicated breast surgeons performed all surgeries. Surgery was by lumpectomy, total simple mastectomy or modified radical mastectomy. Exclusion criteria were: previous breast surgery, planned immediate breast reconstruction, chronic pain syndromes (e.g. fibromyalgia, osteoarthritis), regular analgesic medication for 2 weeks preceding surgery, pre-existing central nervous system pathology (e.g. stroke, dementia), conditions predisposing to neuropathy (e.g. diabetes mellitus, alcohol abuse), inability to comply with testing procedures or to give informed consent, presence of contra-indications to COX-2 therapy (including untreated hypertension, active or recent gastrointestinal ulceration) and contraindications to paravertebral blockade.Randomization and treatmentAfter obtaining informed consent during an outpatient anesthesia visit, eligible patients were randomized in a one-to-one ratio to receive perioperative COX-2 inhibition or placebo. A pseudo-random code was computer generated for the randomization blocks that had a size of six. Stratified random sampling ensured equal distribution of axillary lymph node dissections over groups. The hospital pharmacy held the randomization scheme for the trial and supplied parecoxib and celecoxib (active treatment) or placebo in blinded packages. Parecoxib is currently not FDA approved, but is widely available worldwide, including in the European Union as the only injectable COX-2 specific inhibitor. The morning of surgery, patients received oral midazolam premedication (7.5 mg). In the operating theatre, COX-2 inhibition group patients received parecoxib 40 mg i.v. 30 minutes before surgery start. This injection was repeated 6 hours later. The postoperative morning, patients started celecoxib 200mg, continued to the morning of day five postoperatively. The placebo group received placebo injections and tablets according to the same regime. Medication was blinded, neither observers nor persons involved in patient management were aware of patient assignment.Anesthesia and analgesiaParavertebral blockade was by standard technique (20 ml ropivacaine 0.75%). Before surgery, local anaesthetic blockade was tested using pin-prick. Unsuccessful block, as defined by no hypoalgesia to pinprick, led to patient exclusion. Patients received standardized general anaesthesia [28], (propofol 2–3 mg/kg, fentanyl 3 μg/kg, rocuronium 0.5 mg/kg, air/oxygen (40%), sevoflurane) to achieve haemodynamic values within 20% of preoperative baseline. For procedures longer than 45 minutes, further fentanyl supplementation (1 μg/kg) was permitted at 45 minutes and at further 45-minute intervals. No further myorelaxants were given and no antagonisation was performed. In the recovery room, initial analgesia consisted of piritramide as soon as patients complained of pain, titrated to VAS≤3 by the recovery room nurse using 3 mg intravenous increments. Thereafter, standard postoperative analgesia consisted of a fixed acetaminophen scheme (4 X 1g /day) together with on-demand tramadol (drops, maximum 300 mg/day) up to day 5 postoperatively.Measurement protocolsTrained research personnel performed all testing in a standardized fashion in a quiet room. All subjects underwent familiarization training with sensory testing before the study. Pain was assessed via 100 mm visual analogue scores at rest (lying quietly in bed) and on movement (immediately after sitting up on bed). For all postoperative pain scores, the patient was explicitly asked to report pain associated with surgery at that moment. At several time points patients were asked to complete a quality of life questionnaire assessing surgery-related symptoms and functional impairment.Postoperative changes in pain sensitivity (hyperalgesia) were quantified using electric and pressure pain tolerance thresholds. Electricity stimulates mainly cutaneous nerve endings [29], bypassing nociceptors; pressure reveals deep tissue sensitivity (e.g. muscle), with only minimal cutaneous contributions [30]. Thus electric pain tolerance thresholds mainly reflect cutaneous sensitivity and pressure pain tolerance thresholds mainly reflect deep tissue sensitivity. Thresholds were measured close to the affected breast and distant from the site of surgery to obtain measures of secondary (peri-incisional) and spreading (or generalizing) hyperalgesia, respectively. Pain modulation was assessed preoperatively via conditioned pain modulation (CPM) paradigm [31]. At no time were patients or treating personnel aware of results of pain processing tests.Baseline demographic data, electric pain tolerance thresholds, pressure pain tolerance thresholds and CPM were collected the preoperative afternoon. Pain scores, electric pain tolerance thresholds and pressure pain tolerance thresholds were collected 1, 5 and 15 days after surgery and at 1, 3, 6 and 12 months after surgery.Electric and pressure pain tolerance thresholdsElectric pain tolerance threshold testing was performed using an electric stimulation device (QST-3; JNI, Aalborg, Denmark), delivering electrical tetanic stimulation (100 Hz, 0.2-ms square waves, 0.1mA/s ramping rate) via self-adhesive skin electrodes 3 cm apart. A trained research assistant operated the device and documented the value at which stimulation became intolerable and was discontinued. Pain tolerance thresholds were determined three times and the mean value was used. Pressure pain tolerance thresholds were assessed using a pressure algometer (Somedic Sales AB, Horby, Sweden) with a 1.0 cm2 probe and a ramping rate of 50 kPa/s[28] until the patient did not accept a higher stimulus intensity. The electric pain tolerance thresholds were measured at each of the following sites on both the affected body side and the contralateral side: Radial upper arm (C6 dermatome), mid-axillary line (T4 dermatome, 5–10 cm from incision, affected side) and iliac crest (L1 dermatome). The pressure pain tolerance thresholds were measured bilaterally on the index finger (C6 dermatome), iliac crest (L1 dermatome) and sternum in the midline (T4 dermatome). To avoid mass significance and as a measure of central sensitization the sum of all the thresholds (SOT) across dermatomes was calculated [14] for the electric thresholds and for the pressure thresholds. Postoperative changes in SOTs were expressed as percentage changes compared to preoperative baseline.Conditioned pain modulation (CPM) paradigmThe condition pain modulation paradigm tests the ability to generate descending inhibitory modulation [31]. An electric pain threshold (test stimulus) was determined before and after a cold pressor task (conditioning stimulus), and the CPM effect was determined as the relative change (%) in electric pain threshold. For the cold pressor task the dominant hand was immersed in ice-chilled water (1.0°C ±0.3°C) stirred by pump. The patient was told to remove the hand from the water after two minutes of immersion–or sooner if the pain was considered intolerable–and immersion time was noted. Immediately after the cold pressor task, the subjects rated the pain experienced during the test by VAS for quality control purposes. Electric pain thresholds were obtained in the L1 dermatome immediately before and after ice-water immersion.Quality of lifeAt baseline and 1, 3, 6, and 12 months post surgery patients filled out a quality of life questionnaire (Dutch version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30). The EORTC QLQ-C30 is internationally validated for evaluating quality of life in daily living and symptoms and side effects related to different treatment modalities [32]. The individual functional, symptom and quality of life (QOL) scales were summated to create general sum scores [33]. We calculated symptom, functioning and QOL sum scores from the EORTC questionnaires.Outcome measuresThe primary study outcomes are change in electric and pressure SOT after surgery vs. baseline values. Secondary outcomes are VAS pain and EORTC symptom, functional and QOL sum scores.Power-analysisBased on data from previous postoperative quantitative sensory testing studies by our group [28, 34] we can expect electric pain tolerance thresholds in thoracic dermatomes five days after surgery to be 8.1 mA (SD = 4.5 mA). Sample size calculation based on these data for Type 1 error (alpha) of 0.05 and power (beta) of 80% predicts ability to detect a clinically relevant change in pain tolerance thresholds of one third with a sample size per group of 45 patients. Assuming a drop-out rate of 20–25%, a sample size of n = 55 per group should suffice to detect clinically relevant reductions of one-third in the pain tolerance threshold (vs. the other group) at 5 days postoperatively.Data and statistical analysisData were analyzed with Statistica (version 12.0, Statsoft, Tulsa, OK, USA), p<0.05 was considered significant. Results are expressed as mean ± 95% confidence interval. Postoperative sums of thresholds were expressed as percentage change compared to preoperative baseline. Chi-squared tests and t-tests were used to assess differences between the treatment groups regarding axillary lymph node dissection, type of surgery, duration of surgery, surgical complications, size of specimen removed, baseline electric SOT, baseline pressure SOT, baseline CPM, baseline QOL-score, baseline functioning score and baseline symptom score.Our main analysis was aimed at testing our primary hypothesis that perioperative COX-2 inhibition would result in less hyperalgesia as a sign of central sensitization following surgery compared to a placebo-supplemented group. We performed mixed model analyses on change in electric and pressure SOT, and on secondary outcomes VAS scores and EORTC sum scores with fixed factors medication (COX-2 inhibition vs. placebo) and time, and subjects were included as random factor. Preoperative CPM is reported in the literature as a predictor for persistent postsurgical pain development and was included as covariate [35]. We performed a (modified) intention to treat analysis, which included all patients that received at least one dose of study drug (COX-2 inhibition or placebo) [36–39]. Post-hoc tests with Bonferroni correction were used to identify significant differences between medication groups or time levels when a main or interaction effect for the factors was found. A two-sided p-value <0.05 was considered significant for all tests.To test our secondary hypothesis that patients developing persistent pain 12 months postoperatively would exhibit more hyperalgesia following surgery than patients not complaining of persisting pain two groups were formed post hoc: patients with persistent pain 12 months postoperatively (answering “yes” to the question:” do you have persistent pain due to your surgery”, plus reporting pain at rest or on movement of >30 mm on VAS) or those without persistent pain. The chosen cutoff score >30 mm VAS is widely used in the pain literature [40, 41], corresponds to moderate or severe pain [42], and a 30 mm VAS difference is a relevant treatment difference [43, 44]. We performed additional mixed model analyses on SOTs, pain scores and QOL scores to assess differences between these two groups. Post-hoc tests with Bonferroni correction were used to identify significant differences between patients with and without persistent pain or time levels when a main or interaction effect for the factors was found.ResultsFrom October 2006 to December 2010 a total of 327 patients were screened for eligibility and 138 patients were randomized (Fig 1). There was relatively high exclusion rate due to treatment failure (unsuccessful paravertebral block) in 5 patients and failure of the hospital pharmacy to deliver study drugs to the operating room on time in 30 patients. 6 patients were excluded because they were found not to be suffering from malignant disease after pathological examination. 94 patients were analyzed in the modified intention to treat analyses. When we compared demographics of excluded patients for mastectomy rate (32 vs. 28%, chi-squared test p = 0.59) and age (56 ± 14 vs. 53 ± 10, unpaired t-test p = 0.27) we found them to be comparable to the analyzed groups.10.1371/journal.pone.0166601.g001Fig 1Study enrollment and randomization.There were no differences in baseline and demographic data between the placebo and COX-2 inhibition group (Table 1). Surgical complications occurred in 5 patients in the placebo group, consisting of hematomas that had to be drained in 3 patients, an abscess that had to be drained, and a nipple granuloma that had to be removed operatively. One patient in the COX-2 inhibition group developed an infected seroma that had to be drained. Because immediate reconstruction was an exclusion criterion, there was only one patient (in the COX-2 inhibition group) that underwent reconstruction by insertion of a tissue expander and subpectoral prosthesis implantation (495 cc, Mentor©, Minneapolis, MN, USA) in the year following the initial breast cancer surgery. There were no harmful or unintended effects associated with COX-2 inhibition.10.1371/journal.pone.0166601.t001Table 1Demographic data of patients receiving COX-2 inhibition and placebo medication.COX-2 inhibition (n = 48)Placebo (n = 46)P-valueAge in years51 ± 955 ± 110.09Body Mass Index in kg/m226 ± 525 ± 40.46All mastectomies in %25300.56Modified radical mastectomy in %1590.57Axillary lymph node dissection in %35390.71Duration of surgery in minutes48 ± 2544 ± 200.39Size of specimen removed in cm3435 ± 747437 ± 6950.99Surgical complications in %2110.08Chemotherapy in %35430.42Radiotherapy in %67500.10Electric SOT in mA59 ± 2958 ± 200.86Pressure SOT in kPa3167 ± 13972797 ± 11020.16CPM in %40 ± 4329 ± 350.19Functioning score82 ± 1486 ± 120.14Symptom score11 ± 129 ± 70.34QOL score70 ± 2376 ± 180.23Data are mean ± sd, continuous data were compared using unpaired t-tests, binomial data using chi-squared tests. SOT, sum of thresholds, CPM, conditioned pain modulation, QOL, quality of life.Primary hypothesis: hyperalgesia and COX-2 inhibitionElectric and pressure SOTPerioperative treatment with COX-2 inhibition was not associated with postoperative differences in tolerance to electric or pressure stimulation (Fig 2 and Table 2).10.1371/journal.pone.0166601.g002Fig 2Effect of medication on electric and pressure SOT and VAS scores.Panels A + B show mean change ± 95% CI of SOT versus baseline, panels C + D show the mean ± 95 CI of VAS scores at the different time points. *Different vs. baseline (Bonferroni adjusted p<0.05); †Different vs. COX-2 inhibition (Bonferroni adjusted p<0.05). SOT, sum of thresholds, VAS, Visual Analogue Score.10.1371/journal.pone.0166601.t002Table 2Results of the main and secondary analyses.Main AnalysisSecondary AnalysisFactorMedicationTime x MedicationCPMPersistent painTime x Persistent painCPMEffect on electric SOT (P-value, effect size)0.74, 4.420.52, N/A0.04, 0.110.88, -9.560.37, N/A0.03, 0.14Pairwise comparisons (P-value, effect-size)Day 1N/AN/ADay 5N/AN/ADay 15N/AN/AMonth 1N/AN/AMonth 3N/AN/AMonth 6N/AN/AMonth 12N/AN/AEffect on pressure SOT (P-value, effect size)0.12, -7.930.99, N/A0.06, 0.16<0.01, -30.510.36, N/A0.07, 0.17Pairwise comparisons (P-value, effect-size)Day 1N/A0.35, -12.68Day 5N/A0.02, -30,96Day 15N/A<0.01, -34.97Month 1N/A<0.01, -47.09Month 3N/A0.02, -30.95Month 6N/A<0.01, -41.47Month 12N/A0.03, -30.51Effect on VAS at rest (P-value, effect size)0.47, -0.180.31, N/A0.61, -0.01<0.01, 18.97<0.01, N/A0.14, -0.03Pairwise comparisons(P-value, effect-size)BaselineN/A0.57, 2.00Day 1N/A<0.01, 22.10Day 5N/A0.05, 6.75Day 15N/A0.03, 7.74Month 1N/A0.02, 7.98Month 3N/A<0.01, 12.89Month 6N/A<0.01, 14.75Month 12N/A<0.01, 18.97Effect on VAS on movement (P-value, effect size)0.44, -0.280.02, N/A0.70, 0.01<0.01, 47.20<0.01, N/A0.73, 0.01Pairwise comparisons (P-value, effect-size)Baseline0.92, -0.390.29, 5.34Day 1<0.01, -11.09<0.01, 29.41Day 50.75, -1.24<0.01, 18.71Day 150.35, 3.70<0.01, 17.03Month 10.12, -6.19<0.01, 17.66Month 30.98, -0.12<0.01, 28.83Month 60.71, -1.50<0.01, 27.22Month 120.95, -0.28<0.01, 47.20Effect on function score (P-value, effect size)0.31, -0.520.48, N/A0.39, 0.03<0.01, -12.590.38, N/A0.34, 0.04Pairwise comparisons (P-value, effect-size)BaselineN/A0.19, -6.52Month 1N/A0.06, -9.47Month 3N/A<0.01, -15.91Month 6N/A<0.01, -13.29Month 12N/A0.02, -12.59Effect on symptom score (P-value, effect size)0.30, -0.250.21, N/A0.73, -0.01<0.01, 16.69<0.01, N/A0.41, -0.02Pairwise comparisons (P-value, effect-size)BaselineN/A0.24, 4.08Month 1N/A<0.01, 9.56Month 3N/A<0.01, 16.37Month 6N/A<0.01, 13.05Month 12N/A<0.01, 16.69Effect on QOL score (P-value, effect size)0.28, 0.040.57, N/A0.53, 0.02<0.01, -14.140.14, N/A0.34, 0.03Pairwise comparisons (P-value, effect-size)BaselineN/A0.14, -6.13Month 1N/A0.02, -9.56Month 3N/A<0.01, -15.55Month 6N/A<0.01, -12.28Month 12N/A<0.01, -14.14SOT, sum of thresholds, VAS, vusual analogue scale, QOL, quality of life. P-values for post-hoc test were adjusted for multiple testing using Bonferroni correction.VAS scoresCOX-2 inhibition did not affect VAS scores at rest but influenced VAS scores on movement (Time x Medication: p = 0.02)–Fig 2 and Table 2. Post-hoc testing revealed that COX-2 inhibition led to lower postoperative VAS score on movement only on postoperative day 5.Preoperative CPMCovariate preoperative CPM significantly affected electric SOT (p = 0.04), and showed a trend towards significance on pressure SOT (p = 0.06)–Table 2. Impaired preoperative CPM was related to more negative postoperative change in sensitivity. Of note, preoperative CPM did not influence postoperative VAS scores at rest or on movement.EORTC sum scoresEORTC functioning, symptom and QOL score were comparable between treatment groups (Fig 3 and Table 2).10.1371/journal.pone.0166601.g003Fig 3Effects of medication on EORTC function, symptom and QOL sum scores.Panels A-C show the mean ± 95% CI at the different time points. No difference between treatment groups at any time (all p>0.05). QOL, quality of life.Secondary hypothesis: persistent pain and hyperalgesiaPersistent postsurgical painTwelve months postoperatively 11 patients (13%) complained of persistent pain with VAS>30 mm. Characteristics of patients that eventually would develop persistent pain and patients free of pain are displayed in Table 3. Patients that would eventually develop persistent pain had higher baseline pressure SOT and electric SOT.10.1371/journal.pone.0166601.t003Table 3Baseline characteristics of patients that eventually developed persistent and patients without pain.With/Without persistent postsurgical painWith persistent pain (n = 11)Without persistent pain (n = 83)P-valueAge in years53 ± 754 ± 100.79Body mass index in kg/m227 ± 726 ± 40.37All mastectomies in %36270.53Modified radical mastectomy in %2780.17Axillary lymph node dissection in %54360.23Duration of surgery in minutes46 ± 2253 ± 270.34Size of specimen removed in cm3508 ± 872459 ± 7410.84Surgical complications in %960.70Chemotherapy in %45390.66Radiotherapy in %64600.82Electric SOT in mA81 ± 3756 ± 22<0.01Pressure SOT in kPa4114 ± 14162821 ± 1224<0.01CPM in %28 ± 5633 ± 330.65Functioning score78 ± 1685 ± 130.12Symptom score14 ± 129 ± 90.20QOL score80 ± 1387± 110.09Data are mean ± sd, continuous data were compared using unpaired t-tests, binomial data using chi-squared tests. SOT, sum of thresholds, QOL, quality of life, CPM, conditioned pain modulation.Electric and pressure SOTPatients in the persistent postsurgical pain group did not exhibit postoperative hyperalgesia to electric stimulation, but were significantly more hyperalgesic postoperatively to pressure stimulation (Persistent pain: p<0.01)–Fig 4 and Table 2. Post-hoc analysis revealed that persistent pain patients were hyperalgesic to pressure stimulation versus patients not developing pain on day 5 and throughout the rest of the postoperative year.10.1371/journal.pone.0166601.g004Fig 4Electric and pressure SOT and VAS scores in persistent pain patients versus women without pain.Panels A + B show mean change ± 95% CI of SOT versus baseline, panels C + D show the mean ± 95% CI of VAS scores at the different time points. *Different vs. baseline (Bonferroni adjusted p<0.05); † Different vs. No persistent pain (Bonferroni adjusted p<0.05). SOT, sum of thresholds, VAS, Visual Analogue Score.VAS scoresPersistent pain patients had significantly higher postoperative pain VAS scores at rest (Persistent pain: p<0.01, Time x Persistent pain: p<0.01) and on movement (Persistent pain: p = <0.01, Time x Persistent pain: p<0.01)–Fig 4 and Table 2. These differences existed at all early and late postoperative timepoints, except for VAS at rest on day 5. Paravertebral blockade provided excellent postoperative pain relief in the patients not developing persistent postsurgical pain.Preoperative CPMCovariate preoperative CPM significantly affected electric SOT (p = 0.03) and showed a trend towards significance on pressure SOT (p = 0.07)–Table 2. Impaired preoperative CPM was related to more negative postoperative change in sensitivity. Preoperative CPM did not influence postoperative VAS scores at rest or on movement.EORTC sum scoresPatients in the persistent postsurgical pain group reported lower functioning score (Persistent pain: p<0.01) and total QOL (Persistent pain: p<0.01), and higher symptom score (Persistent pain: p<0.01, Time x Persistent pain: p<0.01)–Fig 5 and Table 2. Lower functioning score was present at 3, 6 and 12 months postoperatively for persistent pain patients. Persistent pain was associated with higher symptom score and lower total QOL score at 1, 3, 6 and 12 months postoperatively.10.1371/journal.pone.0166601.g005Fig 5EORTC function, symptom and QOL sum scores in persistent pain patients versus patients with no pain.Panels A-C show the mean ± 95 CI at the different time points. *Different vs. baseline (Bonferroni adjusted p<0.05); † Different vs. No persistent pain (Bonferroni adjusted p<0.05). QOL, quality of life.DiscussionWe assessed the value of inhibiting the inflammatory component of sensitization added to blockade of neuronal nociceptive input (paravertebral blockade) on central sensitization (expressed as widespread hyperalgesia) and persistent pain after surgery in women undergoing surgery for breast malignancy. Adding perioperative COX-2 inhibition to maximal anti-nociceptive therapy had no impact on change in electric or pressure pain tolerance thresholds as a measure of central sensitization after breast cancer surgery. COX-2 inhibition did lead to lower pain scores on movement at postoperative day 5, but had no effect on later time points and did not affect quality of life scores. Thus, our primary hypothesis was rejected.We found that patients developing persistent postsurgical pain were significantly more hyperalgesic to pressure both early after surgery (5 days) and throughout the rest of the year (15 days to 12 months). Thus, our secondary hypothesis was confirmed. There was no difference in sensitivity to electric quantitative sensory testing. Patients with persisting pain 12 months postoperatively had more pain in the acute postoperative period (1, 5 and 15 days) and the rest of the year (1, 3 and 6 months). Total QOL and functioning scores were lower in persistent pain patients and symptom score was higher vs. patients not developing persisting pain.Our study describes the effects of perioperative COX-2 inhibition on postoperative sensitization of pain processing in a long-term prospective and longitudinal trial. Regarding persistent pain (but not hyperalgesia) after breast surgery some data are available regarding perioperative COX-2 inhibition. Romundstad et al. [45] found no difference versus placebo of a single peri-operative dose of 40 mg parecoxib on persistent pain one year after surgery in patients undergoing augmentation mammaplasty. Another trial [46] reported no impact on pain six months postoperatively of ibuprofen 400 mg before mastectomy plus four additional doses afterwards.Surgical tissue damage is associated with prostanoid production [47]. This release, involving COX-2 induction, occurs peripherally and in the central nervous system [24]. Peripheral release of prostanoids (PGE-2, PGI-2) sensitizes peripheral nociceptors. Centrally synthesized PGE-2, by increased COX-2-expression, leads directly to central sensitization of the pain system [24, 48, 49]. COX-2 inhibitors interfere with both the peripheral and the central prostaglandin production [27]. Therefore, perioperative inhibition of COX-2 was expected to ameliorate central sensitization and to increase pain thresholds, by both inhibiting peripheral nociceptive input and by inhibiting direct central sensitization under influence of prostaglandins. We did not observe this expected difference, suggesting that perioperative COX-2 induction and inflammation subsequent to tissue damage may be of little importance in inducing postoperative central sensitization. Interestingly, a small recent trial with parecoxib failed to induce a difference in pressure pain tolerance thresholds in CPRS patients outside the surgical context [50].The generalized pressure hyperalgesia detected in this study suggests that persistent central sensitization is an important process in persisting pain development after surgery. Other quantitative sensory testing studies have assessed pain processing in women with persistent pain at single time-points after breast cancer surgery. These studies confirm the widespread mechanical hyperalgesia we observed [51, 52]. Others have demonstrated enhanced sensitivity to electrical and thermal stimulation [53, 54], further supporting the presence of central sensitization in persistent pain after breast cancer treatment. Recently, Andersen et al. found a relationship between sensory disturbances and pain one week after surgery for breast cancer [55]. Hyperalgesia has also been reported 5 days after back surgery [56] and early postoperative hyperalgesia has been linked to persistent pain development in smaller studies after abdominal surgery [57, 58]. Hyperalgesia in the postoperative period is likely to be expressed as increased pain experience, which we found for both VAS at rest and on movement. A significant relationship between early postoperative pain and persistent pain has previously been reported for breast cancer surgery [13] and other interventions including cholecystectomy [8, 9], groin hernia repair [10] and thoracic surgery [12].We observed a relatively low incidence of persistent postsurgical pain following surgery (13%) compared to other less recent studies (25 to 60%)[59]. Maximal peri-operative blockade of neuronal nociceptive input (paravertebral blockade), but also identification and attention to sparing intercostobrachial and other nerves during lymph node dissection in the present study [22], may explain the low incidence of persistent pain.ImplicationsOur results indicate that the role of COX-2 and inflammation in the genesis of postoperative hyperalgesia may be less important than that of neuronally mediated nociceptive input. Adding perioperative COX-2 inhibition to maximal neuronal anti-nociceptive therapy (paravertebral blockade) appears of limited clinical value in preventing postoperative hyperalgesia or persistent pain.Despite all patients receiving maximal neuronal anti-nociceptive therapy in the form of paravertebral blockade, 13% of patients still developed persistent pain postoperatively. These patients showed widespread hyperalgesia to pressure in the acute postoperative period and the rest of the year and would seem to be relatively resistant to current therapeutic interventions. Future studies should further explore causes of developing early and persistent postoperative hyperalgesia, possibly an important process during persistent pain development.Clinically, the fact that persistent pain patients showed more widespread hyperalgesia to pressure in the acute postoperative period means that peri-operative monitoring using quantitative sensory testing should be able to identify patients at risk of developing persistent postsurgical pain, possibly allowing for targeted antihyperalgesic treatment.There is increasing interest in the potential for perioperative quantitative sensory testing to predict persistent postsurgical pain. A relationship between peri-operative quantitative sensory testing measures and persistent pain has thus far been shown in only a limited number of studies. These studies demonstrated an association between persistent postsurgical pain and preoperative measures of widespread pain sensitization, such as pressure pain thresholds [60–63]. However most of these studies were conducted in the context of orthopedic joint surgery and represent a very different patient population. In the orthopedic population patients have often suffered from ongoing pain and nociceptive input for a prolonged time preoperatively, which may have lead to sensitized central pain processing even before surgery. Conversely, patients undergoing surgery for breast cancer are highly unlikely to have suffered from significant pain preoperatively and are thus unlikely to express centrally sensitized pain processing preoperatively. Future studies should clarify which quantitative sensory measurement at which time point can best predict persistent pain in the breast cancer population.Prediction and possible interventions targeting persistent pain after breast cancer surgery are especially relevant given the poorer function scores and QOL we found with persistent pain after breast cancer surgery. Furthermore, persistent pain after breast cancer surgery is increasing in prevalence due to increased survival after breast cancer [59].Methods and limitationsWe chose quantitative sensory testing measures as the main outcome measures because we intended to conduct a study investigating relations between COX-2 inhibition, hyperalgesia development and persistent pain after surgery. Pressure quantitative sensory testing detects hyperalgesia of deep tissues such as muscle as a manifestation of central sensitization [30], and is considered a clinically robust and reliable measurement [64]. Electric quantitative sensory testing stimulates peripheral cutaneous nerve endings bypassing peripheral nociceptors in skin and is sensitive to local and descending modulation [29]. These characteristics may explain why we found differences in pressure tolerance thresholds–but not in electric tolerance thresholds–in persistent pain patients.We measured electric and pressure pain tolerance thresholds at multiple topographic sites. Others have advocated extensive multimodal quantitative sensory testing protocols [65]. These protocols permit quantification of several different aspects of hyperalgesia, without, however, achieving testing altered sensitivity at multiple sites, and are time-consuming. We chose our battery of tests for its suitability for implementation into clinical practice. This testing protocol generally lasts about 30 minutes and is well-accepted by patients with good reproducibility (within 20%)[66].Two limitations pertain to this study. First, we were unable to include some patients in the modified intention to treat analysis due to treatment failure, and had to exclude some patients due to an incorrect initial diagnosis. However, we achieved the group size we calculated beforehand to deliver sufficient power to detect a 30% difference from baseline and the analyzed treatment groups were comparable for baseline characteristics. A second limitation was the small number of patients developing pain 12 months postoperatively. A larger study population and thus a larger group of pain patients might have provided more insight into the deferential characteristics of persistent pain patients vs. patients not suffering from pain, even though we were able to detect several significant differences between the groups that we analyzed.ConclusionsIn conclusion, we found that adding perioperative COX-2 inhibition to current maximal anti-nociceptive therapy (paravertebral blockade) has no significant impact on central sensitization, persistent pain and QOL in the year following breast cancer surgery. Patients that developed persistent pain after breast cancer surgery were significantly more hyperalgesic, had higher pain scores and lower QOL throughout the year following surgery. 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Epub 2012/05/26. 10.1111/j.1365-2354.2012.01367.x\n2262466334Wilder-SmithOH, Arendt-NielsenL, GaumannD, TassonyiE, RifatKR. Sensory changes and pain after abdominal hysterectomy: a comparison of anesthetic supplementation with fentanyl versus magnesium or ketamine. Anesthesia and analgesia. 1998;86(1):95–101. Epub 1998/01/16. 942885935YarnitskyD. Conditioned pain modulation (the diffuse noxious inhibitory control-like effect): its relevance for acute and chronic pain states. Current opinion in anaesthesiology. 2010;23(5):611–5. Epub 2010/06/15. 10.1097/ACO.0b013e32833c348b\n2054367636WalshTJ, FinbergRW, ArndtC, HiemenzJ, SchwartzC, BodensteinerD, et al\nLiposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group. The New England journal of medicine. 1999;340(10):764–71. Epub 1999/03/11. 10.1056/NEJM199903113401004\n1007241137SolomkinJS, WilsonSE, ChristouNV, RotsteinOD, DellingerEP, BennionRS, et al\nResults of a clinical trial of clinafloxacin versus imipenem/cilastatin for intraabdominal infections. Annals of surgery. 2001;233(1):79–87. Epub 2001/01/05. PubMed Central PMCID: PMCPMC1421170. 1114122938VahdatLT, PruittB, FabianCJ, RiveraRR, SmithDA, Tan-ChiuE, et al\nPhase II study of eribulin mesylate, a halichondrin B analog, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2009;27(18):2954–61. Epub 2009/04/08.1934955039CaraceniA, ZeccaE, BonezziC, ArcuriE, Yaya TurR, MaltoniM, et al\nGabapentin for neuropathic cancer pain: a randomized controlled trial from the Gabapentin Cancer Pain Study Group. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2004;22(14):2909–17. 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Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain. 2001;94(2):149–58. Epub 2001/11/03. 1169072845RomundstadL, BreivikH, RoaldH, SkolleborgK, RomundstadPR, StubhaugA. Chronic pain and sensory changes after augmentation mammoplasty: long term effects of preincisional administration of methylprednisolone. Pain. 2006;124(1–2):92–9. Epub 2006/05/03. 10.1016/j.pain.2006.03.020\n1665058046LakdjaF, DixmeriasF, BussieresE, FonrougeJM, LoberaA. [Preventive analgesic effect of intraoperative administration of ibuprofen-arginine on postmastectomy pain syndrome]. Bulletin du cancer. 1997;84(3):259–63. Epub 1997/03/01. 920787147SamadTA, SapirsteinA, WoolfCJ. Prostanoids and pain: unraveling mechanisms and revealing therapeutic targets. Trends in molecular medicine. 2002;8(8):390–6. Epub 2002/07/20. 1212772548MaW, DuW, EisenachJC. 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Epub 2010/12/15.52SchreiberKL, MartelMO, ShnolH, ShafferJR, GrecoC, VirayN, et al\nPersistent pain in postmastectomy patients: comparison of psychophysical, medical, surgical, and psychosocial characteristics between patients with and without pain. Pain. 2013;154(5):660–8. Epub 2013/01/08. PubMed Central PMCID: PMCPMC3863788. 10.1016/j.pain.2012.11.015\n2329025653GottrupH, AndersenJ, Arendt-NielsenL, JensenTS. Psychophysical examination in patients with post-mastectomy pain. Pain. 2000;87(3):275–84. Epub 2000/08/30. 1096390754VilholmOJ, ColdS, RasmussenL, SindrupSH. Sensory function and pain in a population of patients treated for breast cancer. Acta anaesthesiologica Scandinavica. 2009;53(6):800–6. Epub 2009/04/29. 10.1111/j.1399-6576.2009.01938.x\n1939750555AndersenKG, DuriaudHM, AasvangEK, KehletH. Association between sensory dysfunction and pain 1 week after breast cancer surgery: a psychophysical study. Acta anaesthesiologica Scandinavica. 2015. Epub 2015/10/09.56Wilder-SmithOH, TassonyiE, CrulBJ, Arendt-NielsenL. Quantitative sensory testing and human surgery: effects of analgesic management on postoperative neuroplasticity. Anesthesiology. 2003;98(5):1214–22. Epub 2003/04/30. 1271714457Wilder-SmithOH, SchreyerT, SchefferGJ, Arendt-NielsenL. Patients with chronic pain after abdominal surgery show less preoperative endogenous pain inhibition and more postoperative hyperalgesia: a pilot study. J Pain Palliat Care Pharmacother. 2010;24(2):119–28. Epub 2010/05/28. 10.3109/15360281003706069\n2050413358Lavand'hommeP, De KockM, WaterloosH. Intraoperative epidural analgesia combined with ketamine provides effective preventive analgesia in patients undergoing major digestive surgery. Anesthesiology. 2005;103(4):813–20. Epub 2005/09/30. 1619277459AndersenKG, KehletH. Persistent pain after breast cancer treatment: a critical review of risk factors and strategies for prevention. The journal of pain: official journal of the American Pain Society. 2011;12(7):725–46. Epub 2011/03/26.2143595360WyldeV, SayersA, LenguerrandE, Gooberman-HillR, PykeM, BeswickAD, et al\nPreoperative widespread pain sensitization and chronic pain after hip and knee replacement: a cohort analysis. Pain. 2015;156(1):47–54. Epub 2015/01/20. PubMed Central PMCID: PMCPMC4280282. 10.1016/j.pain.0000000000000002\n2559930061YarnitskyD, CrispelY, EisenbergE, GranovskyY, Ben-NunA, SprecherE, et al\nPrediction of chronic post-operative pain: pre-operative DNIC testing identifies patients at risk. Pain. 2008;138(1):22–8. Epub 2007/12/15. 10.1016/j.pain.2007.10.033\n1807906262LundbladH, KreicbergsA, JanssonKA. Prediction of persistent pain after total knee replacement for osteoarthritis. J Bone Joint Surg Br. 2008;90(2):166–71. Epub 2008/02/08. 10.1302/0301-620X.90B2.19640\n1825608263GwilymSE, OagHC, TraceyI, CarrAJ. Evidence that central sensitisation is present in patients with shoulder impingement syndrome and influences the outcome after surgery. J Bone Joint Surg Br. 2011;93(4):498–502. Epub 2011/04/06. 10.1302/0301-620X.93B4.25054\n2146448964GeberC, KleinT, AzadS, BirkleinF, GierthmuhlenJ, HugeV, et al\nTest-retest and interobserver reliability of quantitative sensory testing according to the protocol of the German Research Network on Neuropathic Pain (DFNS): a multi-centre study. Pain. 2011;152(3):548–56. Epub 2011/01/18. 10.1016/j.pain.2010.11.013\n2123756965RolkeR, BaronR, MaierC, TolleTR, TreedeRD, BeyerA, et al\nQuantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain. 2006;123(3):231–43. Epub 2006/05/16. 10.1016/j.pain.2006.01.041\n1669711066Wilder-SmithOH. A Paradigm-Shift in Pain Medicine: Implementing a Systematic Approach to Altered Pain Processing in Everyday Clinical Practice. Based on Quantitative Sensory Testing. Aalborg, Denmark: Aalborg Univesity; 2013.", 'title': 'Hyperalgesia and Persistent Pain after Breast Cancer Surgery: A Prospective Randomized Controlled Trial with Perioperative COX-2 Inhibition.', 'date': '2016-12-10'}}
| 0
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Surgery
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48
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Is pain intensity 24 (± 12) hours following surgery higher, lower, or the same when comparing NSAIDs to placebo?
|
lower
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low
|
yes
|
['31800611', '16146476', '8770304']
| 34,753,201
| 2,021
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{'31800611': {'article_id': '31800611', 'content': 'PLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of ScienceSan Francisco, CA USA31800611689254410.1371/journal.pone.0225748PONE-D-19-18133Research ArticleMedicine and Health SciencesOncologyCancers and NeoplasmsBreast TumorsBreast CancerMedicine and Health SciencesSurgical and Invasive Medical ProceduresMedicine and Health SciencesOncologyCancer TreatmentSurgical OncologyMedicine and Health SciencesClinical MedicineClinical OncologySurgical OncologyMedicine and Health SciencesOncologyClinical OncologySurgical OncologyMedicine and health sciencesPharmacologyDrugsAnalgesicsNSAIDsMedicine and health sciencesPain managementAnalgesicsNSAIDsMedicine and Health SciencesOncologyCancer TreatmentResearch and Analysis MethodsResearch DesignClinical Research DesignAdverse EventsResearch and Analysis MethodsResearch DesignRetrospective StudiesMedicine and Health SciencesDiagnostic MedicineSigns and SymptomsHemorrhageMedicine and Health SciencesPathology and Laboratory MedicineSigns and SymptomsHemorrhageMedicine and Health SciencesVascular MedicineHemorrhageIntraoperative ketorolac in high-risk breast cancer patients. A prospective, randomized, placebo-controlled clinical trialKetorolac during breast cancer surgeryhttp://orcid.org/0000-0001-5772-8439ForgetPatriceConceptualizationData curationFormal analysisFunding acquisitionInvestigationMethodologyProject administrationResourcesSupervisionValidationVisualizationWriting – original draftWriting – review & editing1*BoucheGauthierConceptualizationInvestigationMethodologyValidationVisualizationWriting – original draftWriting – review & editing2http://orcid.org/0000-0002-5429-7888DuhouxFrancois P.ConceptualizationData curationFormal analysisInvestigationMethodologyValidationWriting – review & editing3http://orcid.org/0000-0003-2916-2938CouliePierre G.ConceptualizationMethodologySupervisionValidationVisualizationWriting – review & editing4http://orcid.org/0000-0001-5812-1823DecloedtJanData curationInvestigationResourcesSupervisionVisualizationWriting – review & editing5DekleermakerAlainConceptualizationData curationInvestigationProject administrationWriting – review & editing6GuillaumeJean-EdouardData curationInvestigationResourcesWriting – review & editing7LedentMarcData curationInvestigationResourcesSupervisionValidationWriting – review & editing8MachielsJean-PascalConceptualizationInvestigationMethodologyResourcesSupervisionValidationWriting – review & editing3MustinVéroniqueData curationInvestigationResourcesSupervisionWriting – review & editing8http://orcid.org/0000-0001-5387-149XSwinnenWalterData curationInvestigationResourcesSupervisionWriting – review & editing9van MaanenAlineConceptualizationData curationMethodologyProject administrationResourcesSupervisionValidationVisualizationWriting – review & editing10Vander EssenLionelData curationInvestigationResourcesSupervisionWriting – review & editing8VerougstraeteJean-ChristopheData curationInvestigationResourcesSupervisionWriting – review & editing11De KockMarcConceptualizationData curationInvestigationMethodologyResourcesSupervisionValidationWriting – review & editing12BerliereMartineConceptualizationData curationInvestigationMethodologyProject administrationResourcesSupervisionValidationWriting – review & editing131\nInstitute of Applied Health Sciences, Epidemiology group, School of Medicine, Medical Science and Nutrition, University of Aberdeen, Department of Anaesthesia, NHS Grampian, Aberdeen, United Kingdom2\nThe Anticancer Fund, Brussels, Belgium3\nInstitut Roi Albert II, Service d’Oncologie Médicale, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (POLE MIRO), UCLouvain, Brussels, Belgium4\nde Duve Institute, UCLouvain, Brussels, Belgium5\nDepartment of Oncology, St-Blasius Hospital, Dendermonde, Belgium6\nClinical Pharmacology Unit, Cliniques Universitaires Saint-Luc, Brussels, Belgium7\nDepartment of Anesthesiology, Ste-Elisabeth hospital, Namur, Belgium8\nDepartment of Anesthesiology, St-Pierre Clinic, Ottignies, Belgium9\nDepartment of Anesthesiology, St-Blasius Hospital, Dendermonde, Belgium10\nBiostatistics Unit, King Albert II Institute, Cliniques Universitaires Saint-Luc, Brussels, Belgium11\nDepartment of Gynecology, St-Pierre Clinic, Ottignies, Belgium12\nDepartment of Anesthesiology, Centre Hospitalier Wallonie Picarde (CHWAPI), Tournai, Belgium13\nDepartment of Gynecology, Breast Clinic, King Albert II Institute, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, BelgiumGuptaSudeepEditorTata Memorial Centre, INDIACompeting Interests: The authors have declared that no competing interests exist.* E-mail: forgetpatrice@yahoo.fr412201920191412e0225748266201910112019© 2019 Forget et al2019Forget et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.BackgroundKetorolac has been associated with a lower risk of recurrence in retrospective studies, especially in patients with positive inflammatory markers. It is still unknown whether a single dose of pre-incisional ketorolac can prolong recurrence-free survival.MethodsThe KBC trial is a multicenter, placebo-controlled, randomized phase III trial in high-risk breast cancer patients powered for 33% reduction in recurrence rate (from 60 to 40%). Patients received one dose of ketorolac tromethamine or a placebo before surgery. Eligible patients were breast cancer patients, planned for curative surgery, and with a Neutrophil-to-Lymphocyte Ratio≥4, node-positive disease or a triple-negative phenotype. The primary endpoint was Disease-Free Survival (DFS) at two years. Secondary endpoints included safety, pain assessment and overall survival.FindingsBetween February 2013 and July 2015, 203 patients were assigned to ketorolac (n = 96) or placebo (n = 107). Baseline characteristics were similar between arms. Patients had a mean age of 55.7 (SD14) years.At two years, 83.1% of the patients were alive and disease free in the ketorolac vs. 89.7% in the placebo arm (HR: 1.23; 95%CI: 0.65–2.31) and, respectively, 96.8% vs. 98.1% were alive (HR: 1.09; 95%CI: 0.34–3.51).ConclusionsA single administration of 30 mg of ketorolac tromethamine before surgery does not increase disease-free survival in high risk breast cancer patients. Overall survival difference between ketorolac tromethamine group and placebo group was not statistically significant. The study was however underpowered because of lower recurrence rates than initially anticipated. No safety concerns were observed.Trial registrationClinicalTrials.gov NCT01806259.Anticancer Fundhttp://orcid.org/0000-0001-5772-8439ForgetPatriceSARBhttp://orcid.org/0000-0001-5772-8439ForgetPatriceFondation Saint-Luchttp://orcid.org/0000-0001-5772-8439ForgetPatriceCommission du Patrimoine, UCLouvainhttp://orcid.org/0000-0001-5772-8439ForgetPatriceThis work is financed by grants received by PF, in the name of his institution: the Anticancer Fund (no grant number) (www.anticancerfund.org); the Belgian Society of Anaesthesia and Resuscitation (no grant number) (www.sarb.be); the Fondation Saint-Luc (no grant number) (www.uclouvain.be); the Commission du Patrimoine of the Université catholique de Louvain, St-Luc Hospital (exceptional grant, no number) (www.uclouvain.be). None of the funders had any role in the study design, data collection and analysis, decision to publish or preparation of the manuscript except the scientific advise of GB, scientific director of the Anticancer Fund.Data AvailabilityThe anonymised data are annexed to this submission.Data AvailabilityThe anonymised data are annexed to this submission.IntroductionNon-steroidal anti-inflammatory drugs (NSAIDs) are recommended to improve pain control in the perioperative period [1]. Beyond their analgesic role, some drugs of the NSAID family, such as aspirin, may improve postoperative oncological outcomes [2, 3].The biological effects of NSAIDs could be particularly relevant to the perioperative period, as this period is marked by an activation of inflammatory pathways, which could contribute to accelerated tumor growth and dissemination [4, 5]. In both animal models [6, 7] and retrospective studies [3, 8], perioperative administration of NSAID has been associated with lower risk of cancer recurrence. Within the NSAID family, ketorolac—routinely used during surgery—has been identified as one of the most interesting candidates to prevent recurrence in breast, lung and ovarian cancer [3, 9–11].In the breast cancer studies, this association was particularly noted in patients at high risk of early recurrence, i.e. related to tumor-related factors (e.g. a triple-negative phenotype), signs of early dissemination (lymph-node invasion) and/or preoperative systemic inflammation as measured by the neutrophil-to-lymphocyte ratio (NLR) [3, 10, 12]. The NLR score has been proposed as a preoperative prognostic factor in multiple cancer types [13] including breast cancer [14]. In our retrospective study, a high NLR was associated with a higher risk of recurrence irrespective of the stage or of the type of breast cancer surgery [15].Ideally, the administration of ketorolac should be limited to the shortest possible period [16], as the use of the intravenous route is limited to a few hours in case of one day surgery. A single dose of ketorolac may also be acceptable for patients with relative contraindications, such as impaired renal function, respiratory contraindication or previous digestive bleeding.Consequently, a randomized, placebo-controlled, trial was designed to test the hypothesis that a single intraoperative dose of ketorolac may be associated with a prolonged disease-free survival after surgery in high risk breast cancer patients (NCT01806259) [15]. The primary objective was to investigate the effect of perioperative ketorolac on disease-free survival (DFS) at 2 years after breast cancer surgery.Patients and methodsStudy designThe study was approved by the institutional review boards of all participating centers (central ethics committee: Université catholique de Louvain, Chairperson: Jean-Marie Maloteaux, EUDRACT 2012-003774-76) and the study was conducted in accordance with the Declaration of Helsinki and applicable national and European laws. Patients provided written informed consent.The KBCt trial was registered before patients enrollment (Principal investigator: Patrice Forget, NCT01806259, date of registration: March 7, 2013). This is a Belgian, multicenter, prospective, double-blind, placebo-controlled, randomized phase III trial in high risk breast cancer patients. Each patient was assigned to the ketorolac or the placebo group. Patients were given one dose of ketorolac tromethamine (Taradyl®, N.V. Roche S.A., Belgium) or a matching placebo. Each patient was randomly assigned on a 1:1 ratio to receive either 30 mg of ketorolac or a placebo during the induction of anesthesia (pre-incision). The placebo consisted of NaCl 0.9% (3 mL) and was identically presented to ensure double blinding. No dose modification was allowed because only one single dose was administered.The standardized anesthetic protocol included: bolus followed by a continuous infusion of propofol (as needed to maintain bispectral index value between 40 to 60 during the surgery), ketamine 0.3 mg/kg, clonidine as needed to maintain hemodynamic stability (up to 4 μg/kg) and sufentanil by boluses of 0.1 μg/kg as needed. Airways were instrumented by a laryngeal mask airway. Postoperative analgesia included, for all the patients, the use of acetaminophen as needed (3 to 4 g/day), tramadol 50 mg (and intramuscular piritramide 10 mg, a lipophilic morphinomimetic with 0.7 of the potency of morphine, every 6 hours in the case of severe pain).Neoadjuvant treatment, surgery and adjuvant treatment were done according to standard practices at the participating centers. Follow-up was performed by the local oncologist, every 3 months after surgery for 2 years, then every 6 months for 3 years, and at least yearly thereafter.PatientsEligible patients were ≥18 and ≤75 years old with histologically or cytologically confirmed, invasive ductal or lobular breast carcinoma planned for curative breast cancer surgery. In addition, to be considered high-risk, patients had to have one of the of 3 following criteria: (i) a NLR≥4 or (ii) node-positive disease (cN1-N3) or (iii) a triple-negative phenotype. The main exclusion criteria were body weight below 50kg or above 100 kg, presence of any contra-indication to ketorolac, and a history of invasive cancer within the previous 5 years.Randomization, endpoints and statistical analysisRandomization of eligible patients was done the day before surgery and used randomization blocks of 4. There was no stratification factor. In each center, a randomization list was kept accessible exclusively to the pharmacist in charge of the preparation of the study product (ketorolac or placebo). For each patient, a sealed opaque envelope was provided to permit immediate unblinding in case of emergency.The primary endpoint of the study was Disease-Free Survival (DFS) defined as time from randomization to recurrence of invasive breast cancer; contralateral invasive breast cancer; second non-breast malignancy; or death from any cause, whichever came first [17]. Secondary endpoints were: overall survival (OS), loco-regional recurrence-free survival (LR-RFS), distant metastasis recurrence-free survival (DM-RFS), safety (intra- & post-operative blood loss, adverse events) and post-operative pain.Based on the retrospective study and other trials in the perioperative setting [18], the study was designed to detect a 33% reduction in the risk of recurrence. With a power of 0.8 and an alpha of 0.05, 100 high risk patients per group was then needed to detect a DFS increase from 40% to 60% at 2 years.The intention-to-treat population was used for all efficacy analyses and per-protocol population was used for sensitivity testing. Patients\' demographics, baseline characteristics (including tumor characteristics and Nottingham Prognostic Index) and oncological treatments were summarized using descriptive statistics (mean, standard deviation, median, minimum and maximum values) for continuous parameters and frequencies and percentages for categorical data. DFS and OS were estimated using the Kaplan-Meier method and compared between groups by the Log-Rank test. Hazard Ratio (HR) comparing ketorolac with placebo and 95% Confidence Intervals (CIs) were estimated from a Cox proportional hazards model. Safety analyses included incidence of SAEs, intra- and postoperative bleeding. Treatment group comparisons were performed using Mann-Whitney test, Fisher or Chi-square as appropriate. All statistical tests were 2-sided with a 5% Type I error.All data were collected using REDCap (Research Electronic Data Capture System, Vanderbilt University) and analyzed using SAS statistical software version 9.4 (Copyright, SAS Institute Inc.).ResultsBetween February 2013 and July 2015, 203 patients from 4 sites in Belgium were randomly assigned to ketorolac (n = 96) or placebo (n = 107) (Fig 1). A difference in patient numbers appeared due to the use of a stratified randomization (by block, by centres).10.1371/journal.pone.0225748.g001Fig 1CONSORT diagram.The data cutoff for the primary efficacy analysis (DFS) was February 2018 with a median follow-up of 26.9 months.Patients’ characteristicsPatients’ characteristics are summarized in Table 1. Baseline characteristics were similar between arms. Patients were considered at high risk of recurrence either because of a positive clinical lymph node status (n = 152), because of a triple-negative phenotype (n = 40), because of a NLR ≥4 (n = 28), or because of at least 2 of these criteria (TN & N+ (n = 10), TN & NLR (n = 3), N+ & NLR (n = 4), all 3 criteria (n = 0)). Patients had a mean age of 55.7 (SD 14) years ranging from 28 to 85. All were female except for 1 male in the ketorolac group. One patient was included despite a metastasis at diagnosis (site) and was randomized to ketorolac. This patient was included in all further analyses (intention-to-treat). All patients received the allocated treatment and all underwent surgery after randomization.10.1371/journal.pone.0225748.t001Table 1Baseline characteristics of the patients, tumors, and treatments.CharacteristicsKetorolacN = 96PlaceboN = 107Age, years\xa0\xa0\xa0\xa0Mean (SD)56.1 (14.0)55.4 (13.9)\xa0\xa0\xa0\xa0Range30–8528–85Gender, N (%)\xa0\xa0\xa0\xa0Female95(99%)100(100%)\xa0\xa0\xa0\xa0Male1(1%)0(0%)cT, N (%)\xa0\xa0\xa0\xa0T129(30%)28(26%)\xa0\xa0\xa0\xa0T256(58%)63(59%)\xa0\xa0\xa0\xa0T311(12%)14(13%)\xa0\xa0\xa0\xa0Missing0(0%)2(2%)cN, N (%)\xa0\xa0\xa0\xa0N018(19%)23(21%)\xa0\xa0\xa0\xa0N+78(81%)83(78%)\xa0\xa0\xa0\xa0Missing0(0%)1(1%)cM, N (%)\xa0\xa0\xa0\xa0M092(96%)102(95%)\xa0\xa0\xa0\xa0M11(1%)3(3%)\xa0\xa0\xa0\xa0Missing3(3%)2(2%)Histologic type(s), N (%)\xa0\xa0\xa0\xa0Invasive ductal adenocarcinoma80(83%)86(80%)\xa0\xa0\xa0\xa0Invasive lobular adenocarcinoma15(16%)12(11%)\xa0\xa0\xa0\xa0Other3(3%)8(8%)Histologic grade, N (%)\xa0\xa0\xa0\xa015(5%)11(10%)\xa0\xa0\xa0\xa0258(60%)52(49%)\xa0\xa0\xa0\xa0332(33%)42(39%)\xa0\xa0\xa0\xa0Missing1(1%)2(2%)ER, N (%)\xa0\xa0\xa0\xa0Positive66(69%)77(72%)\xa0\xa0\xa0\xa0Negative30(31%)29(27%)\xa0\xa0\xa0\xa0Missing0(0%)1(1%)PR, N (%)\xa0\xa0\xa0\xa0Positive59(62%)65(61%)\xa0\xa0\xa0\xa0Negative36(37%)42(39%)\xa0\xa0\xa0\xa0Missing1(1%)0(0%)HER2/neu (IHC), N (%)\xa0\xa0\xa0\xa0HER2-79(82%)83(77%)\xa0\xa0\xa0\xa0HER2+17(18%)22(21%)\xa0\xa0\xa0\xa0Missing0(0%)2(2%)Triple Negative, N (%)\xa0\xa0\xa0\xa0Yes22(23%)18(17%)\xa0\xa0\xa0\xa0No74(77%)89(83%)NLR >4, N (%)\xa0\xa0\xa0\xa0Yes13(14%)15(14%)\xa0\xa0\xa0\xa0No83(86%)92(86%)Chemotherapy, N (%)\xa0\xa0\xa0\xa0Yes80(83%)81(76%)\xa0\xa0\xa0\xa0No16(17%)26(24%)If chemotherapy, type (%)\xa0\xa0\xa0\xa0Adjuvant27(28%)27(25%)\xa0\xa0\xa0\xa0Neoadjuvant53(55%)54(51%)If chemotherapy, compound (%)\xa0\xa0\xa0\xa0Antracyclins and taxanes80(83%)79(74%)\xa0\xa0\xa0\xa0Missing0(0%)2(2%)If Neoadjuvant chemotherapy, compound (%)\xa0\xa0\xa0\xa0Antracyclins and taxanes53(55%)53(50%)\xa0\xa0\xa0\xa0Missing0(0%)1(1%)If Adjuvant chemotherapy, compound (%)\xa0\xa0\xa0\xa0Antracyclins and taxanes27(28%)26(24%)\xa0\xa0\xa0\xa0Missing0(0%)1(1%)Type of surgery, N (%)\xa0\xa0\xa0\xa0Mastectomy60(63%)59(55%)\xa0\xa0\xa0\xa0Breast-conserving surgery34(35%)48(45%)\xa0\xa0\xa0\xa0Missing2(2%)0(0%)Type of lymphadenectomy, N (%)\xa0\xa0\xa0\xa0None6(6%)8(8%)\xa0\xa0\xa0\xa0Sentinel5(5%)7(6%)\xa0\xa0\xa0\xa0Complete axillary85(89%)91(85%)\xa0\xa0\xa0\xa0Missing0(0%)1(1%)Post-operative radiotherapy, N (%)\xa0\xa0\xa0\xa0Yes77(80%)88(82%)\xa0\xa0\xa0\xa0No19(20%)19(18%)Endocrine therapy, N (%)\xa0\xa0\xa0\xa0Yes69(72%)69(64%)\xa0\xa0\xa0\xa0No27(28%)37(35%)\xa0\xa0\xa0\xa0Missing0(0%)1(1%)If Endocrine therapy, compound (%)\xa0\xa0\xa0\xa0Tamoxifen40(42%)38(36%)\xa0\xa0\xa0\xa0Aromatase inhibitor23(24%)27(25%)\xa0\xa0\xa0\xa0Tamoxifen before an aromatase inhibitor6(6%)4(4%)EfficacyAfter a median follow-up of 26.9 months, there was no difference in DFS (Fig 2) between groups (HR, 1.23 with reference to Placebo; 95% CI, 0.65 to 2.31; p = 0.517). At two years, 83.1% of the patients were alive and disease free in the ketorolac group compared with 89.7% in the placebo arm.10.1371/journal.pone.0225748.g002Fig 2Kaplan-Meier estimates of Disease-Free Survival (DFS) in the overall study population.There was also no difference in OS (HR, 1.09; 95% CI, 0.34 to 3.51; p = 0.884), with 96.8% of the patients who were alive after two years in the ketorolac vs. 98.1% in the placebo arm (Fig 3). Similarly, no difference was observed for LR-RFS (HR, 1.10; 95% CI,0.51 to 2.37; p = 0.816) and DM-RFS (HR, 0.26; 95% CI, 0.74 to 3.01; p = 0.255).10.1371/journal.pone.0225748.g003Fig 3Kaplan-Meier estimates of Overall Survival (OS) in the overall study population.SafetyA summary of perioperative events relevant to ketorolac safety profile and of all serious adverse events is presented in Table 2. There was one postoperative major bleeding in the ketorolac arm that required surgical re-intervention, which resolved the event without the need for blood transfusion. Both intra- and post-operative blood losses were not different between groups (p = 0.063 and 0.114 respectively). There was no difference in pain at D1 after surgery neither at rest (p = 0.620) nor in movement (p = 0.254).10.1371/journal.pone.0225748.t002Table 2Perioperative and adverse events.CharacteristicsKetorolacN = 96PlaceboN = 107p-valuePerioperative eventsHospital stay, days\xa0\xa0\xa0\xa0Mean (SD)3.9 (1.2)3.7 (1.0)0.290\xa0\xa0\xa0\xa0Range1–82–7Intra-operative blood loss, ml\xa0\xa0\xa0\xa0Mean (SD)188 (123)176 (168)0.063\xa0\xa0\xa0\xa0Range0–5040–935Postoperative blood loss in drains, ml\xa0\xa0\xa0\xa0Mean (SD)229 (217)182 (164)0.114\xa0\xa0\xa0\xa0Range0–11000–735Postoperative major bleeding, N (%)1 (1%)*0 (0%)0.473Pain at rest at D1 after surgery Verbal simple scale (0–4), N (%)0.620\xa0\xa0\xa0\xa0018(19%)17(16%)\xa0\xa0\xa0\xa0135(37%)31(29%)\xa0\xa0\xa0\xa0237(38%)47(44%)\xa0\xa0\xa0\xa035(5%)10(9%)\xa0\xa0\xa0\xa041(1%)1(1%)\xa0\xa0\xa0\xa0Missing0(0%)1(1%)Adverse eventsAny serious adverse event8(8%)7(7%)0.789* 1 patient in the ketorolac arm experienced major bleeding at the surgical site that necessitated re-intervention. No transfusion was necessary and the problem resolved after re-interventionDiscussionThis study shows that a single administration of 30 mg of ketorolac tromethamine does not improve disease-free survival in high-risk breast cancer patients. Overall survival is also comparable between the two groups. No safety concerns were raised in this study.We selected patients known to carry a higher risk of recurrence, namely patients with a triple negative phenotype, patients with node involvement or patients with a high NLR. The assumptions about the recurrence rate made when calculating the sample size were unfortunately not respected, which led to our study being underpowered. However, the survival curves are superimposable, which supports the conclusion of a lack of effect of a single administration of ketorolac to prevent breast cancer recurrence.What remains is that several studies indicates that inflammatory pathways are implicated in postoperative cancer recurrences [5, 6, 19]. The surgical stress activates numerous pathways known to promote tumor growth and one possible way to intervene is to use NSAIDs, like ketorolac [20]. But, since nearly all anesthetic and analgesic drugs affect anticancer immunity and other tumor-promoting pathways (such as angiogenesis and VEGF) [21–23], ketorolac represents only one of the perioperative drug candidates to reduce the risk of recurrence [5, 24]. For instance, it could be that targeting both catecholamines and prostaglandins is necessary to prevent the pro-metastatic processes induced by surgical stress as shown in preclinical experiments in several models [25]. A clinical trial using propranolol—a non-selective beta-blocker—and etodolac—an NSAID—in breast cancer patients provided encouraging biological results but could not assess the impact of this approach on recurrence because of a limited size [26].Bimodality in the relapse frequency over time in early stage breast cancer also remains a reality [27]. An early peak, occurring in the first 18 postoperative months, has been observed repeatedly in breast cancer patients [28–30] with particular relevance in patients with large tumor size, high histological grade, lymph node involvement or low expression of estrogen receptors [12, 31]. However, the occurrence of the early peak is not here confirmed. Moreover, a recent retrospective study found that the anticancer effect of ketorolac may be particularly prominent in patients with a high Body Mass Index (BMI) [32]. However, we could not confirm this hypothesis in this prospective trial (data not shown), as no difference in outcomes was observed when stratifying the analyses per BMI group (≤25 vs. >25)—keeping in mind that patients weighting more than 100 kg were excluded from the trial. Taken together, it appears that new works are needed to investigate the patients’ subgroups that may specifically benefit from intraoperative interventions during cancer surgery.If a single dose of ketorolac has no impact on recurrence, it does not preclude an effect of a longer administration. However, our choice of testing a single administration was partly supported by the increased risk of adverse events with prolonged administration of ketorolac [16]. Further studies with ketorolac may focus on the identification of relevant biomarkers, and its effect on these biomarkers in specific patient subgroups. Because multiple biological pathways are modulated by ketorolac (through the inhibition of both the COX-2 and the COX-1 enzymes [33] but also independently [11]), selecting a population more likely to benefit of a longer administration of ketorolac might however be difficult.In summary, these data do not support the use of a single administration of ketorolac before breast cancer surgery to prevent breast cancer recurrence. To progress further, pivotal trials may be performed, focusing on the identification of relevant biomarkers, and the effect of ketorolac on these biomarkers in specific patient subgroups.Supporting informationS1 FileConsort checklist.(DOC)Click here for additional data file.S2 FileData.(XLSX)Click here for additional data file.S3 FileProtocol.(DOC)Click here for additional data file.References1American Society of Anesthesiologists Task Force on Acute Pain Management: Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology\n2012;116:248–73. 10.1097/ALN.0b013e31823c1030\n222277892RothwellPM, WilsonM, PriceJF, BelchJF, MeadeTW, MehtaZ. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet. 2012;379(9826):1591–601. 10.1016/S0140-6736(12)60209-8\n224409473ForgetP, MachielsJ-P, CouliePG, BerliereM, PonceletAJ, TombalB\net al\nNeutrophil:lymphocyte ratio and intraoperative use of ketorolac or diclofenac are prognostic factors in different cohorts of patients undergoing breast, lung and kidney cancer surgery. Ann Surg Oncol\n2013; Suppl 3:S650–60.238847514DemariaS, PikarskyE, KarinM, CoussensLM, ChenYC, El-OmarEM\net al\nCancer and inflammation: promise for biologic therapy. J Immunother. 2010;33(4):335–51. 10.1097/CJI.0b013e3181d32e74\n203864725HillerJG, PerryNJ, PoulogiannisG, RiedelB, SloanEK. Perioperative events influence cancer recurrence risk after surgery. Nat Rev Clin Oncol. 2018;15(4):205–218\n10.1038/nrclinonc.2017.194\n292831706KrallJA, ReinhardtF, MercuryOA, PattabiramanDR, BrooksMW, DouganM\net alThe systemic response to surgery triggers the outgrowth of distant immune-controlled tumors in mouse models of dormancy. Sci Transl Med. 2018;10(436).7NeemanE, ZmoraO, Ben-EliyahuS. A new approach to reducing postsurgical cancer recurrence: perioperative targeting of catecholamines and prostaglandins. Clin Cancer Res. 2012;18(18):4895–902. 10.1158/1078-0432.CCR-12-1087\n227535878ForgetP, VandenhendeJ, BerliereM, MachielsJP, NussbaumB, LegrandC\net al\nDo intraoperative Analgesics Influence Breast Cancer Recurrence After Mastectomy? A Retrospective Analysis. Anesth Analg\n2010;110(6):1630–5. 10.1213/ANE.0b013e3181d2ad07\n204359509ForgetP, MachielsJP, CouliePG, BerliereM, PonceletAJ, TombalB\net al\nNeutrophil:lymphocyte ratio and intraoperative use of ketorolac or diclofenac are prognostic factors in different cohorts of patients undergoing breast, lung, and kidney cancer surgery. Ann Surg Oncol. 2013;20\nSuppl 3:S650–60.2388475110ForgetP, BentinC, MachielsJP, BerliereM, CouliePG, De KockM. Intraoperative use of ketorolac or diclofenac is associated with improved disease-free survival and overall survival in conservative breast cancer surgery. Br J Anaesth. 2014;113\nSuppl 1:i82–7.2446461111GuoY, KenneySR, CookL, AdamsSF, RutledgeT, RomeroE\net al\nA Novel Pharmacologic Activity of Ketorolac for Therapeutic Benefit in Ovarian Cancer Patients. Clin Cancer Res. 2015;21(22):5064–72. 10.1158/1078-0432.CCR-15-0461\n2607148212RetskyM, RogersR, DemicheliR, HrusheskyWJM, GukasI, VaidyaJS\net al\nNSAID analgesic ketorolac used perioperatively may suppress early breast cancer relapse: particular relevance to triple negative subgroup. Breast Cancer Res Treat\n2012; 134(2):881–8. 10.1007/s10549-012-2094-5\n2262281013ProctorMJ, MorrisonDS, TalwarD, BalmerSM, FletcherCD, O\'ReillyDS\net al\nA comparison of inflammation-based prognostic scores in patients with cancer. A Glasgow Inflammation Outcome Study. Eur J Cancer\n2011;47(17):2633–41. 10.1016/j.ejca.2011.03.028\n2172438314EthierJL, DesautelsD, TempletonA, ShahPS, AmirE. Prognostic role of neutrophil-to-lymphocyte ratio in breast cancer: a systematic review and meta-analysis. Breast Cancer Res. 2017;19(1):2\n10.1186/s13058-016-0794-1\n2805704615ForgetP, BerlièreM, van MaanenA, DuhouxFP, MachielsJP, CouliePG\net al\nKetorolac in Breast Cancer trial (KBCtrial) group. Perioperative ketorolac in high risk breast cancer patients. Rationale, feasibility and methodology of a prospective randomized placebo-controlled trial. Med Hypotheses\n2013; 81:707–12. 10.1016/j.mehy.2013.07.033\n2393799616ReinhartDJ. Minimising the Adverse Effects of Ketorolac. Drug Saf\n2000;22:487–497. 10.2165/00002018-200022060-00007\n1087704217HudisCA, BarlowWE, CostantinoJP, GrayRJ, PritchardKI, ChapmanJA\net al\nProposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: the STEEP system. J Clin Oncol. 2007;25(15):2127–32. 10.1200/JCO.2006.10.3523\n1751382018SesslerD, Ben-EliyahuS, MaschaEJ, ParatMO, BuggyDJ. Can regional analgesia reduce the risk of recurrence after breast cancer? Methodology of a multicenter randomized trial. Contemporary Clinical Trials\n2008;29:517–26. 10.1016/j.cct.2008.01.002\n1829172719HorowitzM, NeemanE, SharonE, Ben-EliyahuS. Exploiting the critical perioperative period to improve long-term cancer outcomes. Nat Rev Clin Oncol. 2015;12(4):213–26. 10.1038/nrclinonc.2014.224\n2560144220HussainM, JaveedA, AshrafM, Al-ZaubaiN, StewartA, MukhtarMM. Non-steroidal anti-inflammatory drugs, tumour immunity and immunotherapy. Pharmacol Res. 2012;66(1):7–18. 10.1016/j.phrs.2012.02.003\n2244978821ForgetP, ColletV, Lavand\'hommeP, De KockM. Does analgesia and condition influence immunity after surgery? Effects of fentanyl, ketamine and clonidine on natural killer activity at different ages. Eur J Anaesthesiol. 2010;27(3):233–40. 10.1097/EJA.0b013e32832d540e\n1948794922ForgetP, De KockM. [Could anaesthesia, analgesia and sympathetic modulation affect neoplasic recurrence after surgery? A systematic review centred over the modulation of natural killer cells activity]. Ann Fr Anesth Reanim. 2009;28(9):751–68. 10.1016/j.annfar.2009.07.078\n1971727523ShakharG, Ben-EliyahuS. Potential prophylactic measures against postoperative immunosuppression: Could they reduce recurrence rates in oncological patients?\nAnn Surg Oncol\n2003;10(8):972–92. 10.1245/aso.2003.02.007\n1452791924PantziarkaP, BoucheG, SullivanR, IlbawiAM, DareAJ, MeheusL. Perioperative therapies—Enhancing the impact of cancer surgery with repurposed drugs. Eur J Surg Oncol. 2017;43(11):1985–8. 10.1016/j.ejso.2017.08.010\n2892801125GlasnerA, AvrahamR, RosenneE, BenishM, ZmoraO, ShemerS\net al\nImproving survival rates in two models of spontaneous postoperative metastasis in mice by combined administration of a beta-adrenergic antagonist and a cyclooxygenase-2 inhibitor. J Immunol. 2010;1;184(5):2449–57. 10.4049/jimmunol.0903301\n2012410326ShaashuaL, Shabat-SimonM, HaldarR, MatznerP, ZmoraO, ShabtaiM\net al\nPerioperative COX-2 and β-Adrenergic Blockade Improves Metastatic Biomarkers in Breast Cancer Patients in a Phase-II Randomized Trial. Clin Cancer Res. 2017;23(16):4651–4661. 10.1158/1078-0432.CCR-17-0152\n2849046427RetskyMW, DemicheliR, HrusheskyWJ, BaumM, GukasID. Dormancy and surgery-driven escape from dormancy help explain some clinical features of breast cancer. APMIS. 2008;116(7–8):730–41. 10.1111/j.1600-0463.2008.00990.x\n1883441528JatoiI, TsimelzonA, WeissH, ClarkGM, HilsenbeckSG. Hazard rates of recurrence following diagnosis of primary breast cancer. Breast Cancer Res Treat. 2005;89(2):173–8. 10.1007/s10549-004-1722-0\n1569276029HilsenbeckSG, RavdinPM, de MoorCA, ChamnessGC, OsborneCK, ClarkGM. Time-dependence of hazard ratios for prognostic factors in primary breast cancer. Breast Cancer Res Treat. 1998;52(1–3):227–37. 10.1023/a:1006133418245\n1006608530BaumM, DemicheliR, HrusheskyW, RetskyM. Does surgery unfavourably perturb the "natural history" of early breast cancer by accelerating the appearance of distant metastases?\nEur J Cancer. 2005;41(4):508–15. 10.1016/j.ejca.2004.09.031\n1573755431MansellJ, MonypennyIJ, SkeneAI, AbramP, CarpenterR, GattusoJM\net al\nPatterns and predictors of early recurrence in postmenopausal women with estrogen receptor-positive early breast cancer. Breast Cancer Res Treat. 2009;117(1):91–8. 10.1007/s10549-008-0291-z\n1911261532DesmedtC, DemicheliR, ForniliM, BachirI, DucaM, VigliettiG\net al\nPotential Benefit of Intra-operative Administration of Ketorolac on Breast Cancer Recurrence According to the Patient\'s Body Mass Index. J Natl Cancer Inst. 2018\n4\n30\n10.1093/jnci/djy042\n2971839633WarnerTD, GiulianoF, VojnovicI, BukasaA, MitchellJA, VaneJR. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci U S A. 1999;96(13):7563–8. 10.1073/pnas.96.13.7563\n10377455', 'title': 'Intraoperative ketorolac in high-risk breast cancer patients. A prospective, randomized, placebo-controlled clinical trial.', 'date': '2019-12-05'}, '16146476': {'article_id': '16146476', 'content': 'Breast cancer treatment with mastectomy and immediate breast reconstruction (IBR) is associated with intense pain in the primary post-operative period. The present prospective, placebo-controlled and double-blind study aimed to evaluate the analgesic efficacy of diclofenac, a non-steroid anti-inflammatory drug (NSAID), in combination with paracetamol and opioids. This was done by 64-h assessment of post-operative pain intensity, opioid consumption, blood loss, nausea and tiredness.\nFifty women selected for mastectomy and IBR with submuscular implants with or without axillary lymph node dissection (ALND) were randomized to receive diclofenac 50 mg x 3 or placebo rectally in addition to oral paracetamol and intravenous opioids delivered using a patient-controlled analgesia (PCA) technique.\nDuring the first 20 h post-surgery, patients who received diclofenac experienced significantly less pain when resting than those who received placebo. When moving, a non-significant estimated difference in pain in favour of diclofenac was also noted. Opioid consumption during the first 6 h post-operatively was 34% less with diclofenac than with placebo. Means (SD) were 16.9 (10.3) mg and 25.6 (10.2) mg, respectively (P = 0.007). After 64 h, the difference was no longer statistically significant. Post-operative bleeding was significantly higher with diclofenac than with placebo (P < 0.01). Nausea and tiredness did not differ between the groups.\nThe addition of NSAID to paracetamol and opioid-PCA reduced opioid consumption and improved pain relief during the first 20 h at rest but was not convincingly effective during mobilization. Post-operative blood loss was higher with diclofenac.', 'title': 'Analgesic efficacy of diclofenac in combination with morphine and paracetamol after mastectomy and immediate breast reconstruction.', 'date': '2005-09-09'}, '8770304': {'article_id': '8770304', 'content': 'Ketorolac is a parenteral nonsteroidal antiinflammatory drug (NSAID). Two features have limited its clinical utility: tendency to elicit kidney failure and inability to produce complete analgesia. Because most NSAIDs are weak acids (pKa 3-5) and become concentrated in acidic tissues, such as injured and inflamed tissues, we hypothesized that local administration may enhance its analgesic efficacy while lowering the potential for systemic complications.\nWe conducted a randomized, placebo-controlled study of 60 group I-II (American Society of Anesthesiology criteria) mastectomy patients, 20 in each group. Near the end of surgery and every 6 h postoperatively, 20 ml of the study solution containing normal saline with or without 30 mg of ketorolac were administered simultaneously either via a Jackson-Pratt drain or intravenously in a double-blind fashion. The quality of pain control, the amount and character of the drain fluid, incidence of nausea and vomiting, length of stay in the postoperative care unit, and amount of morphine used for treatment of break-through pain were recorded.\nIntraoperative administration of ketorolac resulted in better quality of pain control in the immediate postoperative period regardless of route of administration. The incidence of nausea was significantly higher in the placebo group, and drain output in the ketorolac groups did not exceed the output in the placebo group.\nAnalgesic of the locally administered ketorolac is equally effective to the efficacy of ketorolac administered intravenously.', 'title': 'Comparison of analgesic effect of locally and systemically administered ketorolac in mastectomy patients.', 'date': '1996-01-01'}}
| 0
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Surgery
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49
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Is the incidence of pneumonia higher, lower, or the same when comparing zinc supplementation to placebo?
|
lower
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low
|
no
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['9651405', '12052800', '16168782', '17593956']
| 27,915,460
| 2,016
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{'9651405': {'article_id': '9651405', 'content': 'Increased acute lower respiratory infection incidence, severity, and mortality are associated with malnutrition, and reduced immunological competence may be a mechanism for this association. Because zinc deficiency results in impaired immunocompetence and zinc supplementation improves immune status, we hypothesized that zinc deficiency is associated with increased incidence and severity of acute lower respiratory infection.\nWe evaluated the effect of daily supplementation with 10 mg of elemental zinc on the incidence and prevalence of acute lower respiratory infection in a double-blind, randomized, controlled trial in 609 children (zinc, n = 298; control, n = 311) 6 to 35 months of age. Supplementation and morbidity surveillance were done for 6 months.\nAfter 120 days of supplementation, the percentage of children with plasma zinc concentrations <60 microg/dL decreased from 35.6% to 11.6% in the zinc group, whereas in the control group it increased from 36.8% to 43.6%. Zinc-supplemented children had 0.19 acute lower respiratory infection episodes/child/year compared with 0.35 episodes/child/year in the control children. After correction for correlation of data using generalized estimating equation regression methods, there was a reduction of 45% (95% confidence interval, 10% to 67%) in the incidence of acute lower respiratory infections in zinc-supplemented children.\nA dietary zinc supplement resulted in a significant reduction in respiratory morbidity in preschool children. These findings suggest that interventions to improve zinc intake will improve the health and survival of children in developing countries.', 'title': 'Zinc supplementation reduces the incidence of acute lower respiratory infections in infants and preschool children: a double-blind, controlled trial.', 'date': '1998-07-04'}, '12052800': {'article_id': '12052800', 'content': 'To evaluate the effect of daily zinc supplementation in children on the incidence of acute lower respiratory tract infections and pneumonia.\nDouble masked, randomised placebo controlled trial.\nA slum community in New Delhi, India.\n2482 children aged 6 to 30 months.\nDaily elemental zinc, 10 mg to infants and 20 mg to older children or placebo for four months. Both groups received single massive dose of vitamin A (100 000 IU for infants and 200 000 IU for older children) at enrollment.\nAll households were visited weekly. Any children with cough and lower chest indrawing or respiratory rate 5 breaths per minute less than the World Health Organization criteria for fast breathing were brought to study physicians.\nAt four months the mean plasma zinc concentration was higher in the zinc group (19.8 (SD 10.1) v 9.3 (2.1) micromol/l, P<0.001). The proportion of children who had acute lower respiratory tract infection during follow up was no different in the two groups (absolute risk reduction -0.2%, 95% confidence interval -3.9% to 3.6%). Zinc supplementation resulted in a lower incidence of pneumonia than placebo (absolute risk reduction 2.5%, 95% confidence interval 0.4% to 4.6%). After correction for multiple episodes in the same child by generalised estimating equations analysis the odds ratio was 0.74, 95% confidence interval 0.56 to 0.99.\nZinc supplementation substantially reduced the incidence of pneumonia in children who had received vitamin A.', 'title': 'Effect of routine zinc supplementation on pneumonia in children aged 6 months to 3 years: randomised controlled trial in an urban slum.', 'date': '2002-06-08'}, '16168782': {'article_id': '16168782', 'content': 'Pneumonia and diarrhoea cause much morbidity and mortality in children younger than 5 years. Most deaths occur during infancy and in developing countries. Daily regimens of zinc have been reported to prevent acute lower respiratory tract infection and diarrhoea, and to reduce child mortality. We aimed to examine whether giving zinc weekly could prevent clinical pneumonia and diarrhoea in children younger than 2 years.\n1665 poor, urban children aged 60 days to 12 months were randomly assigned zinc (70 mg) or placebo orally once weekly for 12 months. Children were assessed every week by field research assistants. Our primary outcomes were the rate of pneumonia and diarrhoea. The rates of other respiratory tract infections were the secondary outcomes. Growth, final serum copper, and final haemoglobin were also measured. Analysis was by intention to treat.\n34 children were excluded before random assignment to treatment group because they had tuberculosis. 809 children were assigned zinc, and 812 placebo. After treatment assignment, 103 children in the treatment group and 44 in the control group withdrew. There were significantly fewer incidents of pneumonia in the zinc group than the control group (199 vs 286; relative risk 0.83, 95% CI 0.73-0.95), and a small but significant effect on incidence of diarrhoea (1881 cases vs 2407; 0.94, 0.88-0.99). There were two deaths in the zinc group and 14 in the placebo group (p=0.013). There were no pneumonia-related deaths in the zinc group, but ten in the placebo group (p=0.013). The zinc group had a small gain in height, but not weight at 10 months compared with the placebo group. Serum copper and haemoglobin concentrations were not adversely affected after 10 months of zinc supplementation.\n70 mg of zinc weekly reduces pneumonia and mortality in young children. However, compliance with weekly intake might be problematic outside a research programme.', 'title': 'Effect of weekly zinc supplements on incidence of pneumonia and diarrhoea in children younger than 2 years in an urban, low-income population in Bangladesh: randomised controlled trial.', 'date': '2005-09-20'}, '17593956': {'article_id': '17593956', 'content': "PLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of ScienceSan Francisco, USA17593956189143807-PONE-CT-0121310.1371/journal.pone.0000541Research ArticleGastroenterology and Hepatology/Gastrointestinal InfectionsInfectious Diseases/Gastrointestinal InfectionsInfectious Diseases/HIV Infection and AIDSPediatrics and Child Health/Respiratory PediatricsPublic Health and Epidemiology/Infectious DiseasesGastroenterology and Hepatology/Gastrointestinal InfectionsInfectious Diseases/Gastrointestinal InfectionsInfectious Diseases/Respiratory InfectionsNutritionNutrition/DeficienciesNutrition/MalnutritionZinc or Multiple Micronutrient Supplementation to Reduce Diarrhea and Respiratory Disease in South African Children: A Randomized Controlled TrialMicronutrients in South African ChildrenLuabeyaKany-Kany Angelique\n1\nMpontshaneNontobeko\n2\nMackayMalanie\n3\nWardHonorine\n4\nElsonInga\n5\nChhaganMeera\n6\n\n7\nTomkinsAndrew\n8\nden BroeckJan Van\n9\nBennishMichael L.\n*\n\n1\nAfrica Centre for Health and Population Studies, University of KwaZulu Natal, Somkhele, South Africa\n\n2\nChurch of Scotland Hospital, Tugela Ferry, South Africa\n\n3\nDepartment of Medical Microbiology, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa\n\n4\nDivision of Geographic Medicine and Infectious Diseases, Tufts-New England Medical Centre, Boston, Massachusetts, United States of America\n\n5\nDepartment of Chemical Pathology, University of KwaZulu-Natal, Durban, South Africa\n\n6\nDepartment of Paediatrics and Child Health, University of KwaZulu-Natal, Durban, South Africa\n\n7\nFriedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts, United States of America\n\n8\nCentre for International Child Health, University of London, London, United Kingdom\n\n9\nTropical Medicine Research Institute, University of the West Indies, Kingston, Jamaica\n\nNuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom\nBelizanJose M.Academic EditorInstitute of Clinical Effectiveness and Health Policy, Argentina* To whom correspondence should be addressed. E-mail: mbennish@hotmail.comPrincipal investigator for the study: MLB. Served as Project Directors: JVdB KAL. Supervised the field work for the study: NM. Conducted the laboratory studies: MM HW IE. Designed the study: MLB AT. Wrote the grant proposal: MLB. Wrote the initial study protocol: MLB JVdB. Revised the study protocol: KAL JVdB MLB. Designed the analysis plan and conducted the analysis: JVdB MLB. Drafted the manuscript: MLB KAL JVdB. Critically reviewed and approved the manuscript: all authors.2007276200726e541352007952007Luabeya et al.2007This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.BackgroundProphylactic zinc supplementation has been shown to reduce diarrhea and respiratory illness in children in many developing countries, but its efficacy in children in Africa is uncertain.ObjectiveTo determine if zinc, or zinc plus multiple micronutrients, reduces diarrhea and respiratory disease prevalence.DesignRandomized, double-blind, controlled trial.SettingRural community in South Africa.ParticipantsThree cohorts: 32 HIV-infected children; 154 HIV-uninfected children born to HIV-infected mothers; and 187 HIV-uninfected children born to HIV-uninfected mothers.InterventionsChildren received either 1250 IU of vitamin A; vitamin A and 10 mg of zinc; or vitamin A, zinc, vitamins B1, B2, B6, B12, C, D, E, and K and copper, iodine, iron, and niacin starting at 6 months and continuing to 24 months of age. Homes were visited weekly.Outcome MeasuresPrimary outcome was percentage of days of diarrhea per child by study arm within each of the three cohorts. Secondary outcomes were prevalence of upper respiratory symptoms and percentage of children who ever had pneumonia by maternal report, or confirmed by the field worker.ResultsAmong HIV-uninfected children born to HIV-infected mothers, median percentage of days with diarrhea was 2.3% for 49 children allocated to vitamin A; 2.5% in 47 children allocated to receive vitamin A and zinc; and 2.2% for 46 children allocated to multiple micronutrients (P\u200a=\u200a0.852). Among HIV-uninfected children born to HIV-uninfected mothers, median percentage of days of diarrhea was 2.4% in 56 children in the vitamin A group; 1.8% in 57 children in the vitamin A and zinc group; and 2.7% in 52 children in the multiple micronutrient group (P\u200a=\u200a0.857). Only 32 HIV-infected children were enrolled, and there were no differences between treatment arms in the prevalence of diarrhea. The prevalence of upper respiratory symptoms or incidence of pneumonia did not differ by treatment arms in any of the cohorts.ConclusionWhen compared with vitamin A alone, supplementation with zinc, or with zinc and multiple micronutrients, did not reduce diarrhea and respiratory morbidity in rural South African children.Trial RegistrationClinicalTrials.gov NCT00156832\nIntroductionMicronutrient deficiencies are common in children in developing countries, including children in South Africa.[1]–[3] Zinc deficiency is especially thought to be associated with an increased susceptibility to infection, and a greater severity of disease when infection occurs.[4] Zinc is now recommended by the WHO for the treatment of children with diarrhea in developing countries,[5] but its role for the prophylaxis of infection is less certain.Studies in Asia and Latin American have generally found that prophylactic zinc reduces the incidence, duration and severity of diarrhea and pneumonia episodes when given to infants and young children.[6] Few studies have been conducted of prophylactic administration of zinc in Africa,[7], [8] which differs, especially from Asia, in diet and patterns of growth in children,[9] and in the burden of infectious diseases, especially HIV. Because micronutrient deficiencies are seldom isolated to a single micronutrient, there have also been efforts to provide supplements containing an array of micronutrients.[1]\nIn KwaZulu-Natal, where this study was conducted, antenatal HIV prevalence is 39%.[10] Children with HIV infection are known to be at high risk of infection and poor nutrition and growth,[11] and those born to HIV-infected mothers but not themselves infected may be at increased risk of nutritional deficiencies because of parental illness.MethodsThe protocol for this trial and supporting CONSORT checklist are available as supporting information; see Checklist S1 and Protocol S1.Study areaThe study was conducted in northern KwaZulu-Natal Province, South Africa. Median household income in the area is one-half the national average, 80% of the population lives below the national poverty line, and unemployment is 75%.[12] There is little subsistence farming in this area despite 98% of households being defined as rural, and food insecurity within households is common.[12] Most infants receive both breast and complementary feeding from early infancy,[13] and the diet is known to be deficient in micronutrients.[14]\nParticipantsChildren were enrolled into the study by nurses at five government primary health care clinics. Study subjects were recruited from children coming to the clinics for routine visits, from households identified as having potentially eligible children based on surveillance conducted by the Africa Centre Demographic Information System, and from children enrolled at birth in an observational study of the determinants of mother-to-child transmission of HIV.Children eligible for study were four to six months old. Children were excluded from study if they were: less than 60% of median weight-for-age using United States National Center for Health Statistics standards;[15] had nutritional edema; had received vitamin or micronutrient supplements in the previous month; had diarrhea for more than seven days at the time of study enrollment; or were enrolled in another study of a clinical intervention.To maintain community blinding to the HIV status of women enrolled in the study, we enrolled children in any cohort which reached targeted enrollment before enrollment was completed in other cohorts, provided them only their initial two weeks of supplement, and did not include them in the analysis.Ethics and study monitoringThe study was approved by the Ethics Review Committee of the University of KwaZulu-Natal and the Institutional Review Board of Tufts-New England Medical Center. Before initiation the study was presented to the Community Advisory Board of the Africa Centre for their review and advice, and interim reports on study progress were provided to this Advisory Board. The study was also monitored by a Data Monitoring and Safety Board established by the NIH. Written informed consent to participate in the study, and to do HIV testing on both the mother and child, was obtained from all mothers whose children participated in the study.InterventionThe three treatment arms were: vitamin A alone; vitamin A plus zinc; and vitamin A, zinc and multiple micronutrients. All supplements were given daily at home from entry into the study until 24 months of age. Vitamin A was given as the comparator regimen, rather than placebo, because the South African Department of Health guidelines recommend routine three-monthly vitamin A supplementation for children and clinics did not consistently provide vitamin A to children. Thus each of the three tablet formulations contained 1250 IU of vitamin A. Two of the three tablet formulations contained 10 mg of zinc as zinc gluconate. The multiple micronutrient tablets were similar to those used in recent international trials of multiple micronutrient supplementation,[16] and in addition to vitamin A and zinc contained : 0.5 mg each of vitamins B1, B2 and B6; 0.9 µg vitamin B12; 35 mg vitamin C; 5 µg vitamin D; 6 mg vitamin E; 10 µg vitamin K; 0.6 mg copper as cupric gluconate; 150 µg folate; 50 µg iodine; 10 mg iron as ferrous fumerate; and 6 mg niacin. The supplements were manufactured as tablets by Hersil Ltd. (Lima, Peru) and packaged in blister packs of seven tablets. All three formulations were similar in color, taste, appearance and size. Because of a delay in shipment, 243 children enrolled in the study did not receive supplements for 11 weeks in 2005.ObjectivesTo study objective was to determine if zinc, or zinc plus multiple micronutrients, would reduce diarrhea and respiratory disease prevalence. We hypothesized that both zinc, and zinc plus multiple micronutrients, would reduce diarrhea and respiratory disease prevalence and examined their efficacy in a randomized controlled trial in children 6–24 months of age born to both HIV-infected and HIV-uninfected mothers.Study OutcomesThe primary study outcome was the percentage of days of diarrhea per child compared between study arms within each of the three cohorts. Secondary diarrheal disease outcomes were measures of the severity of diarrhea (duration of episodes, maximum number of stools during an episode, episodes lasting 14 or more days, diarrhea episodes with blood in the stool, and clinic visits for diarrhea) and the distribution of diarrheal morbidity (proportion of children who ever had diarrhea and number of episodes per child). Respiratory disease outcome measures were the percentage of weeks of upper respiratory symptoms per child, the percentage of children who ever had pneumonia by maternal report, and the percentage of children with pneumonia confirmed by the field worker.Study definitionsDiarrhea was considered to be present on any day the stool was more frequent or looser than normal or the stool contained water or blood. An episode of diarrhea terminated on the last day of diarrhea that was followed by two consecutive days without diarrhea. Blood was considered present in stool if reported by the mother. Upper respiratory tract infection was defined as the history (or presence during the field worker visit) of cough or runny nose. Because field workers asked about the occurrence of these signs since the last visit, rather than by day, the outcome was defined as prevalent weeks. Pneumonia by maternal report was considered to have occurred if there was a history of either fast breathing or chest in-drawing. Confirmed pneumonia was defined as an elevated respiratory rate at rest measured by the fieldworker using WHO/UNICEF Integrated Management of Childhood Illness guidelines.[5]\nSample sizeThis was done separately for each of the three cohorts and was based on percentage of days of diarrhea for each child by cohort and treatment arm. We assumed the percentage of days with diarrhea in HIV-infected children receiving vitamin A alone would be 4.4% (SD±0.9%); for those receiving vitamin A and zinc it would be 3.7%±0.9% (17% less than for those receiving vitamin A alone); and for those receiving multiple micronutrients it would be 3.0%±0.9% (33% less than for those receiving vitamin A alone and 20% less than for those receiving vitamin A and zinc). For HIV-uninfected children we postulated the same differences between treatment groups but with lower diarrhea prevalence rates: 3.3%±0.9% (vitamin A alone); 2.8%±0.9% (vitamin A and zinc); and 2.2%±0.9% (multiple micronutrient group). To determine with a power of 0.8 and a two-sided significance level of .05 if these postulated differences existed, 26 children were required in each of the three arms of the HIV-infected cohort, and 45 children in each of the three arms of the two cohorts of HIV-uninfected children. We expected mortality, migration, and withdrawals to diminish days of observation by 50% in the HIV-infected cohort and 25% in the HIV-uninfected groups. Thus the total sample size required was 156 in the HIV-infected cohort and 180 children in each of the two cohorts of HIV uninfected children.Randomization–sequence generationAn allocation list was prepared using computer-generated random numbers and a block size of six. Assignment to the three treatment arms was done separately for three cohorts of children stratified by HIV status of child and mother: HIV-infected children and mothers; HIV-uninfected children of HIV-infected mothers; and HIV-uninfected children of HIV-uninfected mothers.Randomization–allocation concealment and implementationThe manufacturer prepared numbered packs of tablets corresponding to the allocation list. Children enrolled in the study were assigned by a study physician to one of the three study cohorts after results of the HIV tests became available. The physician then allocated the next pack of tablets from the blocks assigned to that cohort to the participant.BlindingInvestigators, study staff and participants were blind to the treatment assignments.Study proceduresAt enrollment study subjects had a physical examination and medical history taken by the study nurse. Weight was measured to a precision of 0.1 kg using an electronic digital scale and recumbent length to a precision of 0.1 cm using an infantometer. For determination of anthropometric centiles National Center for Health Statistics standards were used.[15] Mothers and children had a blood sample taken for determination of HIV infection status if their status was not already known and documented, and for determining haemoglobin concentration. A two-week supply of tablets were provided at enrolment, and the mothers instructed on administering tablets to their child by crushing it and mixing it with food, and assuring that the child ate all the food the supplement was mixed in.Trained fieldworkers visited the children at home weekly during the study. They supplied sufficient tablets to ensure a two week supply was on hand. Any tablets remaining from the previous supply were counted and recorded. At each home visit field workers observed the preparation and administration of a tablet, and waited for 30 minutes to observe any adverse effect.At each visit field workers administered a standardized questionnaire that focused on diarrheal and respiratory morbidity using locally validated terms.[17] If the mother reported diarrhea then the field worker asked for each day since the last visit if the stool was looser or more frequent than normal, contained water or blood, and the number of stools on the worst day of diarrhea. Mothers were asked if since the last visit the child had a runny nose or cough, difficult or fast breathing, or chest in-drawing. Field workers measured the respiratory rate at rest in any child with current or reported signs or symptoms of respiratory distress.If the mother or another informant familiar with the child was not available during the scheduled home visit two further attempts were made to visit that week, following which the next planned weekly visit was made. Field workers collected information on events that occurred a maximum of 28 days before the visit.Mothers and infants were requested to return for clinic visits at 7, 8, 9, 12, 15, 18, 21 and 24 months of age to assess growth and morbidity. Ill children were referred to the study nurses at the clinics, or for more serious illness to the district hospital. When antiretroviral therapy for children became available in clinics in January 2005 all children with HIV infection in the study were referred for evaluation.Supervisors assessed reliability of field worker assessments by conducting unscheduled visits and comparing findings with interviews conducted the same day by field workersLaboratory methodsHIV testing of children was done using a quantitative HIV RNA assay (Nuclisens HIV-1 QT, Organon Teknika or Nuclisens EasyQ HIV-1, Biomerieux, Boxtel, The Netherlands). Maternal HIV status was determined using two ELISA tests (first Vironostika HIV-1 Microelisa system and then Uni-Form II plus O if the first test was positive, both Biomèrieux) each of which had to be positive for HIV infection to be diagnosed. Hemoglobin determination was done at the clinic by study nurses using a portable HemoCue system (Angelholm, Sweden).Statistical methodsData were entered into an electronic data base using an optical form scanning system (TeleForm version 7.1 Cardiff, Vista CA, USA) and were analyzed using SPSS version 13.0 (SPSS Inc., Chicago, IL, USA) and EpiInfo version 3.3.2 (Centers for Disease Control and Prevention, Atlanta, GA, USA).Analyses were done on a locked dataset using an analysis plan, and tests of significance, that were determined before the analyses were conducted. Analyses were initially conducted using coded treatment groups with the analysts blinded to the actual treatment.Analysis of all outcomes was on an intention-to-treat basis–all participants for whom there were observations on study outcomes were included in the analysis. In addition to comparing baseline characteristics between children in the treatment groups, we also examined features during study that could have confounded study outcome. These were rates of drop-out and death, proportion of missing information, dietary pattern, adherence to treatment, and intake of other vitamin and micronutrient preparations. Any baseline or during treatment characteristics that differed significantly between treatment arms was tested for its association with the study outcome using Spearman's rank correlation test.The primary outcome–percentage of days of diarrhea per child by cohort and treatment group-was not normally distributed as determined by the Kolmogorov-Smirnov test, and a Kruskall-Wallis test was used to determine the overall significance of difference between treatment arms. For secondary outcomes and for baseline characteristics the significance of differences for continuous variables was tested using one-way ANOVA if the variable was normally distributed or the Kruskall-Wallis test if not normally distributed. Differences in proportions were tested with the χ2 test. Comparisons between individual groups were made only if the overall group comparison found a significant difference. To determine the effect size for the primary outcome, we determined the difference between medians, and the 95% confidence intervals for those differences, using the binomial method.[18] All tests of differences or association were two-sided, and were considered significant if the P value was ≤ 0.05.We also tested for any bias in assignment to treatment cohort (on the assumption that blinding may not have been completely effective) using the Berger-Exner test.[19]\nResultsRecruitment, patient flow, and numbers analyzedStudy enrollment began in June 2003 and the last participant enrolled in October 2004. Patient observations were completed 31 January 2006. Three-hundred seventy-three children were enrolled in the study–32 HIV-infected children, 154 children without HIV infection born to HIV-infected mothers, and 187 children born to HIV-uninfected mothers (Figure 1). Thirty-seven children withdrew and one died before any home visits took place, leaving 335 children for whom information on outcomes was available and who were included in the analysis (Figure 1). One-hundred thirteen of these 335 children each received vitamin A alone or vitamin A plus zinc, and 109 of the children received multiple micronutrients. Ten of these 335 children never took the supplement but were included in this intention-to-treat analysis. Berger-Exner tests performed in each cohort separately\xa0showed no evidence of\xa0bias in assignment to treatment group. Controlling for treatment arm, the P-values for the partial correlation between percent days of diarrhea (the main outcome) and the remaining proportion of multivitamin tablets in the block at the time of random assignment to therapy was >0.23 in each of the three cohorts.10.1371/journal.pone.0000541.g001Figure 1Patient FlowchartTwelve (3.6%) of the 335 children with at least one home visit died during the study, including 8 (29%) of the 28 children with HIV infection. An additional 88 (26.2%) of the 335 children who had at least one home visit did not complete the study (Table 1). Fifty-seven children moved out of the area during the study. Reasons given for withdrawal in the other 31 children included lack of time by parent to participate (2 children), the child not liking the taste of the tablets (3 children), objections from grandparent or father (2 children) and unspecified reasons in 24 children. The median duration of enrollment in the study was 447 days and did not differ significantly between groups.10.1371/journal.pone.0000541.t001Table 1Characteristics of 335 children by study cohort and treatment armCharacteristicHIV-infected childrenHIV-uninfected children born to HIV-infected mothersHIV-uninfected children born to HIV-uninfected mothersTreatment groupPTreatment groupPTreatment groupPVitamin A (n\u200a=\u200a8)Vitamin A+zinc (n\u200a=\u200a9)Multiple micronutrients (n\u200a=\u200a11)Vitamin A (n\u200a=\u200a49)Vitamin A+zinc (n\u200a=\u200a47)Multiple micronutrients (n\u200a=\u200a46)Vitamin A (n\u200a=\u200a56)Vitamin A+zinc (n\u200a=\u200a57)Multiple micronutrients (n\u200a=\u200a52)Age at enrollment into study, months5.5 (0.4)5.4 (0.5)5.5 (0.3)0.9935.4 (0.5)5.5 (0.6)5.6 (0.5)0.3725.5 (0.5)5.5 (0.5)5.4 (0.5)0.535Age at initiation of therapy, months8.0 (1.8)7.4 (1.0)8.0 (2.2)0.7377.8 (1.3)8.0 (1.3)7.8 (1.3)0.7607.6 (1.5)7.3 (0.8)7.2 (0.9)0.174Male, n (%)6 (75.0)5 (55.6)4 (36.4)0.24724 (49.0)25 (53.2)21 (45.7)0.76735 (62.5)25 (43.9)28 (53.8)0.139Piped or well water used for preparing feeds, n (%)6 (85.7)5 (83.3)6 (75.0)0.85736 (76.6)36 (80.0)33 (71.7)0.64943 (82.7)40 (70.2)44 (88.0)0.059AnthropometryWeight for age Z-score‡\n−0.02 (1.83)−1.05 (1.35)−0.12 (1.61)0.3400.21 (1.24)0.28 (1.23)0.08 (1.18)0.7220.34 (1.21)0.54 (1.00)0.70 (1.17)0.260Length for age Z-score‡\n−1.37 (0.88)−1.00 (1.42)−1.00 (1.19)0.791−0.64 (0.82)−0.50 (0.98)−0.74 (1.09)0.514−0.36 (0.87)−0.34 (1.02)−0.37 (0.89)0.990Weight for length Z-score‡\n0.80 (2.08)−0.03 (0.74)0.51 (1.36)0.5350.87 (1.29)0.86 (0.94)0.74 (1.01)0.8420.61 (1.06)1.00 (0.95)1.10 (1.13)0.051Hemoglobin, g/dl§\n10.0 (1.4)9.8 (0.7)8.8 (2.5)0.48310.3 (1.3)10.5 (1.3)10.1 (1.1)0.5989.9 (1.2)10.2 (1.1)10.3 (1.2)0.363Withdrew from study or lost to follow-up, n (%)2 (25.0)1 (11.1)3 (27.3)0.65310 (20.4)12 (25.5)14 (30.4)0.53215 (26.8)14 (24.6)17 (32.7)0.624Days of observation per child, median (25th–75th centiles)306 (107–536)181 (62–485)347 (49–527)0.912464 (318–510)418 (255–478)395 (270–501)0.165467 (270–515)486 (342–530)439 (309–529)0.535Percent of study days for which information not available, median (25th–75th centiles) ¶\n3.1 (0.3–7.1)1.3 (0.0–15.9)2.0 (0.0–14.7)0.9674.7 (1.0–14.2)7.7 (2.2–21.4)5.5 (1.3–19.7)0.5024.2 (0.7–12.2)4.6 (1.4–10.2)2.3 (0.4–9.2)0.651Percent of study days supplement not given median (25th–75th centiles), \\\\\n22.0 (14.6–29.0)11.6 (2.5–28.1)33.7 (12.3–100)0.07325.8 (17.9–35.2)25.5 (18.0–33.1)22.7 (13.8–34.9)0.42124.2 (16.3–32.7)22.8 (14.2–30.3)21.6 (14.0–31.5)0.527Percent of study days for which recall period ≤ 7 days72.1 (56.5–79.1) P\u200a=\u200a0.85869.6 (56.7–92.2)76.8 (63.7–80.5)0.85876.8 (62.7–84.5)74.1 (62.5–80.0)74.9 (67.0–82.3)0.43477.3 (70.4–84.7)76.9 (69.0–81.7)75.8 (63.6–83.7)0.553Values are mean (standard deviation) or n (%) unless noted. P values are for the overall group comparison using one-way ANOVA, Kruskall-Wallis or 2 x 3 χ2 test.*Information on water use was not available in the cohort of HIV-infected children for 1 child in the vitamin A group, 3 children in the vitamin A+zinc group, and 1 child in the multiple micronutrient group. In the cohort of HIV-uninfected children born to HIV-infected mothers, information was missing for 2 children in the vitamin A group and 2 children in the multiple micronutrient group. In the cohort of HIV-uninfected children born to HIV-uninfected mothers, information was missing for 4 children in the vitamin A group, and 2 children in the multiple micronutrient group.‡As a Z-score of NCHS standards[15]\n§Hemoglobin values were not available in the cohort of HIV-infected children for 5 children in each of the three treatment groups. In the cohort of HIV-uninfected children born to HIV-infected mothers, hemoglobin determinations were not available for 26 children who received vitamin A, 28 children who received vitamin A+zinc, and 20 children who received multiple micronutrients. In the cohort of HIV-uninfected children born to HIV-uninfected mothers, hemoglobin measurements were not available for 34 children in the vitamin A group, 32 children in the vitamin A+zinc group, and 33 children in the multiple micronutrient group.¶Days study drug was not given were determined during weekly home visits.\\\\Excludes days after withdrawal of study subjects for which home visits were not permitted, lost to follow-up, or death.Baseline dataBaseline demographic characteristics of the treatment groups in the three cohorts did not significantly differ with the exception of weight-for-length in the group of HIV-uninfected children born to HIV-uninfected mothers (Table 1).OutcomesDiarrheal morbidityThere was no significant difference between treatment groups in the primary outcome-percentage of days with diarrhea–in any of the three cohorts (Tables 2 and 3). The median percentage of days with diarrhea ranged from 3.4% to 7.1% in the three treatment arms in HIV-infected children, and from 1.8% to 2.7% in the treatment arms in the two cohorts of HIV-uninfected children. In all comparisons the 95% CI for the differences between groups crossed zero (Table 3). There was no difference between treatment arms in any of the secondary outcome measures of diarrhea severity or frequency (Table 2). Children enrolled in the study had a median of 2 episodes of diarrhea while in the study. During 352 person-years of observation for the children in the study there were a total of 1115 episodes of diarrhea, or 3.2 per year of observation. Only 28 children (8.4%) had episodes of persistent diarrhea lasting >14 days, and 79 (23.6%) ever had blood in their stool.10.1371/journal.pone.0000541.t002Table 2Outcomes of 335 children with at least one home visit by study cohort and treatment armCharacteristicHIV-infected childrenHIV-uninfected children born to HIV-infected mothersHIV-uninfected children born to HIV-uninfected mothersTreatment GroupPTreatment GroupPTreatment GroupPVitamin A (n\u200a=\u200a8)Vitamin A+zinc (n\u200a=\u200a9)Multiple micronutrients (n\u200a=\u200a11)Vitamin A (n\u200a=\u200a49)Vitamin A+zinc (n\u200a=\u200a47)Multiple micronutrients (n\u200a=\u200a46)Vitamin A (n\u200a=\u200a56)Vitamin A+zinc (n\u200a=\u200a57)Multiple micronutrients (n\u200a=\u200a52)\nPrimary outcome\nPercentage of days with diarrhea per child3.4 (0.8–9.4)7.1 (2.4–12.3)5.9 (1.5–16.1)0.6682.3 (0.7–4.0)2.5 (0.8–4.4)2.2 (0.8–5.5)0.8522.4 (0.9–5.0)1.8 (0.5–5.1)2.7 (0.5–4.6)0.857\nSecondary outcomes-diarrhea\nChildren who ever had diarrhea, n (%)7 (87.5)8 (88.9)9 (81.8)0.89144 (89.8)39 (83.0)40 (87.0)0.61647 (83.9)45 (78.9)40 (76.9)0.642Children who ever had blood in stools, n (%)2 (25.0)3 (33.3)6 (54.5)0.38811 (22.4)12 (25.5)11 (23.9)0.93913 (23.2)11 (19.3)10 (19.2)0.838Diarrhea episodes per child2 (1–7)3 (2–7)3 (2–5)0.7902 (1–5)2 (1–4)2 (1–4)0.9563 (1–6)2 (1–4)3(1–5)0.719Duration of diarrhea episode, days3.0 (2.3–5.6)4.4 (3.1–5.5)6.3 (2.8–7.8)0.2603.0 (2.5–4.0)4.0 (2.5–5.3)3.9 (2.4–5.1)0.3533.2 (2.5–5.0)3.9 (2.8–4.9)4.0 (2.0–4.7)0.515Children with diarrhea episodes ≥14 d, n (%)03 (33.3)3 (27.3)0.2063 (6.1)3 (6.4)6 (13.0)0.3952 (3.6)5 (8.8)3 (5.8)0.508Children with >5 stools/day on worst day of diarrhea episode*\n3/7 (42.9)4/8 (50.0)5/9 (55.6)0.88118/44 (40.9)20/39 (51.3)15/40 (37.5)0.43619/47 (40.4)19/45 (42.2)23/40 (57.5)0.226Children who visited clinic for diarrhea, n (%)3 (37.5)6 (66.7)9 (81.8)0.13628 (57.1)19 (40.4)23 (50.0)0.26030 (53.6)23 (40.4)20 (38.5)0.220\nSecondary outcomes–respiratory illness\nPercentage of weeks with upper respiratory symptoms12.4 (2.0–36.2)29.0 (10.1–50.0)23.7 (20.2–33.3)0.22213.1 (7.8–24.7)14.0 (6.2–23.0)14.3 (7.8–22.4)0.94016.6 (9.0–22.9)15.8 (9.0–24.2)14.2 (7.8–25.4)0.766Children who ever had pneumonia by maternal report, n (%)3 (37.5)4 (44.4)6 (54.5)0.75511 (22.4)14 (29.8)5 (10.9)0.0799 (16.1)12 (21.1)10 (19.2)0.791Children who ever had pneumonia confirmed by measured respiratory rate, n (%)3 (37.5)1 (11.1)4 (36.4)0.3718 (16.3)9 (19.1)2 (4.3)0.0846 (10.7)10 (17.5)5 (9.6)0.397\nOther secondary outcomes\nDied during study, N, (%)2 (25.0)4 (44.4)2 (18.2)0.41801 (2.1)1 (2.2)0.5861 (1.8)1 (1.8)00.628Admitted to hospital for any reason during study02 (22.2)4 (36.4)0.1621 (2.0)4 (8.5)4 (8.7)0.3123 (5.4)4 (7.0)3 (5.8)0.929Values are median (25th–75th centiles) or n (%). P values are for the overall group comparison using the Kruskall-Wallis test or 2 x 3 χ2 test.*Denominator is number of study children who ever had diarrhea.10.1371/journal.pone.0000541.t003Table 3Differences in median percentage of days of diarrhea by treatment group and cohort, and for the three cohorts combined.Treatment group comparisonCohortHIV-infected childrenHIV-uninfected children born to HIV-infected mothersHIV-uninfected children born to HIV-uninfected mothersVitamin A versus vitamin A plus zinc−2.6 days (−8.8, 2.5)−0.2 days (−1.3, 0.7)0.2 days (−0.6, 1.2)Vitamin A versus multiple micronutrients−1.9 days (−13.9, 2.8)−0.2 days (−1.2, 0.7)0 days (−0.8, 1.1)Vitamin A plus zinc versus multiple micronutrients0.1 days (−8.3, 7.1)0 days (−0.9, 1.2)0 days (−1.1, 0.8)Three cohorts combinedVitamin A versus vitamin A plus zincVitamin A versus multiple micronutrientsVitamin A plus zinc versus multiple micronutrients0 days (−0.8, 0.6)0 days (−0.5, 0.8)0 days (−0.8, 0.7)Values are the difference between groups in median prevalent days of diarrhea (95% CI for the difference). Differences between groups are estimated by calculating the median of all possible differences between patients in the groups being compared, rather than the arithmetic difference in the population median.Respiratory disease morbidityThere were no differences between study groups in the median percentage of weeks with upper respiratory symptoms, which ranged from 13.1% to 16.6% in the three treatment groups in the two cohorts of children without HIV infection; or in the percentage of children who had pneumonia confirmed by measured respiratory rate, which ranged from 4.3% to 19.1% (Table 2).Combined comparison of all cohortsWhen the three study cohorts were combined there were no significant differences in either the primary or secondary outcomes by supplement given (Table 4).10.1371/journal.pone.0000541.t004Table 4Outcomes of 335 children with at least one home visit by treatment arm for all three cohorts combinedCharacteristicTreatment GroupPVitamin A (n\u200a=\u200a113)Vitamin A+zinc (n\u200a=\u200a113)Multiple micronutrients (n\u200a=\u200a109)\nDiarrhea morbidity\nPercentage of days with diarrhea per child2.3 (0.8–4.5)2.4 (0.7–5.5)2.5 (0.8–5.4)0.935Children who ever had diarrhea, n (%)98 (86.7)92 (81.4)89 (81.7)0.484Children who ever had blood in stools, n (%)26 (23.0)26 (23.0)27 (24.8)0.939Diarrhea episodes per child2 (1–5)3 (1–4)2 (1–5)0.917Duration of diarrhea episodes, days3.0 (2.5–4.6)4.0 (2.7–5.0)4.0 (2.6–5.7)0.067Children who ever had diarrhea episodes ≥14 days, n (%)5 (4.4)11 (9.7)12 (11.0)0.168Children with >5 stools/day on worst day of diarrhea episode*\n40/98 (40.8)43/92 (46.7)43/89 (48.3)0.550Children who ever visited clinic for diarrhea, n (%)61 (54.0)48 (42.5)52 (47.7)0.223Children ever admitted to hospital with diarrhea: n (%)2 (1.8)4 (3.5)7 (6.4)0.195\nRespiratory morbidity\nPercentage of weeks with upper respiratory illness signs per child15.4 (8.4–24.4)15.8 (8.0–26.1)15.7 (8.4–25.0)0.695Children who ever had pneumonia by maternal report, n (%)23 (20.4)30 (26.5)21 (19.3)0.366Children who ever had pneumonia confirmed by respiratory rate, n (%)17 (15.0)20 (17.7)11 (10.1)0.261\nOther outcomes\nDied during study, n (%)3 (2.7)6 (5.3)3 (2.8)0.478Admitted to hospital for any reason during study4 (3.5)10 (8.8)11 (10.1)0.141Values are median (25th–75th centiles) or n (%). P values are for the overall group comparison using the Kruskall-Wallis test or 2 x 3 χ2 test.*Denominator is number of study children who ever had diarrhea.Ancillary analysesThere was no effect of treatment when subjects 6–12 months or 12–24 months, or those less than 1.5 or 2.0 z scores of length-for age, were analyzed separately.Study subjects received supplements 77% of days they were enrolled in the study (Table 1), but there was no significant difference between groups in percentage of days supplement was taken. Among the participant characteristics during study that might have confounded study outcome the only significant differences were the median number of study weeks that study subjects were fed cereal, which differed between treatment groups in both the cohorts of HIV-infected children, and HIV-uninfected children born to HIV-infected mothers; and the clinic used by HIV-infected children. Neither of these variables was associated with days of diarrhea, however, and thus we did not adjust for them in the analyses of outcomes.Adverse EffectsVomiting in the 30 minutes after administration of the supplement was witnessed by the field worker 7 times with vitamin A and zinc, and once each following administration of vitamin A and multiple micronutrients.DiscussionInterpretationIn this study neither zinc combined with vitamin A, nor zinc and vitamin A combined with other micronutrients, reduced diarrhea and respiratory disease morbidity in three cohorts of children 6–24 months of age in rural South Africa–HIV-infected children, HIV-uninfected children born to HIV-infected mothers, or children born to HIV-infected mothers. Enrollment of children with HIV infection was much smaller than the proposed sample size in the study protocol, thus limiting any conclusions about efficacy in this cohort. But enrollment in the other two cohorts was approximately what was planned, and conclusions on findings in these cohorts are thus robust.GeneralizabilityThe findings of this study are in contrast to the preponderance of findings from previous studies.[6] A meta-analysis of seven studies of continuous supplementation with zinc found a 25% reduction in diarrhea prevalence and 18% reduction in diarrhea incidence,[6] and in the four studies included in the meta-analysis that reported the effect of zinc on pneumonia there was a 41% decrease in pneumonia incidence.[6]\nWhat differences in study population, study design or supplement formulation might have accounted for the lack of effect of zinc or micronutrient supplementation on diarrhea or respiratory morbidity in this study when compared to previous studies? Children enrolled in this trial had better anthropometric indices than those reported on in most previous studies. Despite the food insecurity and poverty in the community, only 6.4% of children in this study were <2 z scores for length-for-age, compared to 32–100% of children in studies included in the meta-analysis of prophylactic zinc supplementation. A number of studies have shown the impact of zinc prophylaxis is greatest on those who are stunted or underweight,[7], [20], [21] or enrolled only those who were undernourished.[22], [23]\n[24], [25] Studies that have not found an effect on diarrheal or respiratory morbidity have often included better nourished children.[26] Other studies used zinc supplementation as secondary prophylaxis, enrolling children already ill with diarrhea,[24], [27], [28] which may select for a population at greater risk of disease, and more likely to benefit from supplementation.Diarrhea morbidity in this study was relatively low when compared to some studies showing an effect of zinc, where the reported incidence has been as high as an improbable 30 diarrhea episodes per child per year.[20] Other studies, like ours, have found much lower rates,[7], [8], [29] This suggests that either case definitions, or methods of ascertainment, in addition to biological and epidemiological factors, may play a role in the variation in diarrhea morbidity found in different studies. We used diarrhea case definitions that should be sensitive measures of diarrhea and that incorporated local terminology for diarrheal illness.[17], [30] The same is true for the definition of pneumonia–the commonly used WHO/UNICEF Integrated Management of Childhood Illness definition of pneumonia was used.[5] The schedule of household visits–once per week–is one that is commonly used, and has been sensitive for detecting diarrhea during community-based studies. The incidence and percentage of days with diarrhea was consistent with what was predicted in estimating the sample size.The dosage of zinc used in this study–10 mg per day for six months–is the regimen that has been most commonly used in prophylactic supplementation studies,[6] and previous studies with this formulation of micronutrients have suggested good bio-availability.[31] The proportion of study days that the supplement was taken–77% across all study participants–was lower than in some other studies, which have achieved adherence rates as high as 90%.[28] This study was, however, conducted as an intention-to-treat study, and thus data from study participants who had stopped taking supplements, but who still agreed to home visits, are included in the analysis. Some studies have only provided supplementation six days per week. Other studies have provided 20 mg of zinc as a weekly supplement in order to improve convenience and adherence. The rate at which supplements were taken–effectively 5 days per week in this study–would in any case likely be the best that could be achieved under non-study conditions in a general population.There was no placebo group in this study, and it is possible that vitamin A alone was sufficient to reduce diarrhea and respiratory morbidity. Although there is strong evidence for an effect of vitamin A on mortality in developing countries,[32] there is less consistent evidence that vitamin A supplementation alone reduces diarrhea and respiratory morbidity,[33] and some studies have even reported an increase in respiratory morbidity following vitamin A supplementation.[26]\nIn October 2003, soon after study enrollment began, the South African government implemented regulations requiring the fortification of maize meal and wheat flour, including flour used by bakeries, with zinc and other micronutrients.[34] The amount of fortification (up to 30 mg zinc per kg of maize meal for instance) in these staple foods, although unlikely to provide an amount of zinc equivalent to that in the supplements, may still have improved micronutrient status in children with access to commercially produced meal or bread.[35] A previous study from South Africa, however, suggest that fortification of maize meal, the staple for these children, did not improve zinc nutriture.[36]\nThere has been hope that supplementation with multiple micronutrients might be more beneficial that supplementation with a single micronutrient, especially as deficiencies in one micronutrient may limit the functional activity of other micronutrients.[1] To date, however, there has been little evidence that the addition of other micronutrients, including formulations similar to that used in this study, enhances the efficacy of zinc in reducing diarrhea and respiratory morbidity when the latter has been found effective. [21],[29],[37],[38],[39],[40] In at least two studies multiple micronutrient supplementation actually increased rates of morbidity when compared to placebo or zinc alone.[21],[28]\nNone of the studies reported on in the meta-analysis finding efficacy of zinc prophylaxis for diarrhea or respiratory disease was conducted in Africa.[6] Since the meta-analysis was conducted there have been at least five studies in addition to this one conducted in Africa that have examined the effect of zinc on diarrheal and respiratory morbidity, though in none except this one was it a primary study outcome (Table 5).[7], [8], [40]–[42] In a study in Ethiopia zinc significantly reduced the incidence of diarrhea and cough in children who were <2 z scores for length-for-age, but not in those who were better nourished.[7] In a study in Burkina Faso there was a modest but significant 13% reduction in diarrhea prevalence, but no significant reduction in cough.[8] A study in malnourished children in Lesotho of zinc supplementation for three months after hospital discharge found a reduction in diarrhea prevalence from 37% in the placebo to 3% in the zinc-supplemented group, and a reduction in acute respiratory infection from 39% to 3%.[42] A study of multiple micronutrient supplementation in South Africa did not find an effect of a zinc-containing micronutrient mixture on diarrhea morbidity despite very high rates of diarrhea prevalence.[40] A study in children in South Africa infected with HIV who were not on antiretroviral therapy found a reduction in diarrhea prevalence during scheduled or unscheduled clinic visits.[41] A recent large study from Tanzania found no effect of zinc supplementation on overall mortality, or diarrhea-related mortality.[43]\n10.1371/journal.pone.0000541.t005Table 5Studies of zinc supplementation, either alone or with other micronutrients, for prevention of diarrhea and respiratory illness in African children.AuthorCountryDateStudy populationStudy methodPrimary outcomeIntervention AFrequency and durationIntervention BFrequency and DurationNutritional status Group ANutritional status Group BEffect of intervention on diarrheaEffect of intervention on respiratory illnessUmeta[7]\nEthiopia2000Breast-fed infants 6–12 mDouble-blind RCT. Daily home visitsLinear growth10 mg zinc sulphate. 45 stunted children <2 z score length-for-age; 45 age and sex matched non-stunted childrenDaily except Sunday for six monthsPlacebo. 45 stunted children <2 z score length-for-age; 45 age and sex matched non-stunted childrenDaily except Sunday for six monthsZ-scores for stunted zinc group: −2.74 for length-for-age; −2.46 for weight-for-age; −0.48 for weight-for-length. For non-stunted group: −0.70 for length-for-age; −1.35 for weight-for-age; −1.00 for weight-for-lengthZ-scores for stunted placebo group: −2.87 for length-for-age; −2.70 for weight-for-age; −0.69for weight-for-length. For non-stunted group: −0.57 for length-for-age; −1.45 for weight-for-age; −1.27 for weight-for-lengthFor stunted group, 13 episodes (0.6 episodes per child per year) in zinc-supplemented group vs. 40 episodes (1.7 episodes per year) in placebo group (P<0.001). For non-stunted group, 14 episodes (0.6 episodes per year) in zinc group, 19 episodes (0.8 episodes per year) in placebo group (P\u200a=\u200aNS).For stunted group, 15 episodes of cough (0.7 episodes per child per year) in zinc-supplemented group vs. 30 episodes (1.3 episodes per year) in placebo group (P<0.05). For non-stunted group, 12 episodes (0.5 episodes per year) in zinc group, 21 episodes (0.9 episodes per year) in placebo group (P\u200a=\u200aNS).Müller[8]\nBurkina Faso2001Children 6–31 m from DSSDouble-blind RCT. Home visits 2 per weekReduction in malaria incidence12.5 mg zinc sulphate. 341 childrenDaily except Sunday for six monthsPlacebo. 344 childrenDaily except Sunday for six monthsReported jointly for zinc and placebo groups: 36.3% <2 z score height-for-age; 24.6% <2 z score weight-for-height1.8% days with diarrhea in zinc group; 2.0% in placebo group. RR 0.87 (95% CI 0.79 to 0.95)2.0% days with cough in zinc group; 1.9% in placebo group. RR 1.05 95% CI (0.97 to 1.15)Makonnen[42]\nLesotho2003Malnourished children 6–60 months identified in hospital and followed at home after dischargeDouble-blind RCT. Monthly home visits after discharge from hospitalNot specified10 mg zinc sulphate in 150 childrenDaily for three months after hospital dischargePlacebo in 150 childrenDaily for three months after hospital discharge91% <2 z score weight-for-age87% <2 z score weight-for-ageAt 90 days, prevalence of diarrhea in zinc-supplemented group was 2.9%; in placebo group was 36.7% (95% CI for difference reported as −32 to −15%).At 90 days, prevalence of acute respiratory infection in zinc-supplemented group was 2.9%; in placebo group was 38.8% (95% CI for difference −45 to −26%).Smuts[40]\nSouth Africa2006Infants 6–12 mDouble-blind RCT. Weekly home visitsChange in weight-for-age statusIntervention A: 1 daily allowance of multiple micronutrients given daily to 49 children or six monthsIntervention B: 2 x daily allowance of multiple micronutrients given weekly, with placebo on other days, given to 46 children for six monthsIntervention C: 10 mg elemental iron given daily to 49 children for six monthsIntervention D: placebo given daily to 50 children for six monthsFor total study population, 1.6% <2 z scores for weight for age; 10.7% <2 z scores for length-for-age; 0% <2 z scores for weight-for-length.Prevalent days of diarrhea were 20.9% in placebo group; 22.7% in daily micronutrient group; 21.1% in weekly micronutrient group; and 17.9% in daily iron group (P\u200a=\u200aNS)Prevalent days of upper respiratory illness were 9.0% in the placebo group; 6.8% in the daily micronutrient group; 8.7% with the weekly micronutrient group; and 7.9% in the daily iron group (P\u200a=\u200aNS)Bobat[41]\nSouth Africa2006HIV infected children 6–60 m not on ARTDouble-blind RCT. 7 clinic visits during 6 month supplementation period; 1 visit 3 months after supplementation ended.Change in plasma HIV-1 RNA10 mg zinc sulphate to 46 childrenDaily for six monthsPlacebo to 50 childrenDaily for six monthsHeight-for-age z score: −1.5. Weight-for-height z score: −0.05Height-for-age z score: −1.7. Weight-for-height z score: −0.11In zinc group diarrhea prevalence 6.7% at 360 scheduled clinic visits: 7.4% at 407 total clinic visit; in placebo group rates 105% and 14.5% respectively (P\u200a=\u200a0.001 by logistic regression for all events during all visits).In zinc group pneumonia prevalence 10.8% at 360 scheduled clinic visits: 14% at 407 total clinic visit; in placebo group rates 12.7% and 18.6% respectively (P\u200a=\u200a0.07 by logistic regression for all events during all visits). Rates of upper respiratory infection and ear infection also did not differ significantly.Overall evidenceWhat are the policy implications of this study? Because of the heterogeneity of different populations of children in developing countries and the heterogeneity of the studies of zinc that have been conducted to date, generalizing from any single study is problematic. This study had as its outcomes the efficacy of zinc or multiple micronutrient supplementation as primary prophylaxis of diarrhea and respiratory morbidity. Neither supplement was efficacious for either indication.The study was conducted in children that were less severely stunted than in most previous micronutrient supplementation studies, and who may have benefited from recent efforts to fortify staple food with micronutrients. But it is still a population which has a high burden of ill-health, with an infant mortality rate of 68 per thousand and an child mortality ratio of 98 per thousand.[44] The findings of this study, along with a previously reported study of micronutrient supplementation conducted elsewhere in South Africa that did not show efficacy,[40] do not provide support for the prophylactic use of zinc or multiple micronutrients to reduce diarrhea or respiratory morbidity in the general population of South African children.Supporting InformationChecklist S1CONSORT Checklist(0.05 MB DOC)Click here for additional data file.Protocol S1Trial Protocol(0.41 MB DOC)Click here for additional data file.We thank the community of Umkhanyakude for their support of the study; the mothers, children and families that participated; the nurses, supervisors and field staff for their devotion to and hard work; Nigel Rollins for assistance in conceptualization of the study, proposal and protocol development, and initial study implementation; Portia Mutevedzi and Nathalie Graham for assistance with laboratory studies; Cookie Govender and George Irving for assistance with data entry, and Mario Chen-Mok for advice on statistical methods.Competing Interests: The authors have declared that no competing interests exist.Funding: This study was supported by grants from the United States National Institute of Health (1 UO1 AI45508-01, 1 K24 AI/HDO1671-01, D43TW05572-01 to Dr. Bennish) and the Wellcome Trust (Wellcome 62925 to Dr. Bennish and Wellcome 063009 to Dr. Van den Broeck. The National Institutes of Health provided training in good clinical practice to study staff, arranged for the study to be monitored by a contract research organization to ensure compliance with good clinical practice, and established a Data Monitoring and Safety Board to oversee the trial. The sponsor for the study was the host institution, the Africa Centre for Health and Population Studies, which gave discretion in the investigative team in study design, data analysis, manuscript preparation, and decisions on manuscript submission and publication.References1\nVitamin&mineral deficiency. A global progress report The Micronutrient Initiative.\n(Accessed June 29,2004 at http://www.micronutrient.org/reports/reports/Full_e.pdf.)\n2\nLabadariosDSteynNPMaunderEMacIntryreUGerickeG\n2005\nThe National Food Consumption Survey (NFCS): South Africa, 1999.\nPublic Health Nutr\n8\n533\n43\n161533343\nMostertDSteynNPTempleNJOlwagenR\n2005\nDietary intake of pregnant women and their infants in a poor black South African community.\nCurationis\n28\n12\n9\n164505554\nFischer WalkerCBlackRE\n2004\nZinc and the risk for infectious disease.\nAnnu Rev Nutr\n24\n255\n75\n151891215\nTechnical updates of the guidelines on Integrated Management of Childhood Illness (IMCI): evidence and recommendations for further adaptations World Health Organization.\n(Accessed June 29,2005 at http://www.who.int/child-adolescent-health/New_Publications/IMCI/ISBN_92_4_159348_2.pdf.)\n6\nBhuttaZABlackREBrownKHGardnerJMGoreS\n1999\nPrevention of diarrhea and pneumonia by zinc supplementation in children in developing countries: pooled analysis of randomized controlled trials. Zinc Investigators' Collaborative Group.\nJ Pediatr\n135\n689\n97\n105861707\nUmetaMWestCEHaidarJDeurenbergPHautvastJG\n2000\nZinc supplementation and stunted infants in Ethiopia: a randomised controlled trial.\nLancet\n355\n2021\n6\n108853528\nMullerOBecherHvan ZweedenABYeYDialloDA\n2001\nEffect of zinc supplementation on malaria and other causes of morbidity in west African children: randomised double blind placebo controlled trial.\nBmj\n322\n1567\n114312969\nThe state of the world's children UNICEF.\n(Accessed June 30,2006 at http://www.unicef.org/sowc06/pdfs/sowc06_fullreport.pdf.)\n10\nNational HIV and syphilis prevalence survey South Africa 2005 South Africa Department of Health.\n(Accessed August 6,2006 at http://www.doh.gov.za/docs/reports/2005/hiv.pdf.)\n11\nBaileyRCKamengaMCNsuamiMJNieburgPSt LouisME\n1999\nGrowth of children according to maternal and child HIV, immunological and disease characteristics: a prospective cohort study in Kinshasa, Democratic Republic of Congo.\nInt J Epidemiol\n28\n532\n40\n1040586112\nA profile of KwaZulu-Natal: demographics, poverty, inequality and unemployment Provide Project.\n(Accessed June 30,2005 at http://www.elsenburg.com/provide/documents/BP2005_1_5%20Demographics%20KZ.pdf.)\n13\nBlandRMRollinsNCCoutsoudisACoovadiaHM\n2002\nBreastfeeding practices in an area of high HIV prevalence in rural South Africa.\nActa Paediatr\n91\n704\n11\n1216260614\nFaberM\n2005\nComplementary foods consumed by 6-12-month-old rural infants in South Africa are inadequate in micronutrients.\nPublic Health Nutr\n8\n373\n81\n1597518215\nHamillPVDrizdTAJohnsonCLReedRBRocheAF\n1979\nPhysical growth: National Center for Health Statistics percentiles.\nAm J Clin Nutr\n32\n607\n29\n42015316\nLockG\n2003\nThe foodLET vehicle designed for and used in the IRIS I intervention.\nFood Nutr Bull\n24\nS16\n9\n1456493917\nKauchaliSRollinsNVan den BroeckJ\n2004\nLocal beliefs about childhood diarrhoea: importance for healthcare and research.\nJ Trop Pediatr\n50\n82\n9\n1508879618\nGardnerMJAltmanDG\n1989\nStatistics with confidence. Confidence intervals and statistical guidelines.\nLondon\nBritish Medical Journal\n19\nBergerVWExnerDV\n1999\nDetecting selection bias in randomized clinical trials.\nControl Clin Trials\n20\n319\n27\n1044055920\nRuelMTRiveraJASantizoMCLonnerdalBBrownKH\n1997\nImpact of zinc supplementation on morbidity from diarrhea and respiratory infections among rural Guatemalan children.\nPediatrics\n99\n808\n13\n916477421\nBaquiAHZamanKPerssonLAEl ArifeenSYunusM\n2003\nSimultaneous weekly supplementation of iron and zinc is associated with lower morbidity due to diarrhea and acute lower respiratory infection in Bangladeshi infants.\nJ Nutr\n133\n4150\n7\n1465236422\nNinhNXThissenJPColletteLGerardGKhoiHH\n1996\nZinc supplementation increases growth and circulating insulin-like growth factor I (IGF-I) in growth-retarded Vietnamese children.\nAm J Clin Nutr\n63\n514\n9\n859931423\nMeeks GardnerJWitterMMRamdathDD\n1998\nZinc supplementation: effects on the growth and morbidity of undernourished Jamaican children.\nEur J Clin Nutr\n52\n34\n9\n948153024\nRoySKTomkinsAMHaiderRBehrenRHAkramuzzamanSM\n1999\nImpact of zinc supplementation on subsequent growth and morbidity in Bangladeshi children with acute diarrhoea.\nEur J Clin Nutr\n53\n529\n34\n1045240725\nSurDGuptaDNMondalSKGhoshSMannaB\n2003\nImpact of zinc supplementation on diarrheal morbidity and growth pattern of low birth weight infants in kolkata, India: a randomized, double-blind, placebo-controlled, community-based study.\nPediatrics\n112\n1327\n32\n1465460526\nLongKZMontoyaYHertzmarkESantosJIRosadoJL\n2006\nA double-blind, randomized, clinical trial of the effect of vitamin A and zinc supplementation on diarrheal disease and respiratory tract infections in children in Mexico City, Mexico.\nAm J Clin Nutr\n83\n693\n700\n1652291927\nSazawalSBlackREBhanMKJallaSSinhaA\n1997\nEfficacy of zinc supplementation in reducing the incidence and prevalence of acute diarrhea–a community-based, double-blind, controlled trial.\nAm J Clin Nutr\n66\n413\n8\n925012228\nPennyMEMarinRMDuranAPeersonJMLanataCF\n2004\nRandomized controlled trial of the effect of daily supplementation with zinc or multiple micronutrients on the morbidity, growth, and micronutrient status of young Peruvian children.\nAm J Clin Nutr\n79\n457\n65\n1498522229\nRosadoJLLopezPMunozEMartinezHAllenLH\n1997\nZinc supplementation reduced morbidity, but neither zinc nor iron supplementation affected growth or body composition of Mexican preschoolers.\nAm J Clin Nutr\n65\n13\n9\n898890730\nColdhamCRossDQuigleyMSeguraZChandramohanD\n2000\nProspective validation of a standardized questionnaire for estimating childhood mortality and morbidity due to pneumonia and diarrhoea.\nTrop Med Int Health\n5\n134\n44\n1074727431\nSmutsCMLombardCJBenadeAJDhansayMABergerJ\n2005\nEfficacy of a foodlet-based multiple micronutrient supplement for preventing growth faltering, anemia, and micronutrient deficiency of infants: the four country IRIS trial pooled data analysis.\nJ Nutr\n135\n631S\n8S\n1573510732\nFawziWWChalmersTCHerreraMGMostellerF\n1993\nVitamin A supplementation and child mortality. A meta-analysis.\nJama\n269\n898\n903\n842644933\nVitamin A supplementation and child morbidity and mortality in developing countries United Nations University Press.\n(Accessed July 7,1994 at http://www.unu.edu/unupress/food/8F154e/8F154E04.htm#Vitamin%20A%20supplementation%20and%20child%20morbidity%20and%20mortality%20in%20developing%20countries.)\n34\nRegulations relating to the fortification of certain foodstuffs Ministry of Health South Africa.\n(Accessed July 7,2003 at http://www.doh.gov.za/docs/regulations/2003/ffortification.html.)\n35\nde RomanaDLSalazarMHambidgeKMPennyMEPeersonJM\n2005\nLongitudinal measurements of zinc absorption in Peruvian children consuming wheat products fortified with iron only or iron and 1 of 2 amounts of zinc.\nAm J Clin Nutr\n81\n637\n47\n1575583436\nFaberMKvalsvigJDLombardCJBenadeAJS\n2005\nEffect of a fortified maize-meal porridge on anemia, micronutrient status, and motor development of infants.\nAm J Clin Nutr\n82\n1032\n9\n1628043537\nTielschJMKhatrySKStoltzfusRJKatzJLeClerqSC\n2006\nEffect of routine prophylactic supplementation with iron and folic acid on preschool child mortality in southern Nepal: community-based, cluster-randomised, placebo-controlled trial.\nLancet\n367\n144\n52\n1641387838\nLopez de RomanaGCusirramosSLopez de RomanaDGrossR\n2005\nEfficacy of multiple micronutrient supplementation for improving anemia, micronutrient status, growth, and morbidity of Peruvian infants.\nJ Nutr\n135\n646S\n52\n1573510939\nUntoroJKaryadiEWibowoLErhardtMWGrossR\n2005\nMultiple micronutrient supplements improve micronutrient status and anemia but not growth and morbidity of Indonesian infants: a randomized, double-blind, placebo-controlled trial.\nJ Nutr\n135\n639S\n45\n1573510840\nSmutsCMDhansayMAFaberMvan StuijvenbergMESwanevelderS\n2005\nEfficacy of multiple micronutrient supplementation for improving anemia, micronutrient status, and growth in South African infants.\nJ Nutr\n135\n653S\n9S\n1573511041\nBobatRCoovadiaHStephenCNaidooKLMcKerrowN\n2005\nSafety and efficacy of zinc supplementation for children with HIV-1 infection in South Africa: a randomised double-blind placebo-controlled trial.\nLancet\n366\n1862\n7\n1631055242\nMakonnenBVenterAJoubertG\n2003\nA randomized controlled study of the impact of dietary zinc supplementation in the management of children with protein-energy malnutrition in Lesotho. I: mortality and morbidity.\nJ Trop Pediatr\n49\n340\n52\n1472541143\nSazawalSBlackRERamsanMChwayaHMDuttaA\n2007\nEffect of zinc supplementation on mortality in children aged 1–48 months: a community-based randomised placebo-controlled trial.\nLancet\n369\n927\n34\n1736815444\nGarribAJaffarSKnightSBradshawDBennishML\n2006\nRates and causes of child mortality in an area of high HIV prevalence in rural South Africa.\nTrop Med Int Health\n11\n1841\n8\n17176349", 'title': 'Zinc or multiple micronutrient supplementation to reduce diarrhea and respiratory disease in South African children: a randomized controlled trial.', 'date': '2007-06-28'}}
| 0.5
|
Public Health, Epidemiology & Health Systems
|
50
|
Is overall survival higher, lower, or the same when comparing cisplatin in combination with third‐generation drugs to carboplatin in combination with third‐generation drugs?
|
no difference
|
high
|
no
|
['12928123', '11784875', '28643733', '12377641', '12826316', '12837811', '17409843']
| 31,930,743
| 2,020
|
{'12928123': {'article_id': '12928123', 'content': 'This randomized, multicenter, phase III trial was conducted to compare the tolerability of gemcitabine plus cisplatin (GP) vs. gemcitabine plus carboplatin (GC) in chemonaive patients with stage IIIb and IV non-small cell lung carcinoma (NSCLC). Secondary objectives were to evaluate response, duration of response, time to progressive disease (TTPD), and survival.\nEligible patients were required to have stage IIIb or IV NSCLC, no previous chemotherapy, Karnofsky performance status of at least 70, bidimensionally measurable disease, and age 18-75 years. Randomized patients in both arms were given gemcitabine 1200 mg/m(2) on days 1 and 8, followed on day 1 by cisplatin 80 mg/m(2) (GP) or carboplatin AUC=5 (GC). Treatment cycles were repeated every 21 days for a maximum of six cycles, or until disease progression or unacceptable toxicity occurred.\nEnrolled patients in both arms, 87 in GP and 89 in GC, were well balanced for demographics and disease characteristics. Dose intensity was 93.8 and 92.7% for gemcitabine in GP/GC arms, respectively; 97.7% for cisplatin and 99.9% for carboplatin. Patients with at least one grade 3/4 toxicity excluding nausea, vomiting or alopecia, were 44% in GP arm and 54% in GC arm. The only significantly different toxicities were, nausea and vomiting in GP and thrombocytopenia in GC group. The overall response rates, median TTPD, response duration and survival were, 41/29%, 5.87/4.75 months, 7.48/5.15 months, and 8.75/7.97 months for GP and GC arms, respectively.\nGP and GC are effective and feasible regimens for advanced NSCLC, and are comparable in efficacy and toxicity. GC may offer acceptable option to patients with advanced NSCLC, especially those who are unable to receive cisplatin.', 'title': 'Gemcitabine plus cisplatin vs. gemcitabine plus carboplatin in stage IIIb and IV non-small cell lung cancer: a phase III randomized trial.', 'date': '2003-08-21'}, '11784875': {'article_id': '11784875', 'content': 'We conducted a randomized study to determine whether any of three chemotherapy regimens was superior to cisplatin and paclitaxel in patients with advanced non-small-cell lung cancer.\nA total of 1207 patients with advanced non-small-cell lung cancer were randomly assigned to a reference regimen of cisplatin and paclitaxel or to one of three experimental regimens: cisplatin and gemcitabine, cisplatin and docetaxel, or carboplatin and paclitaxel.\nThe response rate for all 1155 eligible patients was 19 percent, with a median survival of 7.9 months (95 percent confidence interval, 7.3 to 8.5), a 1-year survival rate of 33 percent (95 percent confidence interval, 30 to 36 percent), and a 2-year survival rate of 11 percent (95 percent confidence interval, 8 to 12 percent). The response rate and survival did not differ significantly between patients assigned to receive cisplatin and paclitaxel and those assigned to receive any of the three experimental regimens. Treatment with cisplatin and gemcitabine was associated with a significantly longer time to the progression of disease than was treatment with cisplatin and paclitaxel but was more likely to cause grade 3, 4, or 5 renal toxicity (in 9 percent of patients, vs. 3 percent of those treated with cisplatin plus paclitaxel). Patients with a performance status of 2 had a significantly lower rate of survival than did those with a performance status of 0 or 1.\nNone of four chemotherapy regimens offered a significant advantage over the others in the treatment of advanced non-small-cell lung cancer.', 'title': 'Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.', 'date': '2002-01-11'}, '28643733': {'article_id': '28643733', 'content': 'The use of cisplatin (Cis) versus carboplatin (Carb) in the treatment of advanced nonsmall cell lung cancer (NSCLC) is controversial. The aim of the study was to compare the safety and efficacy of Cis versus Carb in squamous NSCLC.\nA prospective, randomized, controlled, open-label study was conducted on advanced squamous NSCLC patients who were randomly assigned to receive Cis (40 mg/m 2 [day 1 and day 8]) or Carb (area under the curve = 5 [day 1]) combined with gemcitabine [Gem] (1000 mg/m 2 [day 1 and day 8]) of a 3-week schedule for six cycles. Study objectives were a radiological response after three cycles and six cycles, 1-year progression-free survival (PFS), 1-year overall survival (OS), and quality of life (QOL) assessment using functional assessment of cancer therapy-lung at baseline, after three cycles, and after six cycles.\nStatistical analysis was done using Statistical Package for Social Science version 15. A P < 0.05 was considered statistically significant.\nSeventy-one patients were enrolled (Gem/Cis group [n = 36], Gem/Carb group [n = 35]). Response rates were comparable in both arms. Nonsignificant differences were found regarding 1-year PFS (P = 0.308) and 1-year OS (P = 0.929) between the two groups. Neutropenia was significantly higher in Gem/Carb group, while vomiting and ototoxicity were significantly higher in Gem/Cis group. The effect on QOL was similar in both groups.\nCis and Carb have similar efficacy, tolerability, and effect on QOL and both can be used as a first-line treatment of squamous NSCLC.', 'title': 'A prospective randomized controlled study of cisplatin versus carboplatin-based regimen in advanced squamous nonsmall cell lung cancer.', 'date': '2017-06-24'}, '12377641': {'article_id': '12377641', 'content': 'The combination of paclitaxel with cisplatin or carboplatin has significant activity in non-small-cell lung cancer (NSCLC). This phase III study of chemotherapy-naïve advanced NSCLC patients was designed to assess whether response rate in patients receiving a paclitaxel/carboplatin combination was similar to that in patients receiving a paclitaxel/cisplatin combination. Paclitaxel was given at a dose of 200 mg/m(2) (3-h intravenous infusion) followed by either carboplatin at an AUC of 6 or cisplatin at a dose of 80 mg/m(2), all repeated every 3 weeks. Survival, toxicity and quality of life were also compared.\nPatients were randomised to receive one of the two combinations, stratified according to centre, performance status, disease stage and histology. The primary analyses of response rate and survival were carried out on response-evaluable patients. Survival was also analysed for all randomised patients. Toxicity analyses were carried out on all treated patients.\nA total of 618 patients were randomised. The two treatment arms were well balanced with regard to gender (83% male), age (median 58 years), performance status (83% ECOG 0-1), stage (68% IV, 32% IIIB) and histology (38% squamous cell carcinoma). In the paclitaxel/carboplatin arm, 306 patients received a total of 1311 courses (median four courses, range 1-10 courses) while in the paclitaxel/cisplatin arm, 302 patients received a total of 1321 courses (median four courses, range 1-10 courses). In only 76% of courses, carboplatin was administered as planned at an AUC of 6, while in 96% of courses, cisplatin was given at the planned dose of 80 mg/m(2). The response rate was 25% (70 of 279) in the paclitaxel/carboplatin arm and 28% (80 of 284) in the paclitaxel/cisplatin arm (P = 0.45). Responses were reviewed by an independent radiological committee. For all randomised patients, median survival was 8.5 months in the paclitaxel/carboplatin arm and 9.8 months in the paclitaxel/cisplatin arm [hazard ratio 1.20, 90% confidence interval (CI) 1.03-1.40]; the 1-year survival rates were 33% and 38%, respectively. On the same dataset, a survival update after 22 months of additional follow-up yielded a median survival of 8.2 months in the paclitaxel/carboplatin arm and 9.8 months in the paclitaxel/cisplatin arm (hazard ratio 1.22, 90% CI 1.06-1.40; P = 0.019); the 2-year survival rates were 9% and 15%, respectively. Excluding neutropenia and thrombocytopenia, which were more frequent in the paclitaxel/carboplatin arm, and nausea/vomiting and nephrotoxicity, which were more frequent in the paclitaxel/cisplatin arm, the rate of severe toxicities was generally low and comparable between the two arms. Overall quality of life (EORTC QLQ-C30 and LC-13) was also similar between the two arms.\nThis is the first trial comparing carboplatin and cisplatin in the treatment of advanced NSCLC. Although paclitaxel/carboplatin yielded a similar response rate, the significantly longer median survival obtained with paclitaxel/cisplatin indicates that cisplatin-based chemotherapy should be the first treatment option.', 'title': 'Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trial.', 'date': '2002-10-16'}, '12826316': {'article_id': '12826316', 'content': 'We conducted a phase II randomized study to assess the efficacy, with response as the primary endpoint, and the toxicity of gemcitabine/cisplatin (GP) and gemcitabine/carboplatin (GC) in patients with advanced non-small cell lung cancer (NSCLC).\nPatients were randomized to GP (gemcitabine 1200 mg/m(2), days 1 and 8 plus cisplatin 80 mg/m(2) day 2) or GC (gemcitabine 1200 mg/m(2), days 1 and 8 plus carboplatin AUC=5 day 2). Cycles were repeated every 3 weeks.\nSixty-two patients were randomized to GP and 58 to GC. A total of 533 cycles were delivered (264 GP, 269 GC), with a median of four cycles/patient. The objective response rate was 41.9% (95% C.I., 29.6-54.2%) for GP and 31.0% (95% C.I., 18.2-42.8%) for GC (P=0.29). No significant differences between arms were observed in median survival (10.4 months GP, 10.8 months GC) and median time to progression (5.4 months GP, 5.1 months GC). Both regimens were very well tolerated with no statistical differences between arms in grade 3/4 toxicities. When all toxicity grades were combined, emesis, neuropathy and renal toxicity occurred more frequently on the GP arm (P<0.005).\nGC arm did not provide a significant difference in response rate compared with GP arm, with better overall tolerability. Carboplatin could be a valid alternative to cisplatin in the palliative setting.', 'title': 'Randomized, multicenter, phase II study of gemcitabine plus cisplatin versus gemcitabine plus carboplatin in patients with advanced non-small cell lung cancer.', 'date': '2003-06-27'}, '12837811': {'article_id': '12837811', 'content': 'To investigate whether docetaxel plus platinum regimens improve survival and affect quality of life (QoL) in advanced non-small-cell lung cancer (NSCLC) compared with vinorelbine plus cisplatin as first-line chemotherapy.\nPatients (n = 1,218) with stage IIIB to IV NSCLC were randomly assigned to receive docetaxel 75 mg/m2 and cisplatin 75 mg/m2 every 3 weeks (DC); docetaxel 75 mg/m2 and carboplatin area under the curve of 6 mg/mL * min every 3 weeks (DCb); or vinorelbine 25 mg/m2/wk and cisplatin 100 mg/m2 every 4 weeks (VC).\nPatients treated with DC had a median survival of 11.3 v 10.1 months for VC-treated patients (P =.044; hazard ratio, 1.183 [97.2% confidence interval, 0.989 to 1.416]). The 2-year survival rate was 21% for DC-treated patients and 14% for VC-treated patients. Overall response rate was 31.6% for DC-treated patients v 24.5% for VC-treated patients (P =.029). Median survival (9.4 v 9.9 months [for VC]; P =.657; hazard ratio, 1.048 [97.2 confidence interval, 0.877 to 1.253]) and response (23.9%) with DCb were similar to those results for VC. Neutropenia, thrombocytopenia, infection, and febrile neutropenia were similar with all three regimens. Grade 3 to 4 anemia, nausea, and vomiting were more common (P <.01) with VC than with DC or DCb. Patients treated with either docetaxel regimen had consistently improved QoL compared with VC-treated patients, who experienced deterioration in QoL.\nDC resulted in a more favorable overall response and survival rate than VC. Both DC and DCb were better tolerated and provided patients with consistently improved QoL compared with VC. These findings demonstrate that a docetaxel plus platinum combination is an effective treatment option with a favorable therapeutic index for first-line treatment of advanced or metastatic NSCLC.', 'title': 'Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group.', 'date': '2003-07-03'}, '17409843': {'article_id': '17409843', 'content': 'Paclitaxel plus carboplatin (CAR) or cisplatin (CIS) has shown activity in the treatment of advanced non-small cell lung cancer (NSCLC). Our aim was to determine whether paclitaxel plus platinum is an appropriate regimen for chemo-naïve NSCLC in patients aged 70 years or older. Patients were randomized into paclitaxel plus CAR or paclitaxel plus CIS treatment arms. Treatment consisted of paclitaxel 160 mg/m and carboplatin at AUC = 6 (predicted using measured clearances and the Calvert formula) IV infusion on day 1 every 3 weeks, or paclitaxel 160 mg/m and cisplatin 60 mg/m IV on day 1 every 3 weeks. In total, 81 patients were enrolled from September 2000 to February 2005, including 40 who received CAR treatment and 41 who received CIS treatment. In all, 152 cycles of CAR (median, four cycles per patient) and 172 cycles of CIS (median, four cycles per patient) were given. Each arm had one complete response and 15 partial responses to the treatment, with overall response rates of 40% and 39%, respectively. Myelosuppression was mild in both arms, and there was no statistical difference between the two arms. Alopecia (P < 0.001), peripheral neuropathy (P = 0.017), and fatigue (P < 0.001) were more severe in the CIS treatment arm than in the CAR treatment arm. Median time to disease progression was 6.6 months in the CAR arm and 6.9 months in the CIS arm. Median survival time was 10.3 months in the CAR arm and 10.5 months in the CIS arm. In conclusion, paclitaxel plus CAR or CIS treatment is feasible in elderly patients and has similar activity. However, paclitaxel plus CAR had less non-hematological toxicity than paclitaxel plus CIS.', 'title': 'A Phase II randomized study of paclitaxel plus carboplatin or cisplatin against chemo-naive inoperable non-small cell lung cancer in the elderly.', 'date': '2007-04-06'}}
| 0.428571
|
Oncology & Hematology
|
51
|
Is response rate higher, lower, or the same when comparing cisplatin in combination with third‐generation drugs to carboplatin in combination with third‐generation drugs?
|
no difference
|
high
|
no
|
['12928123', '11784875', '28643733', '12377641', '12826316', '12837811', '17409843', '28780466', '21047474', '11745199', '21333222']
| 31,930,743
| 2,020
|
{'12928123': {'article_id': '12928123', 'content': 'This randomized, multicenter, phase III trial was conducted to compare the tolerability of gemcitabine plus cisplatin (GP) vs. gemcitabine plus carboplatin (GC) in chemonaive patients with stage IIIb and IV non-small cell lung carcinoma (NSCLC). Secondary objectives were to evaluate response, duration of response, time to progressive disease (TTPD), and survival.\nEligible patients were required to have stage IIIb or IV NSCLC, no previous chemotherapy, Karnofsky performance status of at least 70, bidimensionally measurable disease, and age 18-75 years. Randomized patients in both arms were given gemcitabine 1200 mg/m(2) on days 1 and 8, followed on day 1 by cisplatin 80 mg/m(2) (GP) or carboplatin AUC=5 (GC). Treatment cycles were repeated every 21 days for a maximum of six cycles, or until disease progression or unacceptable toxicity occurred.\nEnrolled patients in both arms, 87 in GP and 89 in GC, were well balanced for demographics and disease characteristics. Dose intensity was 93.8 and 92.7% for gemcitabine in GP/GC arms, respectively; 97.7% for cisplatin and 99.9% for carboplatin. Patients with at least one grade 3/4 toxicity excluding nausea, vomiting or alopecia, were 44% in GP arm and 54% in GC arm. The only significantly different toxicities were, nausea and vomiting in GP and thrombocytopenia in GC group. The overall response rates, median TTPD, response duration and survival were, 41/29%, 5.87/4.75 months, 7.48/5.15 months, and 8.75/7.97 months for GP and GC arms, respectively.\nGP and GC are effective and feasible regimens for advanced NSCLC, and are comparable in efficacy and toxicity. GC may offer acceptable option to patients with advanced NSCLC, especially those who are unable to receive cisplatin.', 'title': 'Gemcitabine plus cisplatin vs. gemcitabine plus carboplatin in stage IIIb and IV non-small cell lung cancer: a phase III randomized trial.', 'date': '2003-08-21'}, '11784875': {'article_id': '11784875', 'content': 'We conducted a randomized study to determine whether any of three chemotherapy regimens was superior to cisplatin and paclitaxel in patients with advanced non-small-cell lung cancer.\nA total of 1207 patients with advanced non-small-cell lung cancer were randomly assigned to a reference regimen of cisplatin and paclitaxel or to one of three experimental regimens: cisplatin and gemcitabine, cisplatin and docetaxel, or carboplatin and paclitaxel.\nThe response rate for all 1155 eligible patients was 19 percent, with a median survival of 7.9 months (95 percent confidence interval, 7.3 to 8.5), a 1-year survival rate of 33 percent (95 percent confidence interval, 30 to 36 percent), and a 2-year survival rate of 11 percent (95 percent confidence interval, 8 to 12 percent). The response rate and survival did not differ significantly between patients assigned to receive cisplatin and paclitaxel and those assigned to receive any of the three experimental regimens. Treatment with cisplatin and gemcitabine was associated with a significantly longer time to the progression of disease than was treatment with cisplatin and paclitaxel but was more likely to cause grade 3, 4, or 5 renal toxicity (in 9 percent of patients, vs. 3 percent of those treated with cisplatin plus paclitaxel). Patients with a performance status of 2 had a significantly lower rate of survival than did those with a performance status of 0 or 1.\nNone of four chemotherapy regimens offered a significant advantage over the others in the treatment of advanced non-small-cell lung cancer.', 'title': 'Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.', 'date': '2002-01-11'}, '28643733': {'article_id': '28643733', 'content': 'The use of cisplatin (Cis) versus carboplatin (Carb) in the treatment of advanced nonsmall cell lung cancer (NSCLC) is controversial. The aim of the study was to compare the safety and efficacy of Cis versus Carb in squamous NSCLC.\nA prospective, randomized, controlled, open-label study was conducted on advanced squamous NSCLC patients who were randomly assigned to receive Cis (40 mg/m 2 [day 1 and day 8]) or Carb (area under the curve = 5 [day 1]) combined with gemcitabine [Gem] (1000 mg/m 2 [day 1 and day 8]) of a 3-week schedule for six cycles. Study objectives were a radiological response after three cycles and six cycles, 1-year progression-free survival (PFS), 1-year overall survival (OS), and quality of life (QOL) assessment using functional assessment of cancer therapy-lung at baseline, after three cycles, and after six cycles.\nStatistical analysis was done using Statistical Package for Social Science version 15. A P < 0.05 was considered statistically significant.\nSeventy-one patients were enrolled (Gem/Cis group [n = 36], Gem/Carb group [n = 35]). Response rates were comparable in both arms. Nonsignificant differences were found regarding 1-year PFS (P = 0.308) and 1-year OS (P = 0.929) between the two groups. Neutropenia was significantly higher in Gem/Carb group, while vomiting and ototoxicity were significantly higher in Gem/Cis group. The effect on QOL was similar in both groups.\nCis and Carb have similar efficacy, tolerability, and effect on QOL and both can be used as a first-line treatment of squamous NSCLC.', 'title': 'A prospective randomized controlled study of cisplatin versus carboplatin-based regimen in advanced squamous nonsmall cell lung cancer.', 'date': '2017-06-24'}, '12377641': {'article_id': '12377641', 'content': 'The combination of paclitaxel with cisplatin or carboplatin has significant activity in non-small-cell lung cancer (NSCLC). This phase III study of chemotherapy-naïve advanced NSCLC patients was designed to assess whether response rate in patients receiving a paclitaxel/carboplatin combination was similar to that in patients receiving a paclitaxel/cisplatin combination. Paclitaxel was given at a dose of 200 mg/m(2) (3-h intravenous infusion) followed by either carboplatin at an AUC of 6 or cisplatin at a dose of 80 mg/m(2), all repeated every 3 weeks. Survival, toxicity and quality of life were also compared.\nPatients were randomised to receive one of the two combinations, stratified according to centre, performance status, disease stage and histology. The primary analyses of response rate and survival were carried out on response-evaluable patients. Survival was also analysed for all randomised patients. Toxicity analyses were carried out on all treated patients.\nA total of 618 patients were randomised. The two treatment arms were well balanced with regard to gender (83% male), age (median 58 years), performance status (83% ECOG 0-1), stage (68% IV, 32% IIIB) and histology (38% squamous cell carcinoma). In the paclitaxel/carboplatin arm, 306 patients received a total of 1311 courses (median four courses, range 1-10 courses) while in the paclitaxel/cisplatin arm, 302 patients received a total of 1321 courses (median four courses, range 1-10 courses). In only 76% of courses, carboplatin was administered as planned at an AUC of 6, while in 96% of courses, cisplatin was given at the planned dose of 80 mg/m(2). The response rate was 25% (70 of 279) in the paclitaxel/carboplatin arm and 28% (80 of 284) in the paclitaxel/cisplatin arm (P = 0.45). Responses were reviewed by an independent radiological committee. For all randomised patients, median survival was 8.5 months in the paclitaxel/carboplatin arm and 9.8 months in the paclitaxel/cisplatin arm [hazard ratio 1.20, 90% confidence interval (CI) 1.03-1.40]; the 1-year survival rates were 33% and 38%, respectively. On the same dataset, a survival update after 22 months of additional follow-up yielded a median survival of 8.2 months in the paclitaxel/carboplatin arm and 9.8 months in the paclitaxel/cisplatin arm (hazard ratio 1.22, 90% CI 1.06-1.40; P = 0.019); the 2-year survival rates were 9% and 15%, respectively. Excluding neutropenia and thrombocytopenia, which were more frequent in the paclitaxel/carboplatin arm, and nausea/vomiting and nephrotoxicity, which were more frequent in the paclitaxel/cisplatin arm, the rate of severe toxicities was generally low and comparable between the two arms. Overall quality of life (EORTC QLQ-C30 and LC-13) was also similar between the two arms.\nThis is the first trial comparing carboplatin and cisplatin in the treatment of advanced NSCLC. Although paclitaxel/carboplatin yielded a similar response rate, the significantly longer median survival obtained with paclitaxel/cisplatin indicates that cisplatin-based chemotherapy should be the first treatment option.', 'title': 'Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trial.', 'date': '2002-10-16'}, '12826316': {'article_id': '12826316', 'content': 'We conducted a phase II randomized study to assess the efficacy, with response as the primary endpoint, and the toxicity of gemcitabine/cisplatin (GP) and gemcitabine/carboplatin (GC) in patients with advanced non-small cell lung cancer (NSCLC).\nPatients were randomized to GP (gemcitabine 1200 mg/m(2), days 1 and 8 plus cisplatin 80 mg/m(2) day 2) or GC (gemcitabine 1200 mg/m(2), days 1 and 8 plus carboplatin AUC=5 day 2). Cycles were repeated every 3 weeks.\nSixty-two patients were randomized to GP and 58 to GC. A total of 533 cycles were delivered (264 GP, 269 GC), with a median of four cycles/patient. The objective response rate was 41.9% (95% C.I., 29.6-54.2%) for GP and 31.0% (95% C.I., 18.2-42.8%) for GC (P=0.29). No significant differences between arms were observed in median survival (10.4 months GP, 10.8 months GC) and median time to progression (5.4 months GP, 5.1 months GC). Both regimens were very well tolerated with no statistical differences between arms in grade 3/4 toxicities. When all toxicity grades were combined, emesis, neuropathy and renal toxicity occurred more frequently on the GP arm (P<0.005).\nGC arm did not provide a significant difference in response rate compared with GP arm, with better overall tolerability. Carboplatin could be a valid alternative to cisplatin in the palliative setting.', 'title': 'Randomized, multicenter, phase II study of gemcitabine plus cisplatin versus gemcitabine plus carboplatin in patients with advanced non-small cell lung cancer.', 'date': '2003-06-27'}, '12837811': {'article_id': '12837811', 'content': 'To investigate whether docetaxel plus platinum regimens improve survival and affect quality of life (QoL) in advanced non-small-cell lung cancer (NSCLC) compared with vinorelbine plus cisplatin as first-line chemotherapy.\nPatients (n = 1,218) with stage IIIB to IV NSCLC were randomly assigned to receive docetaxel 75 mg/m2 and cisplatin 75 mg/m2 every 3 weeks (DC); docetaxel 75 mg/m2 and carboplatin area under the curve of 6 mg/mL * min every 3 weeks (DCb); or vinorelbine 25 mg/m2/wk and cisplatin 100 mg/m2 every 4 weeks (VC).\nPatients treated with DC had a median survival of 11.3 v 10.1 months for VC-treated patients (P =.044; hazard ratio, 1.183 [97.2% confidence interval, 0.989 to 1.416]). The 2-year survival rate was 21% for DC-treated patients and 14% for VC-treated patients. Overall response rate was 31.6% for DC-treated patients v 24.5% for VC-treated patients (P =.029). Median survival (9.4 v 9.9 months [for VC]; P =.657; hazard ratio, 1.048 [97.2 confidence interval, 0.877 to 1.253]) and response (23.9%) with DCb were similar to those results for VC. Neutropenia, thrombocytopenia, infection, and febrile neutropenia were similar with all three regimens. Grade 3 to 4 anemia, nausea, and vomiting were more common (P <.01) with VC than with DC or DCb. Patients treated with either docetaxel regimen had consistently improved QoL compared with VC-treated patients, who experienced deterioration in QoL.\nDC resulted in a more favorable overall response and survival rate than VC. Both DC and DCb were better tolerated and provided patients with consistently improved QoL compared with VC. These findings demonstrate that a docetaxel plus platinum combination is an effective treatment option with a favorable therapeutic index for first-line treatment of advanced or metastatic NSCLC.', 'title': 'Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group.', 'date': '2003-07-03'}, '17409843': {'article_id': '17409843', 'content': 'Paclitaxel plus carboplatin (CAR) or cisplatin (CIS) has shown activity in the treatment of advanced non-small cell lung cancer (NSCLC). Our aim was to determine whether paclitaxel plus platinum is an appropriate regimen for chemo-naïve NSCLC in patients aged 70 years or older. Patients were randomized into paclitaxel plus CAR or paclitaxel plus CIS treatment arms. Treatment consisted of paclitaxel 160 mg/m and carboplatin at AUC = 6 (predicted using measured clearances and the Calvert formula) IV infusion on day 1 every 3 weeks, or paclitaxel 160 mg/m and cisplatin 60 mg/m IV on day 1 every 3 weeks. In total, 81 patients were enrolled from September 2000 to February 2005, including 40 who received CAR treatment and 41 who received CIS treatment. In all, 152 cycles of CAR (median, four cycles per patient) and 172 cycles of CIS (median, four cycles per patient) were given. Each arm had one complete response and 15 partial responses to the treatment, with overall response rates of 40% and 39%, respectively. Myelosuppression was mild in both arms, and there was no statistical difference between the two arms. Alopecia (P < 0.001), peripheral neuropathy (P = 0.017), and fatigue (P < 0.001) were more severe in the CIS treatment arm than in the CAR treatment arm. Median time to disease progression was 6.6 months in the CAR arm and 6.9 months in the CIS arm. Median survival time was 10.3 months in the CAR arm and 10.5 months in the CIS arm. In conclusion, paclitaxel plus CAR or CIS treatment is feasible in elderly patients and has similar activity. However, paclitaxel plus CAR had less non-hematological toxicity than paclitaxel plus CIS.', 'title': 'A Phase II randomized study of paclitaxel plus carboplatin or cisplatin against chemo-naive inoperable non-small cell lung cancer in the elderly.', 'date': '2007-04-06'}, '28780466': {'article_id': '28780466', 'content': "Eur J CancerEur. J. CancerEuropean Journal of Cancer0959-80491879-0852Elsevier Science Ltd287804665597318S0959-8049(17)31001-810.1016/j.ejca.2017.05.037Clinical TrialCarboplatin versus two doses of cisplatin in combination with gemcitabine in the treatment of advanced non-small-cell lung cancer: Results from a British Thoracic Oncology Group randomised phase III trialFerryDavida1BillinghamLucindaL.J.Billingham@bham.ac.ukb∗JarrettHughbDunlopDavidcWollPenella J.dNicolsonMarianneeShahRiyazfThompsonJoycegSpicerJameshMuthukumarD.iSkailesGeraldinejLeonardPaulinekChetiyawardanaA.D.lWellsPaulamLewanskiConradnCrosseBarbaraoHillMichellebGauntPiersbO'ByrneKennethp2aRoyal Wolverhampton NHS Trust, Wolverhampton, UKbCancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UKcBeatson West of Scotland Cancer Centre, Glasgow, UKdWeston Park Hospital, University of Sheffield, Sheffield, UKeAberdeen Royal Infirmary, Aberdeen, UKfKent Oncology Centre, Maidstone Hospital, Maidstone, UKgHeart of England NHS Foundation Trust, Birmingham, UKhKing's College London, Guy's Hospital, London, UKiColchester General Hospital, Colchester, UKjLancashire Teaching Hospitals NHS Foundation Trust, Preston, UKkWhittington Health NHS Trust, Whittington Hospital, London, UKlQueen Elizabeth Hospital, Birmingham, UKmBarts Health NHS Trust, London, UKnImperial College Healthcare, Charing Cross Hospital, London, UKoCalderdale and Huddersfield NHS Foundation Trust, Huddersfield, UKpSt James' Hospital, Dublin, Ireland∗Corresponding author: Cancer Research UK Clinical Trials Unit, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.Cancer Research UK Clinical Trials UnitUniversity of BirminghamEdgbastonBirminghamB15 2TTUK L.J.Billingham@bham.ac.uk1Current affiliation: Eli Lilly and Company Limited, New Jersey, USA.2Current affiliation: Princess Alexandra Hospital and Queensland University of Technology, Brisbane, Australia.192017920178330231210520171952017© 2017 The Authors2017This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).BackgroundPlatinum-based combination chemotherapy is standard treatment for the majority of patients with advanced non-small-cell lung cancer (NSCLC). The trial investigates the importance of the choice of platinum agent and dose of cisplatin in relation to patient outcomes.MethodsThe three-arm randomised phase III trial assigned patients with chemo-naïve stage IIIB/IV NSCLC in a 1:1:1 ratio to receive gemcitabine 1250\xa0mg/m2 on days 1 and 8 of a 3-week cycle with cisplatin 80\xa0mg/m2 (GC80) or cisplatin 50\xa0mg/m2 (GC50) or carboplatin AUC6 (GCb6) for a maximum of four cycles. Primary outcome measure was survival time, aiming to test for a difference between treatment arms and also assess non-inferiority with pre-defined margin selected as hazard ratio (HR) of 1.2. Secondary outcome measures included response rate, adverse events and quality of life (QoL).FindingsThe trial recruited 1363 patients. Survival time differed significantly across the three treatment arms (p\xa0=\xa00.046) with GC50 worst with median 8.2 months compared to 9.5 for GC80 and 10.0 for GCb6. HRs (adjusted) for GC50 compared to GC80 was 1.13 (95% confidence interval [CI] 0.99–1.29) and for GC50 compared to GCb6 was 1.23 (95% CI: 1.08–1.41). GCb6 was significantly non-inferior to GC80 (HR\xa0=\xa00.93, upper limit of one-sided 95% CI 1.04). Adjusting for QoL did not change the findings. Best objective response rates were 29% (GC80), 20% (GC50) and 27% (GCb6), p\xa0<\xa00.007. There were more dose reductions and treatment delays in the GCb6 arm and more adverse events (60% with at least one grade 3–4 compared to 43% GC80 and 30% GC50).InterpretationIn combination with gemcitabine, carboplatin at AUC6 is not inferior to cisplatin at 80\xa0mg/m2 in terms of survival. Carboplatin was associated with more adverse events and not with better quality of life. Cisplatin at the lower dose of 50\xa0mg/m2 has worse survival which is not compensated by better quality of life.ClinicalTrials.gov identifierNCT00112710.EudraCT Number2004-003868-30.Cancer Research UK trial identifierCRUK/04/009.Highlights•Large randomised phase III trial in advanced non-small cell lung cancer is reported.•Platinum-based chemotherapy remains standard first-line treatment for majority.•Trial provides definitive evidence-base for choice of platinum in this setting.•Cisplatin 50\xa0mg/m2 gives inferior survival, not compensated by better quality of life.•Carboplatin AUC6 is not inferior to cisplatin 80 mg/m2 in terms of survival time and is not associated with better quality of life.KeywordsNon-small-cell lung cancerCarboplatinCisplatinGemcitabineRandomised phase III trialQuality of life1IntroductionLung cancer is the leading cause of cancer death worldwide [1] and is responsible for more than 20% of cancer deaths in the United Kingdom [2]. Non-small-cell lung cancer (NSCLC) accounts for more than 80% of lung cancers and poor outcomes are driven by the fact that the vast majority present at clinic with advanced disease [3]. This paper reports a large randomised phase III trial in advanced NSCLC, set up by the British Thoracic Oncology Group (the BTOG2 trial), to provide definitive evidence to inform choice of standard first-line treatments. Early presentations of the results from the trial have already influenced clinical practice and this paper provides the final conclusive published evidence.There is continued uncertainty about the optimal first-line chemotherapy for patients with advanced NSCLC and hence clinical practice remains variable. Platinum-based combination chemotherapy was firmly established following a meta-analysis of eight cisplatin randomised trials [4] which was later confirmed by an updated meta-analysis of 16 further trials [5] but there was ongoing ambiguity about whether cisplatin or carboplatin gave better patient outcomes. This was driven by conflicting trial results, in particular emerging results from an influential UK trial giving evidence that carboplatin with gemcitabine gave better survival than cisplatin (low dose 50\xa0mg/m2) combined with mitomycin and ifosfamide [6] and a meta-analysis of five trials suggesting that in combination with third generation drugs, such as gemcitabine and taxanes, cisplatin gave better survival and higher radiological response rates than carboplatin [7].In addition, there was uncertainty about the preferred dose of cisplatin due to a lack of definitive evidence, with practitioners in the UK more inclined to opt for the lower dose of 50\xa0mg/m2 every three weeks [6] than counterparts in Europe and the United States which considered 75–100\xa0mg/m2\xa0as standard [8], [9]. The cisplatin burden of intravenous hydration and inpatient administration together with the toxicity of emesis, neuropathy and perception of poor tolerance led many clinicians to adopt carboplatin as the preferred option. Carboplatin however is largely renally cleared and must be correctly dosed according to glomerular filtration rate (GFR) [10] and measurement of GFR with 51-Cr-EDTA is cumbersome and expensive. Even when dosed optimally, carboplatin causes more severe neutropenia and thrombocytopaenia than cisplatin [11]. The BTOG2 trial aimed to resolve this cisplatin versus carboplatin debate.A large randomised trial in advanced NSCLC in the USA had shown no differences in response rate or survival for platinum combinations with gemcitabine, paclitaxel or docetaxel [8]. At the time of trial set-up, the most commonly used companion drug for platinum in the UK was gemcitabine, so this was adopted for the trial for all types of histology. It was not until 2008 that evidence arose to show that pemetrexed was a marginally superior companion drug to gemcitabine in non-squamous NSCLC [12]. However, with the focus of the BTOG2 trial on platinum choice, the trial remains relevant for all types of histology. The other key changes in standard of care is that patients with epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) gene rearrangements will receive tyrosine kinase inhibitors as standard first-line treatment as per European and USA guidelines [13], [14]. However this only affects a very small proportion of all NSCLC patients in the UK, 8% and 2%, respectively [15]. Recent results from a phase III trial [16] have lead to the additional option of an immune-checkpoint inhibitor in the first-line setting for a limited number (likely to be around 15% in real world practice) of patients with high PD-L1 expression. Thus platinum-based chemotherapy remains the standard of care and our trial results remain relevant for the majority of patients.This paper reports the final results from the BTOG2 trial, which evaluates two doses of cisplatin compared with carboplatin in combination with gemcitabine as first-line treatment for advanced NSCLC to determine which gives the most benefit to patients. The trial has the major added strength of assessing long-term quality of life alongside survival in all participants.2Methods2.1Study designBTOG2 was a three-arm randomised phase III clinical trial recruiting patients from 78 hospitals in the United Kingdom and Ireland. Ethics approval for the trial protocol (ultimately Version 4) was obtained from West Midlands Research Ethics Committee and local institutional review boards and ethical committees in accordance with national and international guidelines.2.2PatientsEligible patients had histologically or cytologically confirmed NSCLC with radiologically verified stage IIIB/IV disease not amenable to potentially curative treatment, with no clinically apparent brain metastases. Patients had no known concomitant or previous malignancy likely to interfere with protocol treatment or trial evaluations and no prior chemotherapy or radiotherapy. They were at least 18 years old with a World Health Organization performance status (PS) score of 0–2 and life expectancy of >12 weeks, adequate organ and haematologic function and no severe acute or chronic medical condition that would have impaired the ability to participate in the study or the interpretation of results. Pregnant and breast-feeding women were excluded and those with reproductive potential were required to use effective methods of contraception. All patients gave written informed consent.2.3Randomisation and maskingEligible patients were randomly assigned 1:1:1 to receive gemcitabine 1250\xa0mg/m2 days 1 and 8 of a 3-week cycle plus on day 1 cisplatin 80\xa0mg/m2 (GC80) or cisplatin 50\xa0mg/m2 (GC50) or carboplatin AUC6 (GCb6) for a maximum of four cycles. Treatment allocation was by telephone to the central randomisation service at the Cancer Research UK Clinical Trials Unit at University of Birmingham. Randomisation was stratified by stage of disease (IIIB versus IV) and PS (0 versus 1 versus 2) and balanced within treatment centres. Treatment was allocated to patients sequentially using an in-house validated minimisation algorithm.2.4ProceduresProtocol drugs were delivered intravenously either as inpatient or outpatient, according to local practice. The estimate of GFR\xa0used in the Calvert formula, both for carboplatin dosing and to determine eligibility (creatinine clearance >60\xa0mL/min), used the Wright equation (the version with creatinine kinase correction and either enzymatic or Jaffe serum creatinine measurement) which is equivalent to 51-Cr-EDTA clearance [17]. To ensure correct dosing we provided an Excel spreadsheet calculator (Supplementary Material Appendix 1). Also to ensure optimal and pragmatic hydration for cisplatin patients, all participating centres complied with the BTOG2 recommended schedule (Supplementary Material Appendix 2). Dose adjustments and cycle delays (up to 3 weeks) were permitted in the event of toxicity with protocol-specific recommendations. Patients were to be treated for four cycles or until disease progression or unacceptable toxicity as per physician judgement. Standard anti-emetics were 5\xa0d\xa0of a 5-HT3 antagonist plus dexamethasone 4\xa0mg twice daily or, after day 8 gemcitabine, oral domperidone 20\xa0mg up to four times daily as required.Pre-treatment evaluation included: medical history (including cancer history and prior anti-cancer treatments), clinical examination (including PS, blood pressure, ECG), laboratory analyses (complete blood count and coagulation tests, blood chemistry, creatinine clearance with Wright equation) and tumour assessment by appropriate imaging techniques with measurable lesions being a requirement for the trial. Computed tomography scan was performed at baseline, after two cycles (6 weeks), four cycles (12 weeks) and where possible was repeated at time of withdrawing from treatment. Response was assessed with Response Evaluation Criteria in Solid Tumours (RECIST) 1.0 [18] locally but there was no requirement for confirmation of response. Patients had chest x-rays during treatment and follow-up in accordance with local practice. Adverse events according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0 [19] were recorded at every clinic visit. Follow-up data were collected at standard post-treatment clinic visits at approximately monthly intervals. Quality of life questionnaires were administered by research nurses prior to randomisation and on day 1 of each treatment cycle prior to receiving treatment and at every follow-up visit (typically monthly). They were completed independently by patients.2.5OutcomesThe primary outcome was survival time measured in whole days from randomisation to death from any cause, with censoring at date of last follow-up for those with no death date at time of database lock (28th May 2014). Quality of life was an important secondary outcome measure. Eligibility criteria required the patient to be willing and able to complete quality of life questionnaires which included three validated instruments: the generic and lung cancer instruments developed by the European Organisation for Research and Treatment of Cancer EORTC QLQ-C30 [20] and QLQ-LC13 [21] and the standardised instrument to measure utilities developed by the EuroQol Group, EQ-5D [22]. Other secondary outcome measures included: best overall response (based on RECIST 1.0) [18]; dose intensity of chemotherapy (calculated for each drug as the mean of dose intensities for each cycle received, given by actual versus expected dose per day); proportion of cycles given as an outpatient; incidence of adverse events (graded ≥2 according to NCI-CTCAE version 3.0) [19] and costs and cost-effectiveness (to be reported in a separate paper).2.6Statistical analysisThe survivor function for each treatment arm is estimated using Kaplan–Meier method from which medians and 1-year rates are reported with Greenwood's formula used for 95% confidence intervals (CIs). All treatment arms could be considered ‘standard practice’ so the primary analysis tests the null hypothesis of no difference between the three treatment arms initially using a log-rank test as specified in the protocol but supplemented by Cox regression model that accounts for stratification factors of stage and PS as the more recently preferred analytical approach [23]. Regression coefficients from the model provide estimates of hazard ratios (HR) with two-sided 95% CIs to compare treatment arms. As planned, the analysis also tests for non-inferiority between treatment arms, permissible under the closed test procedure [24], using one-sided 95% CI for HRs with non-inferiority inferred when the entire CI falls within the non-inferiority region pre-defined by a margin for the HR of 1.2. All analyses of the primary outcome measure were based on an intention-to-treat (ITT) principle.At the design stage, sample size calculations were based on the primary outcome measure of survival time. For a log-rank test comparing three treatment arms, 400 deaths were required per arm to enable a difference in median survival of 2 months (7 versus 9) to be detected between any of the three arms with 90% power. This is equivalent to an absolute difference in 1-year survival rates of the order of 35% versus 45% and an HR of 0.78. Assuming an accrual period of 3 years and follow-up period of 1 year, it was estimated that 450 patients per arm would be need to achieve the required number of events giving total target recruitment of 1350. With 400 deaths per arm and using a one-sided 95% CI there is 80% power to detect non-inferiority based on a pre-defined non-inferiority margin for the HR of 1.2 or absolute difference in median survival of 6 weeks.Detailed analysis of the longitudinal quality of life (QoL) data will be reported in a separate paper but quality-adjusted survival time is reported here using a method called the integrated quality-survival product [25]. Survival time, represented by the Kaplan–Meier function, is adjusted for QoL using a step function of the utility measure from EQ-5D, representing the mean of all responses from participants still alive at each point across time. The analysis is based on ITT and restricted to 12 months from trial entry.Objective response rates are compared using an ITT analysis and chi-square test. Analysis of the remaining secondary outcome measures was based on the per-protocol population defined as those who received at least one cycle of their assigned treatment. Dose intensity for platinum and gemcitabine are compared using one-way analysis of variance. Proportion of chemotherapy delivery days as an outpatient rather than inpatient are compared using a chi-square test. Incidence of each type of adverse event is reported descriptively with a chi-square test pre-selected in the statistical analysis plan to compare incidence of at least one grade 3 or 4 adverse event during treatment.An independent Data Monitoring Committee reviewed interim data annually to ensure patient safety. There were no formal stopping rules. The trial was registered on the EU Clinical Trials Register with EudraCT number 2004-003868-30.2.7Role of the funding sourceThe trial was sponsored by University of Birmingham and run by the Cancer Research UK Clinical Trials Unit located there. Funding came from Cancer Research UK supplemented by an educational grant from Eli Lilly and Company Ltd. The trial was initiated and conducted independently by the trial investigators. The funder had no role in trial design, data collection, data analysis, data interpretation or writing of the report. The corresponding author had full access to all the data in the trial and had final responsibility for the decision to submit for publication.3ResultsBetween April 2005 and November 2009, 1363 patients were randomised, 456 to GC80, 454 to GC50 and 453 to GCb6 (Fig.\xa01). Patient characteristics and disease history at baseline were well balanced across the treatment arms (Table 1). The median age for patients in the trial was 63 years (range 29–83) with predominance of males (62%) and PS 1 (60%) but also including 8% PS 2. Stage IV disease was most common (68%) with 38% having adenocarcinoma histology, 35% squamous cell, 3% large cell and the remaining 23% unspecified. Post-randomisation, 16 patients were found to be ineligible with the most common reason being biochemical measures found to be marginally outside of the required range, but half received protocol treatment and all are included in the ITT analysis.Fig.\xa01: Trial profile. aMultiple reasons were recorded and frequencies reporting the top four reasons are given here; bincludes grade 3 or 4 non-haematological or symptomatic grade 4 haematological; cdied within 28\xa0d\xa0of day 1 of the last cycle received.Fig.\xa01Table 1Baseline patient and disease characteristics.Table 1CharacteristicGC80 (N\xa0=\xa0456)GC50 (N\xa0=\xa0454)GCb6 (N\xa0=\xa0453)Male286 (63%)291 (64%)268 (59%)Female170 (37%)163 (36%)185 (41%)AgeMedian636363IQ range57.5–6857–6957–68Range30–7932–8229–83StageaIIIB146 (32%)145 (32%)144 (32%)IV310 (68%)309 (68%)309 (68%)WHO PSa0146 (32%)146 (32%)145 (32%)1275 (60%)274 (60%)274 (60%)235 (8%)34 (8%)34 (8%)Prior surgeryNo427 (97%)416 (95%)412 (95%)Yes15 (3%)20 (5%)23 (5%)Not reported141818HistologySquamous149 (33%)152 (33%)156 (34%)Adenocarcinoma169 (37%)156 (34%)182 (40%)Large cell14 (3%)12 (3%)13 (3%)Unspecified124 (27%)134 (30%)102 (23%)BSAN440440441Median1.821.841.82IQ range1.68–1.981.67–1.971.67–1.98Range1.35–2.261.26–2.451.28–2.49Target lesion size (mm)N425421430Median828283IQ range57–11752–12556–121Range4–5535–38910–420WHO PS, World Health Organization performance status; IQ, interquartile; BSA, body surface area.aIndicates stratification factors.Treatment delivery details within each of the treatment arms is summarised in Fig.\xa01. The majority of patients (62%) received the planned four cycles of treatment and this was balanced across treatment arms. 39 patients (2.9%) did not start treatment due to clinical deterioration. The most common reason for early withdrawal from treatment in all arms is tumour progression or stable disease. Grade 3 or 4 non-haematological toxicity and general intolerable side-effects from treatment was most common in GC80. Symptomatic grade 4 haematological toxicity was most common in GCb6. Across cycles, dose reductions and cycle delays occurred most in GCb6 and least in GC50 (Supplementary Material Appendix 3) which translated into a significant difference in dose intensity of platinum and gemcitabine across treatment arms (Table 2; p\xa0<\xa00.0001 for both). Dose intensity was lowest for GCb6 but medians on all treatment arms were at least 80%. Dosing of carboplatin used the Wright equation which gave prescribed doses on average 10% more (interquartile range 4%–17% and range −14% to 51%) than the Cockcroft–Gault formula (Supplementary Material Appendix 4).Table 2Comparison of secondary outcome measures across treatment arms.Table 2Secondary outcome measureGC80GC50GCb6p-valueBest overall response rateNumber (%) of patients with reported CR or PR132/456 (29%)92/454 (20%)123/453 (27%)0.007Dose intensity for platinumN423430406Median94%98%83%<0.0001Interquartile range81%–99%90%–100%72%–97%Range22%–116%19%–113%19%–118%Number (%) of patients ≥90%256 (61%)327 (76%)146 (36%)Dose intensity for gemcitabineN419429423Median87%94%80%Interquartile range74–98%83–99%68–94%<0.0001Range40–116%43–107%32–106%Number (%) of patients ≥90%192 (46%)260 (61%)127 (30%)Proportion of chemotherapy delivery days as an outpatientN441444439Median87.5%100%100%<0.0001Number (%) of patients 100%207 (47%)246 (55%)281 (64%)Adverse eventsNumber (%) of patients with at least 1 grade 3 or 4 adverse event reported during treatment190/441 (43%)133/444 (30%)263/439 (60%)<0.0001CR, complete response; PR, partial response.The incidence of key adverse events at grades 2–4 are shown in Table 3. Of the total 6802 events reported across the 4284 patient-cycles received, the majority (77%) were grade 2, 15% grade 3 and 4% grade 4 (3% unspecified grade). Hearing loss and tinnitus were predominantly reported for GC80 but at a low rate with patient-cycle incidence rate of 7% and only 2% reported as grade 3 or 4. As expected, rates of nausea and vomiting were higher in GC80 compared to GC50 but absolute differences were small in levels of grade 3–4 (2.8% versus 0.6% for nausea and 2.9% versus 0.2% for vomiting). GCb6 was associated with the highest rates of myelosuppression but with low rates for grade 3–4; anaemia 4%, neutropenia 16% and thrombocytopaenia 10%. Fatigue was no different between GC80 and GCb6 with grade 3–4 patient-cycle incidence rates of 3.7% versus 3.4%, respectively. Documented infections occurred at a similar low rate on the three arms. Overall, the patient incidence rates for at least one reported grade 3 or 4 adverse event differed significantly across the three treatment arms (Table 2; p\xa0<\xa00.0001) with greatest of 60% on GCb6 compared with 30% on GC50.Table 3Comparison of treatment arms in terms of key adverse events (i.e. patient-cycle grade 2–4 incidence ≥10% and/or difference ≥5%).Table 3Adverse eventGradePatient-cycles with adverse events of the specified gradeTreated patients with at least one adverse event of specified gradeGC80 (N\xa0=\xa01393)GC50 (N\xa0=\xa01448)GCb6 (N\xa0=\xa01443)GC80 (N\xa0=\xa0441)GC50 (N\xa0=\xa0444)GCb6 (N\xa0=\xa0439)Nausea≥2262 (19%)118 (8%)151 (11%)161 (37%)85 (19%)108 (25%)≥339 (2.8%)9 (0.6%)19 (1.3%)34 (7.7%)8 (1.8%)16 (3.6%)Vomiting≥2178 (13%)59 (4%)77 (5%)121 (27%)45 (10%)58 (13%)≥334 (2.9%)3 (0.2%)12 (0.8%)29 (6.6%)2 (0.5%)10 (2.3%)Constipation≥2166 (12%)134 (9%)144 (10%)121 (27%)90 (20%)101 (23%)≥35 (0.3%)5 (0.3%)5 (0.3%)5 (1.1%)5 (1.1%)5 (1.1%)Dyspnoea≥2136 (10%)105 (7%)180 (13%)90 (20%)87 (20%)119 (27%)≥324 (1.7%)27 (1.9%)29 (2.0%)23 (5.2%)25 (5.6%)23 (5.2%)Anaemia≥2173 (12%)154 (11%)419 (29%)110 (25%)103 (23%)233 (53%)≥313 (0.9%)10 (0.7%)58 (4.0%)10 (2.3%)9 (2.0%)49 (11.2%)Neutropenia≥2155 (11%)105 (7%)384 (27%)109 (25%)77 (17%)238 (54%)≥374 (5.3%)49 (3.4%)227 (15.7%)60 (13.6%)40 (9.0%)163 (37.1%)Thrombocytopaenia≥267 (5%)32 (2%)213 (15%)55 (12%)28 (6%)138 (31%)≥332 (2.3%)13 (0.9%)144 (10.0%)29 (6.6%)12 (2.7%)103 (23.5%)Fatigue≥2379 (27%)326 (23%)389 (27%)222 (50%)193 (43%)225 (51%)≥351 (3.7%)29 (2.0%)49 (3.4%)43 (9.8%)25 (5.6%)42 (9.6%)Ototoxicity≥292 (7%)44 (3%)17 (1%)66 (15%)28 (6%)10 (2%)≥318 (1.3%)2 (0.1%)0 (0%)15 (3.4%)1 (0.2%)0 (0%)The proportion of patients treated in the outpatient setting is significantly greater for GCb6 (Table 2; p\xa0<\xa00.0001) with 64% of patients receiving all their cycles as an outpatient compared to only 47% of patients on GC80. Best response rate to treatment significantly differed between the three treatment arms (p\xa0=\xa00.007; Table 2) with comparable rates for GC80 (29%) and GCb6 (27%) and a lower rate for GC50 (20%).At the time of data lock (28th May 2014) there were 1306 deaths. Of the 57 patients still alive, median follow-up time was 29 months with maximum of 80 and including 5 patients lost to follow-up within 12 months of entry. Eleven patients died within 28\xa0d\xa0of randomisation without starting treatment and 80 patients died during treatment i.e. within 28\xa0d\xa0of day 1 of their last cycle of chemotherapy (29, 31 and 20 on GC80, GC50 and GCb6, respectively). Kaplan–Meier estimates of survival (Fig.\xa02A, Table 4) show that GC50 had the worst survival time with median 8.2 months whilst GC80 and GCb6 were comparable with medians of 9.5 and 10.0 months, respectively. This difference between treatment arms was statistically significant (unadjusted and adjusted p-values 0.046 and 0.01, respectively). Paired comparisons of treatments (Fig.\xa02B) show that this difference is driven primarily by the inferior survival of GC50 compared to the other two arms (adjusted HR for GC50 versus GC80 of 1.13, two-sided 95% CI: 0.99–1.29 and adjusted HR for GC50 versus GCb6 of 1.23, two-sided 95% CI: 1.08–1.41). Furthermore, GCb6 was found to be significantly non-inferior to GC80 with adjusted HR\xa0=\xa00.93 (unadjusted 0.94) and upper limit of one-sided 95% CI as 1.04 (unadjusted 1.05).Fig.\xa02(A) Kaplan–Meier survivor functions for each treatment group. (B) Pairwise comparisons of survival showing HRs (adjusted for stage and performance status) with two-sided 95% CIs (solid line) for assessment of difference (compare either end against HR\xa0=\xa01) and one-sided 95% CIs (dashed line) for assessment of non-inferiority (compare upper values against HR\xa0=\xa01.2).Fig.\xa02Table 4Comparison of survival time and quality-adjusted survival time across treatment arms.Table 4Summary statisticGC80GC50GCb6One year survival rates (95% CIs)39% (35%–44%)31% (27%–35%)39% (34%–43%)Median survival time in months (95% CIs)9.5 (8.4–10.3)8.2 (7.4–8.7)10.0 (9.2–10.8)Mean quality-adjusted survival time in months (within 12 months) (95% CIs)6.0 (5.7–6.3)5.6 (5.2–5.9)6.1 (5.8–6.5)Overall quality of life over time, as measured by the EQ-5D utility measure (where 0 represents quality equivalent to death and 1 represents ‘perfect health’) is relatively constant over time and similar in all three treatment groups (Fig.\xa03). Quality-adjusted survival time shows the same pattern of results across treatment arms as overall survival time (Table 4) with GC50 worst and GC80 and GCb6 comparable.Fig.\xa03Mean EQ-5D utility score over 12 months (represented as a step function joining the means of all patients still alive at each observed death time in the trial).Fig.\xa034DiscussionThis randomised phase III trial compared the effects of two doses of cisplatin and carboplatin AUC6 in combination with gemcitabine in a treatment naive population of patients with advanced NSCLC. The trial was undertaken in an era before widespread testing for activating mutations of EGFR and ALK, histological differentiation and maintenance chemotherapy were standard practice and the newly introduced immune-checkpoint inhibitor for tumours with high PD-L1 expression. With these changes in clinical practice only relevant for small selected subgroups of patients, platinum-based combination chemotherapy remains the standard first-line treatment for the majority of patients with this disease.The trial included what could be regarded as the highest possible safe dose of carboplatin, using the Wright equation [17] considered to be equivalent to the Calvert formula [10]. For cisplatin, the trial selected the highest dose in common use (80\xa0mg/m2) compared with the lower dose commonly prescribed in the UK (50\xa0mg/m2). The principal conclusion is that GCb6 is not inferior to GC80 in terms of survival time. This key result runs counter to all previous meta-analysis [7], [26], [27] which concluded cisplatin was superior to carboplatin. Such analyses have strengths and correctly identified that cisplatin-based treatment was beneficial in NSCLC, but they also have limitations, especially when details such as dose, dose intensity and how doses of carboplatin were calculated are significant variables. These factors could have contributed to decreased effectiveness of carboplatin in the meta-analysis. This drug has predominant renal excretion and is no longer prescribed on a body surface area formula but on the Calvert formula [10]. Central to using this formula is estimating GFR. In the original work, 51-Cr-EDTA methodology was used and widely regarded as the gold standard. However this can be closely approximated by the Wright formula [17]. This is clearly superior to the Cockcroft–Gault formula, which is easy to compute but underestimates GFR by an average of 10%. Many previous clinical trials allowed sites to vary the method of GFR estimation or used low doses such as AUC5 and Cockcroft–Gault GFR estimation [26]. Having delivered the maximum safe dose of carboplatin combined with gemcitabine, we found that this drug is not inferior in survival terms to the highest reasonable dose of cisplatin (80\xa0mg/m2).Having conducted the largest ever randomised trial comparing carboplatin with cisplatin in NSCLC, we have high resolution adverse event and quality of life data. When first introduced, cisplatin had a deserved reputation for often severe emesis, renal damage and neuropathy [28]. Improvements in anti-emetics, 5-HT3 and NK1 receptor antagonists [29] and better hydration have attenuated these effects such that although GC80 produced more grade 3–4 vomiting (2.9%) than carboplatin (0.8%), the difference is not clinically significant. Also the trial has enabled a reduction in the hydration schedule duration for cisplatin, such that it is easy to deliver cisplatin as a day case. However, carboplatin does produce worse myelosuppresion, neutropenia and thrombocytopaenia but with no significant impact on infections or deaths on treatment. The data on survival, response rates and toxicity are comparable to other large randomised trials. In the trial [12] of gemcitabine plus cisplatin at 75\xa0mg/m2 (GC75) versus pemetrexed plus cisplatin (PC75) the median survival for GC75 was 10.3 (BTOG2 9.5), response rate was 31% (BTOG2 29%) and febrile neutropenia 3.7% (infection rate 3% in BTOG2).In many solid tumours, sequences of chemotherapy regimens have produced dramatic improvement. The best example is possibly colorectal cancer where overall survival has increased over the last 20 years from around 10–12 months to 25–30 months [30]. Instead of only 5FU/folinic acid these patients have combinations of 5FU, oxalipaltin and irinotecan often combined with the antiangiogenic bevacizumab. To RAS wild type patients, anti-EGFR antibodies are also given. NSCLC has been slower to develop sequential therapy, but for adenocarcinoma patients maintenance therapy with pemetrexed immediately after first line cisplatin-gemcitabine and taxanes after carboplatin-gemcitabine were each shown to be beneficial. The recent KEYNOTE-024 trial [16], which included comparable patients to BTOG2 including both squamous and non-squamous histologies and selected for high expression of PD-L1, demonstrated that the immune-checkpoint inhibitor pembrolizumab improves progression-free survival time and overall survival time in the first-line setting in comparison to chemotherapy and may become the first-line treatment of choice for selected patients. Of the 1934 patients screened, 1653 had samples that could be evaluated for PD-L1, 500 (30%) had high expression and 305 were randomised into the trial demonstrating that this treatment was an option for only 15% of the screened population. Because patients are not cured by first-line checkpoint inhibitors, for those who are eligible for this option, it is important that optimal platinum-based combination chemotherapy follows to produce best results for patients. This illustrates that chemotherapy practice and principles will remain the same, but sequencing for some may change. Optimising all aspects of anti-cancer treatments is essential, especially the doses and schedules of chemotherapy drugs which may impact survival and the BTOG2 trial contributes important data in this regard.In summary, the BTOG2 trial provides definitive evidence on the choice of platinum to partner with a second drug in standard first-line chemotherapy for advanced NSCLC and provides for the first time comprehensive quality of life data to support decision-making. Carboplatin dosed at AUC6 using the Wright equation (or Calvert equation) gives non-inferior survival to cisplatin dosed at 80\xa0mg/m2 and cisplatin at the lower dose of 50\xa0mg/m2 has worse survival which is not compensated by better quality of life.FundingFunding was from Cancer Research UK supplemented by an educational grant from Eli Lilly and Company Ltd. The trial was initiated and conducted independently by the trial investigators.Conflict of interest statementDavid Ferry reports personal fees from Eli Lilly and Company during the conduct of the study. Lucinda Billingham reports an educational grant paid to the University of Birmingham from Eli Lilly and Company during the conduct of the study and personal fees from Eli Lilly and Company, Astra Zeneca, Pfizer, Roche and Celgene outside the submitted work. Hugh Jarrett reports an educational grant paid to University of Birmingham from Eli Lilly and Company during the conduct of the study. Riyaz Shah reports free drug for the trial supplied by Eli and Lilly and Company during the conduct of the study and personal fees from Eli Lilly and Company outside the submitted work. Pauline Leonard reports personal fees from Eli Lilly and Company, Amgen, Bristol-Myers Squibb, Pfizer, Teva and Otsuka outside of the submitted work. Conrad Lewanski reports personal fees from Eli Lilly and Company, Roche and Astra Zeneca outside the submitted work. Kenneth O'Byrne has received advisory board and/or speaker bureau and/or meeting travel/registration support from Bristol-Myers Squibb, MSD, Eli Lilly and Company, Boehringer-Ingelheim, Pfizer, Novartis, Roche-Genentech and Astra Zeneca. Other authors have nothing to disclose.References1LozanoR.NaghaviM.ForemanK.LimS.ShibuyaK.AboyansV.Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010Lancet380201220952128232456042Cancer Research UK, http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/lung-cancer#heading-One [Accessed December 2016].3GettingerS.LynchT.A decade of advances in treatment for advanced non-small cell lung cancerClin Chest Med322011839851220548904Non-small Cell Lung Cancer Collaborative GroupChemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trialsBrit Med J311199589990975805465NSCLC Meta-Analyses Collaborative GroupChemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data from 16 randomized controlled trialsJ Clin Oncol26200846174625186788356RuddR.M.GowerN.H.SpiroS.G.EisenT.G.HarperP.G.LittlerJ.A.Gemcitabine plus carboplatin versus mitomycin, ifosfamide, and cisplatin in patients with stage IIIB or IV non-small-cell lung cancer: a phase III randomized study of the London Lung Cancer GroupJ Clin Oncol232005142153156253697HottaK.MatsuoK.UeokaH.KiuraK.TabataM.TanimotoM.Meta-analysis of randomized clinical trials comparing cisplatin to carboplatin in patients with advanced non–small cell lung cancerJ Clin Oncol22200438523859153261958SchillerJ.H.HarringtonD.BelaniC.P.LangerC.SandlerA.KrookJ.Comparison of four chemotherapy regimens for advanced non-small-cell lung cancerN Engl J Med34620029298117848759ScagliottiG.V.De MarinisF.RinaldiM.CrinoL.GridelliC.RicciS.Phase III randomised trial comparing three platinum-based doublets in advanced non-small cell lung cancerJ Clin Oncol20212002428542911240932610CalvertA.H.NewellD.R.GumbrellL.A.O'ReillyS.BurnellM.BoxallF.E.Carboplatin dosage: prospective evaluation of a simple formula based on renal functionJ Clin Oncol7198917481756268155711RosellR.GatzemeierU.BetticherD.C.KepplerU.MachaH.N.PirkerR.Phase III randomised trial comparing paclitaxel/carboplatin versus paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trialAnn Oncol132002153915491237764112ScagliottiG.V.ParikhP.von PawelJ.BiesmaB.VansteenkisteJ.ManegoldC.Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naïve patients with advanced-stage non-small-cell lung cancerJ Clin Oncol262008354335511850602513MastersG.A.TeminS.AzzoliC.G.GiacconeG.BakerS.Jr.BrahmerJ.R.Systemic therapy for stage IV non-small-cell lung cancer: American Society of Clinical Oncology clinical practice guideline updateJ Clin Oncol332015348835152632436714ReckM.PopatS.ReinmuthN.De RuysscherD.KerrK.M.PetersS.on behalf of the ESMO Guidelines Working GroupMetastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-upAnn Oncol25Suppl. 32014iii27iii392511530515LindsayC.R.ShawE.BrentonJ.D.ButlerR.DaviesJ.de CastroGonzalezA national platform for molecular diagnostics: results from phase I of the Cancer Research UK Stratified Medicine ProgrammeNCRI cancer conference abstracts201516ReckM.Rodriguez-AbreuD.RobinsonA.G.HuiR.CsosziT.FulopA.for the KEYNOTE-024 InvestigatorsPembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancerN Engl J Med375192016182318332771884717WrightJ.G.BoddyA.V.HighltyM.FenwickJ.McGillA.CalvertA.H.Estimation of glomerular filtration rate in cancer patientsBr J Cancer8420014524591120703718TherasseP.ArbuckS.G.EisenhauerE.A.WandersJ.KaplanR.S.RubinsteinL.New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of CanadaJ Natl Cancer Inst9220002052161065543719Cancer Therapy Evaluation ProgramCommon terminology criteria for adverse events, version 3.0, DCTD, NCI, NIH, DHHS March 312003http://ctep.cancer.govPublish Date: August 9, 200620AaronsonN.K.AhmedzaiS.BergmanB.BullingerM.CullA.DuesN.J.The European Organisation for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncologyJ Natl Cancer Inst851993365376843339021BergmanB.AaronsonN.K.AhmedzaiS.KaasaS.SullivanM.The EORTC QLQ-LC13: a modular supplement to the EORTC Core Quality of Life Questionnaire (QLQ-C30) for use in lung cancer clinical trialsEur J Cancer30A1994635642808067922The EuroQol groupEuroQol—a new facility for the measurement of health related quality of lifeHealth Policy1619901992081010980123KahanB.C.MorrisT.P.Improper analysis of trials randomised using stratified blocks or minimisationStat Med3120123283402213989124MorikawaT.YoshidaM.A useful testing strategy in phase III trials: combined test of superiority and test of equivalenceJ Biopharm Stat531995297306858093025BillinghamL.J.AbramsK.R.Simultaneous analysis of quality of life and survival dataStat Methods Med Res11200225481192399226ArdizzoniA.BoniL.TiseoM.FossellaF.V.SchillerJ.H.PaesmansM.Cisplatin-versus carboplatin-based chemotherapy in first-line treatment of advanced non-small-cell lung cancer: an individual patient data meta-analysisJ Natl Cancer Inst9920078478571755114527JiangJ.LiangX.ZhouX.HuangR.ChuZ.A meta-analysis of randomized controlled trials comparing carboplatin-based to cisplatin-based chemotherapy in advanced non-small cell lung cancerLung Cancer5720073483581748513328GoR.S.AdjeiA.A.Review of the comparative pharmacology and clinical activity of cisplatin and carboplatinJ Clin Oncol1719994094221045826029GrunbergS.M.HeskethP.J.Control of chemotherapy-induced emesisN Engl J Med329199317901796823248930SchmollH.J.Van CutsemE.SteinA.ValentiniV.GlimeliusB.HaustermansK.ESMO consensus guidelines for management of patients with colon and rectal cancer: a personalised approach to clinical decision makingAnn Oncol2320122479251623012255Appendix ASupplementary dataThe following are the supplementary data related to this article:AcknowledgementsThe authors are grateful to all the patients and their families who participated in the trial. Also they thank\xa0all the participating clinicians. The authors also thank\xa0all staff at Cancer Research UK Clinical Trials Unit at University of Birmingham who have supported the trial; in particular John Mason and Sarah Pirrie for their valuable contributions to data management and analysis. The research was supported by Cancer Research UK (Grant Identifiers C8246/A8982 and C8246/A4257 and Trial Identifier CRUK/04/009) and Eli Lilly and Company Limited.Research in contextEvidence before this studyPlatinum-based combination chemotherapy was firmly established as the standard first-line treatment for patients with advanced NSCLC following a meta-analysis of eight randomised trials but clinical practice varied regarding the choice and dose of platinum agent. The evidence on whether cisplatin or carboplatin gave better patient outcomes was ambiguous and following an influential trial there was a move towards the greater use of carboplatin, despite a meta-analysis demonstrating superiority of cisplatin. In addition for those choosing cisplatin, there was uncertainty regarding the dose, with practitioners in the United Kingdom often opting for a lower dose than counterparts in Europe and the United States.Added value of this studyThis large randomised phase III trial provides the definitive evidence-base for the choice of platinum in standard first-line combination chemotherapy for advanced NSCLC. It establishes conclusively that the lower dose of 50\xa0mg/m2 of cisplatin commonly used in the United Kingdom gives inferior survival outcomes which are not compensated by better quality of life. It also clarifies that carboplatin delivered at a dose of AUC6 is not inferior to cisplatin at 80\xa0mg/m2 in terms of survival time. In addition carboplatin unexpectedly was associated with significantly more adverse events and not associated with better quality of life.Implications of all the available evidencePlatinum-based combination chemotherapy remains the standard first-line treatment for the majority of patients with advanced NSCLC. Although patients with EGFR mutations, ALK gene rearrangements or high PDL1 expression can now receive targeted treatments, this only affects a minority of patients (approximately 8%, 2% and 15%, respectively in the UK). Taken together with previous studies, the BTOG2 trial shows that carboplatin AUC6 and cisplatin 80\xa0mg/m2 offer comparable survival benefits in advanced NSCLC, but a lower dose of cisplatin is inferior. In choosing between these two superior options, the burden of adverse events related to carboplatin should not be underestimated and better quality of life associated with carboplatin should not be assumed. Therefore, in patients for whom a targeted treatment is not available, platinum-based combination chemotherapy should be considered with either carboplatin AUC6 or cisplatin 80\xa0mg/m2.Appendix ASupplementary data related to this article can be found at http://dx.doi.org/10.1016/j.ejca.2017.05.037.", 'title': 'Carboplatin versus two doses of cisplatin in combination with gemcitabine in the treatment of advanced non-small-cell lung cancer: Results from a British Thoracic Oncology Group randomised phase III trial.', 'date': '2017-08-07'}, '21047474': {'article_id': '21047474', 'content': 'To compare the efficacy and toxicity of paclitaxel-carboplatin (TAX-CBP) and paclitaxel-cisplatin (TAX-DDP) chemotherapy protocols for advanced non-small cell lung cancer.\nOne hundred and twenty-six patients with non-small cell lung cancer were randomized into TAX-DDP and TAX-CBP groups. TAX-CBP group: TAX 175 mg/m² and CBP 350 mg/m², d1 iv; TAX-DDP group: TAX 175 mg/m² and DDP 100 mg/m² d1 iv. The therapy was repeated every 28 days. The response rate was assessed after three treatments.\nTAX-CBP group: response rate (RR) was 36% (22/61), 1-year survival rate was 34.1%. TAX-DDP group: RR was 33.9% (21/62),1-year survival rate was 33.1%. There was no significant difference of RR and 1-year survival rate between TAX-CBP and TAX-DDP group (P>0.05). The median survival time of TAX-CBP group (11.2 months) was significant higher than that of TAX-DDP group (9 months) (P<0.05). The major toxicity associated with paclitaxel included alpecia, myelosuppression, gastrointestinal reaction and myalgia or arthralgia. The thrombocytopenia in TAX-CBP group was more severe than that in TAX-DDP group (P<0.05). The Gastrointestinal and myalgia or arthralgia in TAX-DDP group were more severe than those in TAX-CBP group (P<0.05).\nTAX-CBP and TAX-DDP chemotherapy may be used as first choice protocol in the chemotherapy of non-small cell lung cancer.', 'title': '[A randomized phase II trial of paclitaxel in combination chemotherapy with platinum in the treatment of non-small cell lung cancer].', 'date': '2001-06-20'}, '11745199': {'article_id': '11745199', 'content': 'Eastern Cooperative Oncology Group (ECOG) Study E1594 compared paclitaxel and cisplatin with three newer chemotherapy doublets in the treatment of patients with advanced nonsmall cell lung carcinoma (NSCLC). The accrual of patients with an ECOG performance status (PS) of 2 was discontinued due to a perceived rate of unacceptable toxicity.\nPatients were stratified by PS and randomized to one of the following treatments: 1) paclitaxel (135 mg/m2) over 24 hours with cisplatin (75 mg/m2) on a 21-day cycle; 2) cisplatin (100 mg/m2) with gemcitabine (1 g/m2) on Days 1, 8, and 15 on a 28-day cycle; 3) cisplatin (75 mg/m2) with docetaxel (75 mg/m2) on a 21-day cycle; and 4) paclitaxel (225 mg/m2) over 3 hours with carboplatin (area under the curve, 6). All tests of statistical significance were two-sided.\nSixty-eight patients with an ECOG PS of 2 were enrolled, and 64 patients were evaluable for toxicity and response. Fifty-six percent of 64 evaluable patients were male, and 81% had Stage IV disease. Grade 3-4 hematologic toxicities occurred in > 50% of the patients in each treatment group. Nonhematologic Grade 3-4 toxicities occurred significantly less often in the paclitaxel and carboplatin arm (P = 0.0032). The overall rate of toxicity did not differ significantly from the rate of toxicity in the PS-0 or PS-1 cohorts. There were 5 deaths (7.35%) among 68 patients with a PS of 2 during therapy; however, only 2 of those deaths were attributed to therapy. The overall response rate for the 64 evaluable patients was 14%. The overall median survival of all 68 patients with a PS of 2, as determined by an intent-to-treat analysis, was 4.1 months.\nPatients with advanced NSCLC and a PS of 2 experienced a large number of adverse reactions and overall poor survival. A comparison with patients with a PS of 0-1 suggests that these events and the shorter survival were related to disease process rather than treatment. Alternative strategies need to be explored with therapy specifically tailored for this group of patients.', 'title': 'Outcome of patients with a performance status of 2 in Eastern Cooperative Oncology Group Study E1594: a Phase II trial in patients with metastatic nonsmall cell lung carcinoma .', 'date': '2001-12-18'}, '21333222': {'article_id': '21333222', 'content': 'To observe the efficacy and toxicity of gemcitabine plus carboplatin (GCarb) versus gemcitabine plus cisplatin (GCis) in the treatment of advanced non-small cell lung cancer (NSCLC).\nForty patients with histologically confirmed NSCLC were randomized to enter the study. GCarb group:Gemcitabine 1 000 mg/m² IV on day 1,8; carboplatin AUC 4-6 IV on day 1. GCis group: Gemcitabine 1 000 mg/m² IV on day 1,8; cisplatin 30-40 mg/m² IV on day 1-3.\nThe response rate was 65% and 60% for GCarb group and GCis group respectively (P > 0.5). Toxicities included myelosuppression, digestive reaction, alopecia and rash. Digestive toxicity in GCarb group was less than that in GCis group (P < 0.05).\nBoth GCarb and GCis regimes can be used as first-line protocol in the chemotherapy of non small cell lung cancer.', 'title': '[Comparison of efficacy and toxicity between gemcitabine plus carboplatin and gemcitabine plus cisplatin in the treatment of advanced non-small cell lung cancer].', 'date': '2002-12-20'}}
| 0.545455
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Oncology & Hematology
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52
|
Is the rate of 50% or greater reduction in seizure frequency higher, lower, or the same when comparing eslicarbazepine acetate (ESL) of any dose to placebo?
|
higher
|
moderate
|
no
|
['20299189', '17319919', '19243424', '19832771', '25528898']
| 29,067,682
| 2,017
|
{'20299189': {'article_id': '20299189', 'content': 'To investigate the efficacy and safety of once-daily eslicarbazepine acetate (ESL) when used as add-on treatment in adults with > or = 4 partial-onset seizures per 4-week despite treatment with 1 to 3 antiepileptic drugs (AEDs).\nThis double-blind, parallel-group, multicenter study consisted of an 8-week observational baseline period, after which patients were randomized to placebo (n=100) or once-daily ESL 400 mg (n=96), 800 mg (n=101), or 1200 mg (n=98). Patients then entered a 14-week double-blind treatment phase. All patients started on their full maintenance dose except for those in the ESL 1200 mg group who received once-daily ESL 800 mg for 2 weeks before reaching their full maintenance dose.\nSeizure frequency per 4-week (primary endpoint) over the 14-week double-blind treatment period was significantly lower than placebo in the ESL 800 mg and 1200 mg (p<0.001) groups. Responder rate (> or = 50% reduction in seizure frequency) was 13.0% (placebo), 16.7% (400 mg), 40.0% (800 mg, p<0.001), and 37.1% (1200 mg, p<0.001). Median relative reduction in seizure frequency was 0.8% (placebo), 18.7% (400 mg), 32.6% (800 mg, p<0.001), and 32.8% (1200 mg). Discontinuation rates due to adverse events (AEs) were 3.0% (placebo), 12.5% (400 mg), 18.8% (800 mg), and 26.5% (1200 mg). The most common (>5%) AEs in any group were dizziness, somnolence, headache, nausea, diplopia, abnormal coordination, vomiting, blurred vision, and fatigue. The majority of AEs were of mild or moderate severity.\nTreatment with once-daily eslicarbazepine acetate 800 mg and 1200 mg was more effective than placebo and generally well tolerated in patients with partial-onset seizures refractory to treatment with 1 to 3 concomitant AEDs.', 'title': 'Eslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsy.', 'date': '2010-03-20'}, '17319919': {'article_id': '17319919', 'content': 'To explore the efficacy and safety of eslicarbazepine acetate (BIA 2-093), a new antiepileptic drug, as adjunctive therapy in adult patients with partial epilepsy.\nA multicenter, double-blind, randomized, placebo-controlled study was conducted in 143 refractory patients aged 18-65 years with >or=4 partial-onset seizures/month. The study consisted of a 12-week treatment period followed by a 1-week tapering off. Patients were randomly assigned to one of three groups: treatment with eslicarbazepine acetate once daily (QD, n=50), twice daily (BID, n=46), or placebo (PL, n=47). The daily dose was titrated from 400 mg to 800 mg and to 1,200 mg at 4-week intervals. The proportion of responders (patients with a >or=50% seizure reduction) was the primary end point.\nThe percentage of responders versus baseline showed a statistically significant difference between QD and PL groups (54% vs. 28%; 90% CI =-infinity, -14; p=0.008). The difference between the BID (41%) and PL did not reach statistical significance (90% CI =-infinity, -1; p=0.12). A significantly higher proportion of responders in weeks 5-8 was found in the QD group than in the BID group (58% vs. 33%, respectively, p=0.022). At the end of the 12-week treatment, the number of seizure-free patients in the QD and BID groups was 24%, which was significantly different from the PL group. The incidence of adverse events was similar between the treatment groups and no drug-related serious adverse events occurred.\nEslicarbazepine acetate was efficacious and well tolerated as an adjunctive therapy of refractory epileptic patients.', 'title': 'Eslicarbazepine acetate: a double-blind, add-on, placebo-controlled exploratory trial in adult patients with partial-onset seizures.', 'date': '2007-02-27'}, '19243424': {'article_id': '19243424', 'content': 'To study the efficacy and safety of eslicarbazepine acetate (ESL) as adjunctive therapy for refractory partial seizures in adults with >or=4 partial-onset seizures (simple or complex, with or without secondary generalization) per 4 weeks despite treatment with 1-2 antiepileptic drugs (AEDs).\nThis multicenter, parallel-group study had an 8-week, single-blind, placebo baseline phase, after which patients were randomized to placebo (n = 102) or once-daily ESL 400 mg (n = 100), 800 mg (n = 98), or 1,200 mg (n = 102) in the double-blind treatment phase. ESL starting dose was 400 mg; thereafter, ESL was titrated at weekly 400-mg steps to the full maintenance dose (12 weeks).\nSeizure frequency adjusted per 4 weeks over the maintenance period (primary endpoint) was significantly lower than placebo in the ESL 1,200-mg (p = 0.0003) and 800-mg (p = 0.0028) groups [analysis of covariance (ANCOVA) of log-transformed seizure frequency]. Responder rate was 20% (placebo), 23% (400 mg), 34% (800 mg), and 43% (1,200 mg). Median relative reduction in seizure frequency was 16% (placebo), 26% (400 mg), 36% (800 mg), and 45% (1,200 mg). The most frequent concomitant AEDs were carbamazepine (56-62% of patients), lamotrigine (25-27%), and valproic acid (22-28%). Similar efficacy results were obtained in patients administered ESL with or without carbamazepine as concomitant AED. Discontinuation rates caused by adverse events (AEs) were 3.9% (placebo), 4% (400 mg), 8.2% (800 mg), and 19.6% (1,200 mg). AEs in >10% of any group were dizziness, headache, and diplopia. Most AEs were mild or moderate.\nESL, 800 and 1,200 mg once-daily, was well tolerated and more effective than placebo in patients who were refractory to treatment with one or two concomitant AEDs.', 'title': 'Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures: a randomized, double-blind, placebo-controlled, parallel-group phase III study.', 'date': '2009-02-27'}, '19832771': {'article_id': '19832771', 'content': 'To evaluate the efficacy and safety of eslicarbazepine acetate (ESL) as adjunctive therapy in adults with partial-onset seizures.\nDouble-blind, placebo-controlled, parallel-group, multicenter study consisting of an 8-week baseline period, after which patients were randomized to placebo (n = 87) or once-daily ESL 800 mg (n = 85) or 1200 mg (n = 80). Patients received half dose during 2 weeks preceding a 12-week maintenance period.\nSeizure frequency over the maintenance period was significantly (P < 0.05) lower than placebo in both ESL groups. Responder rate was 23% (placebo), 35% (800 mg), and 38% (1200 mg). Median relative reduction in seizure frequency was 17% (placebo), 38% (800 mg), and 42% (1200 mg). The most common adverse events (AEs) (>10%) were dizziness, somnolence, headache, and nausea. The majority of AEs were of mild or moderate severity.\nOnce-daily treatment with ESL 800 and 1200 mg was effective and generally well tolerated.', 'title': 'Efficacy and safety of 800 and 1200 mg eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures.', 'date': '2009-10-17'}, '25528898': {'article_id': '25528898', 'content': "EpilepsiaEpilepsiaepiEpilepsia0013-95801528-1167BlackWell Publishing LtdOxford, UK25528898435426010.1111/epi.12894Full-Length Original ResearchEslicarbazepine acetate as adjunctive therapy in patients with uncontrolled partial-onset seizures: Results of a phase III, double-blind, randomized, placebo-controlled trialSperlingMichael R**Abou-KhalilBassel†HarveyJay‡RoginJoanne B§BirabenArnaud¶GalimbertiCarlo A#KowacsPedro A**HongSeung Bong††ChengHailong‡‡BlumDavid‡‡NunesTeresa§§Soares-da-SilvaPatrício§§¶¶on behalf of the 304 Study Team*Thomas Jefferson UniversityPhiladelphia, Pennsylvania, U.S.A†Vanderbilt University Medical CenterNashville, Tennessee, U.S.A‡Texas Epilepsy GroupDallas, Texas, U.S.A§Midwest Center for Seizure Disorders, Minneapolis Clinic of NeurologyGolden Valley, Minnesota, U.S.A¶C.H.U. de RennesRennes, France#I.R.C.C.S., C. Mondino National Neurological InstitutePavia, Italy**Curitiba Neurological InstituteCuritiba, Brazil††Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of MedicineSeoul, South Korea‡‡Sunovion Pharmaceuticals Inc.Marlborough, Massachusetts, U.S.A§§BIAL-Portela & Ca S.A.S. Mamede do Coronado, Portugal¶¶MedInUP – Center for Drug Discovery and Innovative Medicines, University of PortoPorto, Portugal\nAddress correspondence to Michael Sperling, Thomas Jefferson University, Philadelphia, PA, U.S.A. E-mail: michael.sperling@jefferson.edu220152212201456224425312112014© 2014 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.2014This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.ObjectiveTo evaluate the efficacy and safety of adjunctive eslicarbazepine acetate (ESL) in patients with refractory partial-onset seizures.MethodsThis randomized, placebo-controlled, double-blind, parallel-group, phase III study was conducted at 173 centers in 19 countries, including the United States and Canada. Eligible patients were aged ≥16\xa0years and had uncontrolled partial-onset seizures despite treatment with 1–2 antiepileptic drugs (AEDs). After an 8-week baseline period, patients were randomized to once-daily placebo (n\xa0=\xa0226), ESL 800\xa0mg (n\xa0=\xa0216), or ESL 1,200\xa0mg (n\xa0=\xa0211). Following a 2-week titration period, patients received ESL 800 or 1,200\xa0mg once-daily for 12\xa0weeks. Seizure data were captured and documented using event-entry or daily entry diaries.ResultsStandardized seizure frequency (SSF) during the maintenance period (primary end point) was reduced with ESL 1,200\xa0mg (p\xa0=\xa00.004), and there was a trend toward improvement with ESL 800\xa0mg (p\xa0=\xa00.06), compared with placebo. When data for titration and maintenance periods were combined, ESL 800\xa0mg (p\xa0=\xa00.001) and 1,200\xa0mg (p\xa0<\xa00.001) both reduced SSF. There were no statistically significant interactions between treatment response and geographical region (p\xa0=\xa00.38) or diary version (p\xa0=\xa00.76). Responder rate (≥50% reduction in SSF) was significantly higher with ESL 1,200\xa0mg (42.6%, p\xa0<\xa00.001) but not ESL 800\xa0mg (30.5%, p\xa0=\xa00.07) than placebo (23.1%). Incidence of treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation increased with ESL dose. The most common TEAEs were dizziness, somnolence, nausea, headache, and diplopia.SignificanceAdjunctive ESL 1,200\xa0mg once-daily was more efficacious than placebo in adult patients with refractory partial-onset seizures. The once-daily 800\xa0mg dose showed a marginal effect on SSF, but did not reach statistical significance. Both doses were well tolerated. Efficacy assessment was not affected by diary format used.Adjunctive therapyAntiepileptic drugsEslicarbazepine acetateNorth AmericaPartial-onset seizuresRefractory epilepsyEslicarbazepine acetate (ESL) is a new molecular entity belonging to the dibenzazepine carboxamide chemical class of antiepileptic drugs. ESL, carbamazepine (CBZ), and oxcarbazepine (OXC) all contain a dibenzazepine nucleus bearing a 5-carboxamide substitute, but ESL is structurally different at the 10,11 position.1,2 This molecular variation results in differences in metabolism and pharmacology. Following oral administration, ESL is rapidly and extensively converted to the major active metabolite, (S)-licarbazepine (eslicarbazepine) via hydrolytic first-pass metabolism;2,3 consequently, ESL is undetectable in plasma as early as 15\xa0min postdose.4 Approximately 95% of oral ESL exposure is accounted for by eslicarbazepine, and <1% by OXC.5 In contrast, the major metabolite of OXC is the monohydroxy derivative (MHD: a racemic mixture of 4:1 eslicarbazepine to (R)-licarbazepine);6 3% of OXC exposure is accounted for by residual oxcarbazepine.5 In contrast to CBZ, ESL is not metabolized to potentially toxic epoxide metabolites,3 and is not susceptible to metabolic autoinduction.7,8Eslicarbazepine is believed to act by stabilizing the inactivated state of voltage-gated sodium channels (VGSCs), and shows higher selectivity for the inactivated state of the channel versus the resting state3 (Ki[resting]/Ki[inactivated]\xa0=\xa060) than CBZ (Ki[r]/Ki[i]\xa0=\xa019), OXC (Ki[r]/Ki[i]\xa0=\xa044), and the enantiomer (R)-licarbazepine (Ki[r]/Ki[i]\xa0=\xa028).9 The greater selectivity of eslicarbazepine for the inactivated state of VGSCs is thought to confer a greater inhibitory effect on rapidly firing (or “epileptic”) neurons compared with neurons in the resting state.10Previous double-blind placebo-controlled studies demonstrated that ESL (800 or 1,200\xa0mg once-daily [QD]) is well-tolerated as adjunctive therapy and is significantly more effective than placebo in patients with partial-onset seizures refractory to treatment with between one and three concomitant antiepileptic drugs (AEDs).11,12 In these studies, ESL significantly reduced standardized seizure frequency (per 4\xa0weeks) during a maintenance period of 12\xa0weeks, and increased the rate of response (defined as the proportion of patients with ≥50% reduction in seizure frequency) compared with placebo.This article reports primary efficacy and safety data from an additional double-blind placebo-controlled trial (the trial is registered at ClinicalTrials.gov, number NCT00988429) that was undertaken to evaluate further the efficacy, safety, and tolerability of ESL as adjunctive therapy in patients aged ≥16 with refractory partial-onset (focal) seizures receiving one or two AEDs. The impact of an alternative seizure diary format on evaluation of ESL efficacy was also assessed. Previous trials of ESL made use of event-entry (EE) diaries (in which patients provide entries only when seizures occur); however, when using EE diaries, it is not possible to determine whether days with no entry reflect a true absence of seizures, or failure of the patient to make a diary entry. To address this issue, the current trial mainly used daily entry (DE) diaries, in which patients were instructed to document seizure data every day, irrespective of whether a seizure had occurred. To our knowledge, this is the first clinical trial to report efficacy data of an AED in patients with partial-onset seizures using either EE or DE diaries.MethodsStudy designThis randomized, placebo-controlled, double-blind, parallel-group study was conducted at 173 centers in 19 countries (Argentina, Australia, Brazil, Belgium, Canada, Cyprus, France, Germany, Greece, Hungary, India, Italy, Poland, Turkey, South Korea, Romania, South Africa, Ukraine, and the United States) between December 2008 and January 2012.Patients aged ≥16\xa0years were eligible for screening if they satisfied all of the following criteria: in general good health except for a documented diagnosis of epilepsy for a minimum of 12\xa0months; had ≥4 simple or complex partial-onset seizures (with or without secondary generalization) within the 4-week period prior to screening; treated with a stable dose of one to two AEDs (except OXC) for ≥1\xa0month prior to screening (vagus nerve stimulation therapy was not considered to be an AED and was permitted, as was vigabatrin, if the patients were stable and safety was monitored). Eligibility criteria for randomization included the following: ≥8 partial-onset seizures that were documented in a diary during the baseline period (with ≥3 seizures during each 4-week period and no seizure-free interval exceeding 28 consecutive days) and satisfactorily completed diaries.Criteria for exclusion included the following: simple partial seizures with no motor symptoms; primarily generalized seizures; known progressive neurologic disorder; status epilepticus or cluster seizures within 3\xa0months before screening, or seizures of nonepileptic or psychogenic origin within 2\xa0years; history of schizophrenia or suicide attempts; current treatment with OXC (Patients taking OXC were excluded from study participation to avoid the possibility of excessive exposure to eslicarbazepine.), or using benzodiazepines >2 times per week (except when used chronically as an AED); hypersensitivity to CBZ or CBZ derivatives; second- or third-degree atrioventricular blockade not corrected with a pacemaker; relevant clinical laboratory abnormalities; a positive major histocompatibility complex, class I, B*1502 test (for patients of Asian ancestry); at randomization, inadequate compliance to the study protocol during the baseline period.Following screening, patients entered an observational 8-week baseline period, during which they were instructed on how to complete their seizure diaries. Patients with at least eight seizures during the baseline period then entered a double-blind phase that comprised a 2-week titration period, a 12-week maintenance period, and a 2-week tapering-off period. At the start of the titration period, eligible patients were randomized in a 1:1:1 ratio to receive placebo, ESL 800\xa0mg, or ESL 1,200\xa0mg (all QD). Randomization and allocation to treatment group was performed using an interactive voice-response system. The randomization code was prepared by a third party using a computer-generated schedule, and followed a permuted-block design (block size\xa0=\xa08). Each patient was assigned a unique screening number that was used for identification purposes throughout the study. Investigators were provided with a sealed envelope for each patient containing the patient's unique randomization number but were blinded to study treatment. Treatment codes remained blinded throughout the study. During the titration period, patients in the ESL 800\xa0mg group started treatment at 400\xa0mg QD, and those in the ESL 1,200\xa0mg group started at 800\xa0mg QD (in each group, the dose was increased by 400\xa0mg at the end of the first week). Patients who completed the maintenance phase could enter a 1-year open-label extension study.When the study was first initiated, EE diaries were used to record seizures; patients (with or without assistance) recorded each seizure by date, type, and time of occurrence during the baseline and double-blind treatment phases. Following a protocol amendment, EE diaries were replaced with DE diaries. Patients who were already enrolled prior to the protocol amendment continued to use EE diaries for the duration of the study. Both types of diary were provided in printed form. Of the intent-to-treat (ITT) population, approximately 29% and 71% of patients used EE and DE diaries, respectively. EE and DE subgroups were well matched in terms of demographics and baseline clinical characteristics, although the proportion of patients using vagus nerve stimulation at baseline (8% vs. 0.3%) and the proportion of Asian patients (27% vs. 1.6%) were greater for the DE than for the EE group.Seizure types were classified according to the International League Against Epilepsy (ILAE) Revised Clinical and Electroencephalographic Classification of Epileptic Seizures (1981) into simple partial seizures, complex partial seizures, partial seizures evolving to secondarily generalized seizures, and unclassified.13 In addition, investigators could indicate “other” if the seizure type was unknown or not otherwise captured.AssessmentsEfficacyThe primary efficacy variable was seizure frequency, standardized per 4\xa0weeks (standardized seizure frequency). The primary assessment of efficacy was based on the least squares (LS) mean–adjusted seizure frequency during the maintenance period. For the primary end point, all patients with diaries (of either type) were considered. Secondary efficacy variables included the following: seizure frequency during the 2-week titration period and the maintenance period combined; proportion of responders (patients with ≥50% reduction in seizure frequency vs. baseline); reduction in seizure frequency from baseline; proportion of patients with exacerbations in seizure frequency ≥25% versus baseline; reduction in seizure frequency according to seizure type; proportion of seizure-free patients during the maintenance period; change in Clinical Global Impression (CGI) score from baseline;14 and change in Quality of Life in Epilepsy Inventory-31 (QOLIE-31) total score from baseline.15 CGI scores (global improvement [CGI-I], severity of illness [CGI-S], and therapeutic effect [CGI-efficacy]) and QOLIE-31 ratings were evaluated at randomization and the end of the maintenance period.Safety and tolerabilityAdverse events (AEs) were reported at each clinic visit (irrespective of whether they were considered to be related to the study drug) and coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 13.1. Treatment-emergent AEs (TEAEs) were defined as AEs that occurred on or after the first dose of study drug. Other safety assessments included the following: clinical laboratory tests; vital signs; 12-lead electrocardiography measurements; and Columbia Suicide Severity Rating Scale (C-SSRS) scores.Statistical analysesDetermination of sample sizeFor the primary efficacy analysis, the required sample size was calculated such that a treatment difference of 0.174 (standard deviation [SD]\xa0=\xa00.4) in the primary efficacy variable could be detected with 90% power (using DE diaries). Using Bonferroni adjustment for two comparisons of the two doses of active drug with placebo (α\xa0=\xa00.025 for each), 130\xa0patients would be required per group to achieve 89.4% power. Assuming a drop-out rate of 10% based on previous phase III studies,11,12 435 patients using DE diaries (145\xa0patients per group) were required. Therefore, a total enrollment of 615 patients was required (435 using DE diaries and 185 using EE diaries [the latter group was enrolled prior to the protocol amendment]).DefinitionsThe primary efficacy analysis was based on the ITT population (all randomized patients who received at least one dose of the study drug and had at least one post-baseline seizure frequency assessment). The ITT population included patients who used either EE or DE diaries. In addition, the EE and DE diary ITT populations were analyzed separately. Supportive analyses were performed in the per-protocol (PP) population (patients in the ITT population with no major protocol deviations/violations) and the DE diary ITT population. The safety population consisted of all randomized patients who received at least one dose of study drug.AnalysisFor the primary efficacy variable, the natural logarithm of seizure frequency was compared between groups using an analysis of covariance (ANCOVA), which models seizure frequency as a function of baseline seizure frequency and treatment (with diary type as an additional covariate). Estimates from the ANCOVA model were back-transformed using the exponential function. A two-stage gate-keeping multiple-testing procedure16 was used for comparisons between ESL treatment LS means and placebo LS means for the ITT and DE diary ITT populations in the primary analysis. p-values were subject to Bonferroni adjustment in the first stage; Dunnett's multiple comparison procedure was used in the second stage (p-values from other analyses were not corrected for multiplicity). The proportion of responders, the proportion of patients with exacerbations in seizure frequency ≥25%, and the proportion of patients who were seizure-free were analyzed using a Cochran-Mantel-Haenszel test. The group comparisons in the reduction in seizure frequency and the change in CGI score were analyzed by ANCOVA.This study (BIA 2-093-304) was approved by the appropriate institutional review boards, and was conducted in accordance with international and local regulations of the countries involved. Informed consent was obtained from each patient.ResultsPatientsThe number of patients randomized and their disposition (for the safety, ITT, and PP populations) are summarized in Figure S1. The placebo and active-treatment groups were well balanced in terms of demographics and baseline characteristics (Table1).Table 1Demographic and baseline characteristics (safety population)CharacteristicPlacebo (n\xa0=\xa0224)ESL 800\xa0mg (n\xa0=\xa0216)ESL 1,200\xa0mg (n\xa0=\xa0210)Age, years (median [range])39.0 (16–67)a38.5 (16–71)38.0 (16–69)Male, n (%)112 (50.0)109 (50.5)105 (50.0)Ethnicity, n (%)\u2003Caucasian142 (63.4)137 (63.4)134 (63.8)\u2003Black8 (3.6)8 (3.7)8 (3.8)\u2003Asian46 (20.5)41 (19.0)39 (18.6)\u2003Other28 (12.5)30 (13.9)29 (13.8)BMI, kg/m2b\u2003Mean\xa0±\xa0SD25.7\xa0±\xa05.826.3\xa0±\xa05.626.5\xa0±\xa07.0\u2003Median (range)24.8 (16.2–46.5)25.7 (16.0–55.2)25.4 (15.5–71.4)Duration of epilepsy (years)c\u2003Mean\xa0±\xa0SD21.3\xa0±\xa014.621.6\xa0±\xa013.021.2\xa0±\xa013.0\u2003Median (range)18.3 (1.1–63.4)19.6 (1.4–53.9)18.3 (1.1–57.3)Seizure frequency in the 4\xa0weeks prior to screeningd\u2003Mean\xa0±\xa0SD18.1\xa0±\xa028.718.0\xa0±\xa035.917.6\xa0±\xa030.2\u2003Median (range)8 (4–282)8 (1–420)9 (4–351)Seizure type in the 4\xa0weeks prior to screening,d,e n (%)f\u2003Simple partialg81 (36.8)84 (39.3)66 (32.2)\u2003Complex partialh175 (79.5)170 (79.4)170 (82.9)\u2003Partial evolving to secondarily generalizedi57 (25.9)59 (27.6)63 (30.7)\u2003Unclassifiable2 (0.9)03 (1.5)\u2003Other2 (0.9)1 (0.5)0\u2003Missing010Median (range) SSF during the baseline periodd,j9.0 (2.4–131.8)8.6 (2.0–412.3)8.9 (3.7–163.5)Number of AEDs used during the baseline period,k n (%)\u2003164 (28.6)60 (27.8)59 (28.1)\u20032158 (70.5)153 (70.8)151 (71.9)\u2003≥31 (0.4)00AEDs during baseline used by >15% of patients,l n (%)\u2003Carbamazepine77 (34.4)84 (38.9)89 (42.4)\u2003Levetiracetam66 (29.5)58 (26.9)43 (20.5)\u2003Lamotrigine57 (25.4)51 (23.6)57 (27.1)\u2003Valproic acid42 (18.8)46 (21.3)41 (19.5)AED, antiepileptic drug; BMI, body mass index; ESL, eslicarbazepine acetate; ILAE, International League Against Epilepsy; SD, standard deviation; SSF, standardized seizure frequency.an\xa0=\xa0223.bn\xa0=\xa0222, 215, and 208 for placebo, ESL 800\xa0mg, and ESL 1,200\xa0mg, respectively.cn\xa0=\xa0215 for ESL 800\xa0mg.dIntention-to-treat population.ePatients may have had more than one type of seizure.fn\xa0=\xa0220, 214, and 205 for placebo, ESL 800\xa0mg, and ESL 1,200\xa0mg, respectively.gFocal seizures without impairment of consciousness or awareness.hDyscognitive seizures.iFocal seizures evolving to bilateral convulsive seizures (2010 ILAE classification).17jn\xa0=\xa0220, 215, and 204 for placebo, ESL 800\xa0mg, and ESL 1,200\xa0mg, respectively.kAn AED was considered to be used at baseline if started any time prior to first dose of study drug and continued to the titration period. AEDs used as rescue medication at baseline are not included.lAs specified by the study protocol, none of the patients took OXC during the baseline period.EfficacySeizure frequencyIn the ITT population (Table2), during the 12-week maintenance period seizure frequency was significantly lower in the ESL 1,200\xa0mg group (LS mean: 6.00) than the placebo group (LS mean: 7.88; log difference: −0.26; p\xa0=\xa00.004). Seizure frequency was also numerically lower in the ESL 800\xa0mg group (LS mean: 6.54) than the placebo group (p\xa0=\xa00.06). In the PP population, similar statistically significant effects were observed during the 12-week maintenance period with ESL 1,200\xa0mg (LS\xa0mean 5.78, log difference: −0.29, p\xa0=\xa00.001), but not ESL 800\xa0mg (LS mean: 6.83; log difference: −0.13; p\xa0=\xa00.12) versus placebo (LS mean: 7.85).Table 2Analysis of covariance of standardized seizure frequency during the 12-week maintenance period (ITT population)Study populationPlacebo (n\xa0=\xa0220)ESL 800\xa0mg (n\xa0=\xa0215)ESL 1,200\xa0mg (n\xa0=\xa0205)Overall ITT population\u2003n212200184\u2003LS mean (95% CI)7.88 (6.98–8.90)6.54 (5.77–7.40)6.00 (5.26–6.84)\u2003Log difference in LS mean versus placebo–−0.18−0.26\u2003Bonferroni's procedure-adjusted p-valuea–0.060.004ITT population (daily entry diaries)\u2003n154137136\u2003LS mean (95% CI)7.54 (6.55–8.68)6.32 (5.44–7.35)5.96 (5.12–6.94)\u2003Log difference in LS mean versus placebo–−0.17−0.22\u2003Dunnett's procedure-adjusted p-valueb–0.170.05ITT population (event-entry diaries)\u2003N586348\u2003LS mean (95% CI)7.91 (6.43–9.72)6.33 (5.17–7.72)5.41 (4.28–6.81)\u2003Log difference in LS mean versus placebo–−0.21−0.36\u2003p-valuec–0.130.02CI, confidence interval; ESL, eslicarbazepine acetate; ITT, intention to treat; LS, least squares.aBonferroni's procedure was used to calculate the p-values and the 95% CIs for log differences.bDunnett's procedure was used to calculate the p-values (assessed at p\xa0=\xa00.025 level) and 97.5% CIs for log differences.cUnadjusted p-value for pairwise comparison with placebo.When analyzed for the titration and maintenance periods combined, seizure frequency was significantly lower for both the ESL 1,200\xa0mg group (LS mean: 6.31; log difference: −0.31; p\xa0<\xa00.001) and the ESL 800\xa0mg group (LS mean: 6.60; log difference: −0.26; p\xa0=\xa00.001) than for the placebo group (LS mean: 8.68).A separate ANCOVA demonstrated that there was no significant interaction between treatment and diary version used (p\xa0=\xa00.76); nevertheless the primary end point was analyzed separately in the EE and DE populations. Both diary groups showed similar trends across treatment groups (Table2). Although the influence of geographic region on treatment response was also not statistically significant (p\xa0=\xa00.38), seizure frequency was nevertheless analyzed separately for patients enrolled in North America (n\xa0=\xa0229) and the rest of the world (n\xa0=\xa0411). In the North American subgroup there was no statistically significant difference in seizure frequency between the ESL 1,200\xa0mg group (LS mean: 6.57; log difference: −0.18; p\xa0=\xa00.18) or the ESL 800\xa0mg group (LS mean: 7.63; log difference: −0.03; p\xa0=\xa00.79) and placebo (LS mean: 7.90). In the rest of the world subgroup, seizure frequency was significantly lower in both the ESL 1,200\xa0mg group (LS mean: 5.59; log difference: −0.32, p\xa0=\xa00.003) and the ESL 800\xa0mg group (LS mean: 5.87; log difference: −0.27; p\xa0=\xa00.010) than the placebo group (LS mean: 7.80).Responder rateThe responder rate in the ITT population during the maintenance phase was significantly higher in the ESL 1,200\xa0mg group (42.6%; p\xa0<\xa00.001) but not the ESL 800\xa0mg group (30.5%; p\xa0=\xa00.07) compared with the placebo group (23.1%; Fig.1). In patients taking ESL 1,200\xa0mg, a significantly greater response rate than placebo was observed in both DE (43.0% vs. 26.0%; p\xa0=\xa00.002) and EE (41.7% vs. 15.5%; p\xa0=\xa00.002) diary groups.Figure 1Responder rate (proportion of patients with ≥50% reduction in seizure frequency during the maintenance period versus baseline; ITT population). CI, confidence interval; ESL, eslicarbazepine acetate. *ESL group versus placebo.Reduction in seizure frequencyOverall, the median percent reduction in seizure frequency was 21.8% in the placebo group, 29.7% in the ESL 800\xa0mg group, and 35.6% in the ESL 1,200\xa0mg group. The difference from placebo was significant for the 1,200\xa0mg group (p\xa0=\xa00.02) but not for the ESL 800\xa0mg group (p\xa0=\xa00.07). A similar pattern was observed for different seizure types: simple partial seizures were reduced by 26.5%, 36.6%, and 34.1%; complex partial seizures were reduced by 17.2%, 28.2%, and 34.1%; and partial seizures evolving to secondarily generalized seizures were reduced by 18.7%, 35.9%, and 37.0% (for placebo, ESL 800\xa0mg, and ESL 1,200\xa0mg, respectively). A ≥25% increase in seizure frequency occurred in 31 (14.6%), 26 (13.0%), and 24 (13.1%) patients (placebo, ESL 800\xa0mg, and ESL 1,200\xa0mg, respectively); differences between treatment groups were not statistically significant in the subgroup analyses.Seizure freedomSeizure freedom (during the maintenance period) was achieved by 0.9% of placebo-treated patients, and 2.0% and 2.2% of ESL 800- and 1,200\xa0mg-treated patients, respectively.CGI and QOLIE-31 scoresThe proportions of patients with improvements on the CGI-I and the CGI efficacy scales are shown in Table3, as are the changes in CGI-S and QOLIE-31 scores between baseline and the end of the maintenance period. There were somewhat greater reductions in CGI-S scores with ESL 800\xa0mg and ESL 1,200\xa0mg than with placebo, although the differences were not statistically significant. Overall, 35.3% of patients taking ESL were rated either “very much improved” or “much improved” on the CGI-I scale, versus 20.7% of those taking placebo. Similarly, 44.7% of patients overall who were taking ESL had a “marked” or “moderate” improvement according to the CGI efficacy index, versus 27.8% of those on placebo. Treatment with ESL 1,200\xa0mg and ESL 800\xa0mg led to an increase in total QOLIE-31 scores of approximately five points between baseline and the end of the maintenance period.Table 3CGI and QOLIE-31 scores (ITT population)Placebo (n\xa0=\xa0220)ESL 800\xa0mg (n\xa0=\xa0215)ESL 1,200\xa0mg (n\xa0=\xa0205)CGI-S (change from baseline)a,b\u2003LS mean (95% CI)−0.3 (−0.4, −0.1)−0.5 (−0.6, −0.3)−0.4 (−0.6, −0.3)\u2003Unadjusted p-value0.0540.13CGI-Ia,c\u2003Very much improved, % (n)4.2 (9)6.9 (14)6.1 (12)\u2003Much improved, % (n)16.5 (35)27.5 (56)30.1 (59)CGI efficacy index (therapeutic effect)a,d\u2003Marked improvement, % (n)4.4 (9)9.8 (19)10.5 (19)\u2003Moderate improvement, % (n)23.4 (48)32.6 (63)36.5 (66)QOLIE-31 total score (change from baseline)a\u2003Mean\xa0±\xa0SD2.16\xa0±\xa025.45.35\xa0±\xa023.84.64\xa0±\xa025.7CGI, Clinical Global Impressions; CGI-I, CGI-Improvement; CGI-S, CGI-Severity of illness; CI, confidence interval; ESL, eslicarbazepine acetate; LS, least squares; QOLIE-31, Quality of Life Epilepsy Inventory-31; SD, standard deviation.aBased on last assessment at the end of the maintenance period. Note that not all subjects had evaluable data; percentages are based on evaluable subjects.bn\xa0=\xa0213, 205, and 198 for placebo, ESL 800\xa0mg, and ESL 1,200\xa0mg, respectively.cn\xa0=\xa0212, 204, and 196 for placebo, ESL 800\xa0mg, and ESL 1,200\xa0mg, respectively.dn\xa0=\xa0205, 193, and 181 for placebo, ESL 800\xa0mg, and ESL 1,200\xa0mg, respectively.SafetyTEAEsThe incidence of TEAEs (Table4), TEAEs considered potentially related to treatment, and TEAEs leading to discontinuation increased with ESL dose. The majority of TEAEs were of mild or moderate severity, the most common being dizziness, somnolence, nausea, headache, and diplopia (Table4). The percentage of patients who had at least one severe TEAE was 6.7% for placebo, 11.1% for ESL 800\xa0mg, and 14.8% for ESL 1,200\xa0mg. TEAEs classed as severe and reported in ≥2% of patients were dizziness (1.3%, 1.9%, and 3.8%) and vertigo (0%, 0.5%, and 2.9%) for placebo, ESL 800\xa0mg, and ESL 1,200\xa0mg, respectively. TEAEs leading to discontinuation in ≥2% of patients taking ESL (either dose) were dizziness, nausea, vomiting, ataxia, dysarthria, and somnolence (Table4). TEAEs of special interest included depression (reported in 2.7%, 2.3%, and 2.4% of the placebo, ESL 800\xa0mg, and ESL 1,200\xa0mg groups, respectively) and rash (reported in 1.8%, 1.4%, and 2.4% of the placebo, ESL 800\xa0mg, and ESL 1,200\xa0mg groups, respectively).Table 4TEAEs affecting ≥5% of patients, TEAEs leading to discontinuation in ≥2% of patients, all serious TEAEs, and deaths (safety population)Number (%) of patientsPlacebo(n\xa0=\xa0224)ESL 800\xa0mg(n\xa0=\xa0216)ESL 1,200\xa0mg(n\xa0=\xa0210)Any TEAE125 (55.8)145 (67.1)163 (77.6)\u2003Dizziness19 (8.5)34 (15.7)55 (26.2)\u2003Somnolence12 (5.4)16 (7.4)36 (17.1)\u2003Nausea11 (4.9)16 (7.4)32 (15.2)\u2003Headache17 (7.6)20 (9.3)24 (11.4)\u2003Vomiting3 (1.3)6 (2.8)23 (11.0)\u2003Diplopia4 (1.8)14 (6.5)22 (10.5)\u2003Vertigo1 (0.4)6 (2.8)15 (7.1)\u2003Fatigue6 (2.7)8 (3.7)11 (5.2)Potentially related TEAE83 (37.1)111 (51.4)140 (66.7)TEAEs leading to discontinuation18 (8)26 (12.0)54 (25.7)\u2003Dizziness1 (0.4)11 (5.1)19 (9.0)\u2003Nausea03 (1.4)13 (6.2)\u2003Vomiting008 (3.8)\u2003Ataxia01 (0.5)8 (3.8)\u2003Dysarthria005 (2.4)\u2003Somnolence2 (0.9)2 (0.9)5 (2.4)Serious TEAEs7 (3.1)14 (6.5)3 (1.4)Deathsa1 (0.4)1 (0.5)0ESL, eslicarbazepine acetate; TEAE, treatment-emergent adverse event.aData are based on the double-blind, placebo-controlled period.DeathsOne death occurred during the baseline period of a patient who had not received the study drug. Two deaths occurred during the double-blind period: a 29-year-old Caucasian woman randomized to placebo died of acute respiratory failure after being diagnosed with pneumonia; and a 27-year-old Caucasian man randomized to ESL 800\xa0mg was found dead in bed with a bitten tongue (during the titration phase, while receiving 400\xa0mg ESL). The cause of death according to the autopsy report was status epilepticus.Serious adverse eventsThere were no notable differences in the types of serious TEAEs between treatment groups, and no dose-related trends (the incidence of serious TEAEs was 3.1% for placebo, 6.5% for ESL 800\xa0mg, and 1.4% for ESL 1,200\xa0mg). One patient with a history of suicidal tendencies had a suicide attempt but, as she had responded to the study drug, she was allowed to continue on ESL 800\xa0mg; no other psychiatric symptoms were reported. One serious cutaneous event (leukocytoclastic vasculitis) leading to discontinuation of treatment was reported in a patient taking ESL 800\xa0mg.Clinical laboratory assessmentsOverall, changes in clinical laboratory parameters (other than serum sodium) were not substantially different between the three groups. Data for reductions in serum sodium concentrations are shown in Table5. Overall, 5.1% of patients taking ESL had a reduction in serum sodium of >10\xa0mEq/L, compared with 0.9% of those taking placebo, whereas hyponatremia (serum sodium <125\xa0mEq/L) occurred in 1.5% and 0% of patients, respectively. Between baseline and week 8 of treatment (week 6 of the maintenance period), there were greater reductions in mean serum sodium with ESL 800\xa0mg (−1.6\xa0mEq/L) and ESL 1,200\xa0mg (−2.2\xa0mEq/L) than with placebo (0.1\xa0mEq/L); the reductions tended to stabilize after approximately 2\xa0months of treatment. Hyponatremia was reported as an adverse event (AE) leading to discontinuation in three patients taking ESL 1,200\xa0mg (1.4%), but no patients taking placebo or ESL 800\xa0mg. Vital signs, body weight, and electrocardiography parameters were not substantially different across visits for the placebo and ESL groups. ESL 800 and 1,200\xa0mg had no notable effect on C-SSRS scores.Table 5Serum sodium levels (safety population)No. (%) of patientsa,bPlacebo (n\xa0=\xa0224)ESL 800\xa0mg (n\xa0=\xa0216)ESL 1,200\xa0mg (n\xa0=\xa0210)Total ESL (n\xa0=\xa0426)Serum sodium <125\xa0mEq/L01 (0.5)5 (2.5)6 (1.5)Reduction from baseline in serum sodium of >10\xa0mEq/L2 (0.9)9 (4.3)12 (5.9)21 (5.1)ESL, eslicarbazepine acetate; mEq/L, milliequivalent/liter.aData are for patients in the safety population with at least one post-baseline sodium assessment. Note that not all subjects had evaluable data; percentages are based on evaluable subjects.bn\xa0=\xa0220, 209, 204, and 413 for placebo, ESL 800\xa0mg and ESL 1,200\xa0mg, and Total ESL, respectively.DiscussionESL was developed to enhance the yield of the pharmacologically desirable metabolite eslicarbazepine, while reducing exposure to the less pharmacologically desirable metabolites (R)-licarbazepine and OXC.The present study confirms and extends the findings of efficacy and safety of ESL as adjunctive treatment of partial-onset seizures as reported in two prior randomized placebo-controlled trials.11,12 Once-daily ESL was effective as adjunctive therapy and was generally well tolerated in patients with refractory partial-onset (focal) seizures. During the 12-week maintenance period, seizure frequency was significantly reduced in the ESL 1,200\xa0mg group compared with placebo (p\xa0=\xa00.004), and there was a trend toward improvement in the ESL 800\xa0mg group compared with placebo (p\xa0=\xa00.06). No statistically significant interactions between ESL treatment and geographical region or ESL treatment and diary version (DE or EE) were detected. For the majority of secondary efficacy end points, including response rate and reduction in seizure frequency, there were statistically significant differences between ESL 1,200\xa0mg and placebo, and similar trends occurred with ESL 800\xa0mg. We noted relatively high 50% responder rates in placebo-treated patients, approximating rates reported in other studies of similar design (e.g., perampanel, 19.3%;18 lacosamide, 23.0%;19 and OXC, 28.1%20). This poses a challenge in interpreting the magnitude of effect of new AEDs. Nonetheless, substantially more patients taking ESL were rated at least “much improved” on the CGI-I scale, or had at least “moderate improvement” according to the CGI efficacy scale compared with placebo-treated patients. Patients taking ESL had improvements in QOLIE-31 scores of approximately five points (i.e., comparable to the minimal clinically important improvement described by Borghs et\xa0al.),21 indicating that treatment with ESL led to clinically meaningful improvements in quality of life.In this study, seizure frequency was the primary efficacy end point. Similar clinical trials22,23 previously used either the median percentage change in seizure frequency from baseline, or the responder rate as the primary outcome measure. These measures are susceptible to bias when the distribution of seizure frequencies is not normally distributed. In such circumstances, the log-transformed seizure frequency is a more robust measure, as discussed in an analysis by Siddiqui and Hershkowitz.24The current safety and tolerability findings are consistent with those reported previously for ESL.11,12 The most commonly reported TEAEs were dizziness, somnolence, nausea, headache, vomiting, diplopia, vertigo, and fatigue. Rash was reported in 1.4% and 2.4% of patients, and hyponatremia in 0% and 1.5% of patients (taking ESL 800 and 1,200\xa0mg, respectively). Too few cases occurred to draw conclusions regarding dose and incidence of symptomatic hyponatremia. In previous studies of OXC, rash was reported in 6% of patients25 and hyponatremia in 3.8% of adult patients.26 The incidence of TEAEs and TEAEs leading to discontinuations was higher in the ESL 1,200\xa0mg group than the ESL 800\xa0mg group. However, somewhat more patients in the 1,200\xa0mg group than the 800\xa0mg group were taking other concomitant AEDs with the same mode of action as ESL (sodium channel blockers, i.e., CBZ, lamotrigine). It has been reported that combining sodium channel blockers may lead to increased toxicity.27As in previous ESL trials, these findings indicate that ESL is effective as adjunctive therapy in patients with a long history of partial seizures and poor seizure control, who are taking one or two concomitant AEDs. ESL demonstrated efficacy in patients who previously had continued to have frequent seizures, despite treatment with AEDs including CBZ, levetiracetam, lamotrigine and valproic acid. The current trial is generally consistent with previous trials11,12 in which once-daily ESL (800 and/or 1,200\xa0mg) was efficacious and well-tolerated in patients with refractory partial-onset seizures. In the current trial, the ESL 800\xa0mg dose did not reach statistical significance. It is not clear why this occurred, however, the trends toward improvements were consistent with results in previous studies. Too few patients (n\xa0=\xa036) in the entire ESL development program were taking three concomitant AEDs to assess efficacy as a function of number of AEDs.One important methodologic difference between this trial and previous studies was the use of DE diaries to ensure that seizure data were recorded on every day of the trial, regardless of whether seizures had occurred. Reliability of seizure recording is a key issue in epilepsy trials,28 but to date no formal comparisons of seizure diaries of different designs are available. In the present study, the interaction between the effect of treatment and diary version was not significant (p\xa0=\xa00.76). The results obtained with DE diaries were consistent with those obtained with EE diaries. Selection of diary type was based on time of enrollment, rather than by randomization, which represents a limitation in the method.ConclusionsIn this phase III study, daily dosing with adjunctive ESL was effective in reducing seizures in patients with refractory partial-onset (focal) seizures, and was generally well tolerated. The effect of ESL 1,200\xa0mg on seizure frequency was significantly greater than that of placebo; whereas ESL 800\xa0mg also reduced seizure frequency, the difference versus placebo was not statistically significant. The DE and EE diary methods produced similar results with regard to seizure outcomes; this is the first clinical trial providing efficacy data in patients with partial-onset seizures who used two different diary designs. ESL is a useful addition to current AED pharmacotherapy for the treatment of refractory partial-onset (focal) seizures, on the basis of clinical activity, convenient once-daily dosing, and good tolerability.The authors would like to acknowledge the writing assistance of Tracey Baskerville of FireKite, part of the Knowledge Point 360 Group, an Ashfield company, for support in drafting this manuscript. Medical writing support was funded by Sunovion Pharmaceuticals Inc.Dr. Michael R. Sperling, is Baldwin Keyes Professor of Neurology at Thomas Jefferson University.Disclosure of Conflict of InterestMichael Sperling has received consultancy honoraria from UCB Pharma, ElectroCore, and Accorda Therapeutics and honoraria from Wiley Blackwell for serving as an associate editor for Epilepsia, and has received grants from National Institute of Neurological Disorders and Stroke (NINDS), UCB Pharma, Sunovion Pharmaceuticals Inc., Eisai, SK Life Science, Upsher-Smith, Medtronics, Lundbeck, Visualase, and Brain Sentinel. Bassel Abou-Khalil has received research grants paid to Vanderbilt University Medical Center from Sunovion Pharmaceuticals Inc., UCB Pharma, Pfizer, GlaxoSmithKline, Upsher-Smith, and SK Life Science. Jay Harvey has received financial support for research from Sunovion Pharmaceuticals Inc., UCB Pharma, Upsher-Smith, Marinus, SK Life Science, Cyberonics, Brain Sentinel, and Eisai, and speaker fees from Sunovion Pharmaceuticals Inc. and UCB Pharma. Joanne Rogin has received financial support for research from GlaxoSmithKline, Eisai, Pfizer, UCB Pharma, Sunovion Pharmaceuticals Inc., and Marinus; speaker's fees from GlaxoSmithKline, Pfizer, UCB Pharma, and Supernus; and consultancy honoraria from Pfizer and Sunovion Pharmaceuticals Inc. Arnaud Biraben serves as a member on a corporate scientific board and receives honoraria from GlaxoSmithKline, Eisai, and UCB Pharma. Carlo A. Galimberti received a grant from the Italian Ministry of Health, financial support for research from UCB Pharma, Eisai, and Bial-Portela & Ca S.A.; and speaker's fees from GlaxoSmithKline and UCB Pharma. Pedro A. Kowacs has received consultancy honoraria from Abbott, GlaxoSmithKline, and Cyberonics and financial support for research from Bial-Portela & Ca S.A. Seung Bong Hong has no potential conflicts of interest to disclose. Hailong Cheng and David Blum are paid employees of Sunovion Pharmaceuticals Inc. Teresa Nunes and Patrício Soares-da-Silva are paid employees of Bial-Portela & Ca S.A. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.ReferencesBenesJParadaAFigueiredoAAAnticonvulsant and sodium channel-blocking properties of novel 10,11-dihydro-5H-dibenz[b, f]azepine-5-carboxamide derivativesJ Med Chem1999422582258710411478AlmeidaLPotgieterJHMaiaJPharmacokinetics of eslicarbazepine acetate in patients with moderate hepatic impairmentEur J Clin Pharmacol20086426727318157705HebeisenSBradyKKonradDInhibitory effects of eslicarbazepine acetate and its metabolites against neuronal voltage-gated sodium channelsEpilepsia201152257258AlmeidaLSoares-da-SilvaPSafety, tolerability and pharmacokinetic profile of BIA 2-093, a novel putative antiepileptic agent, during first administration to humansDrugs R D2003426928412952496NunesTRochaJFFalcaoASteady-state plasma and cerebrospinal fluid pharmacokinetics and tolerability of eslicarbazepine acetate and oxcarbazepine in healthy volunteersEpilepsia20135410811622812691StahlSMStahl's essential psychopharmacology – the prescriber's guide2011New YorkCambridge University PressBialerMSoares-da-SilvaPPharmacokinetics and drug interactions of eslicarbazepine acetateEpilepsia20125393594622612290AlmeidaLBialerMSoares-da-SilvaPShorvonSPeruccaEEngelJEslicarbazepine acetateThe treatment of epilepsy20093rd EdOxfordBlackwell Publishing485498Marlborough, MASunovion Pharmaceuticals IncData on fileRagsdaleDSScheuerTCatterallWAFrequency and voltage-dependent inhibition of type IIA Na+ channels, expressed in a mammalian cell line, by local anaesthetic, antiarrhythmic, and anticonvulsant drugsMol Pharmacol1991407567651658608ElgerCHalaszPMaiaJEfficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures: a randomized, double-blind, placebo-controlled, parallel-group Phase III studyEpilepsia20095045446319243424Ben-MenachemEGabbaiAAHufnagelAEslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsyEpilepsy Res20108927828520299189Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the Commission on Classification and Terminology of the International League Against EpilepsyEpilepsia1981224895016790275National Institute of Mental HealthGuyWBonatoRRCGI: clinical global impressionManual for the ECDEU assessment battery19702nd Revised EdChevy Chase, MDNational Institute of Mental Health12-112-6CramerJAPerrineKDevinskyODevelopment and cross-cultural translation of a 31-item quality of life questionnaire (QOLIE-31)Epilepsia19983981889578017DmitrienkoATamhaneACWiensBLGeneral multistage gatekeeping proceduresBiom J20085066767718932130BergATBerkovicSFBrodieMJRevised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009Epilepsia20105167668520196795Perampanel (FYCOMPA)2013US prescribing information. Eisai Inc. Available at: http://www.fycompa.com/sites/all/themes/fycompa/pdf/Fycompa_Prescribing_Information.pdf. Accessed June 23, 2014Lacosamide (VIMPA)2013EPAR – summary for the public. European medicines Agency 710648, 2012. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000863/WC500050339.pdf. Accessed June 23, 2014Oxcarbazepine (Oxtellar®)2012FDA medical review. Available at: http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM328320.pdf. Accessed 23 June, 2014BorghsSde la LogeCCramerJADefining minimally important change in QOLIE-31 scores: estimates from three placebo-controlled lacosamide trials in patients with partial-onset seizuresEpilepsy Behav20122323023422341962BrodieMJLercheHGil-NagelAEfficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsyNeurology2010751817182420944074FrenchJAKraussGLSteinhoffBJEvaluation of adjunctive perampanel in patients with refractory partial-onset seizures: results of randomized global Phase III study 305Epilepsia20135411712522905857SiddiquiOHershkowitzNPrimary efficacy endpoint in clinical trials of antiepileptic drugs: change or percentage changeDrug Inf J201044343350MarsonAGAl-KharusiAMAlwaidhMThe SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trialLancet20073691000101517382827SachdeoRWassersteinAMesenbrinkPOxcarbazepine (Trileptal): effect on serum sodiumEpilepsia199940Suppl. 72.074 AbstractPeruccaEClinically relevant drug interactions with antiepileptic drugsBr J Clin Pharmacol20066124625516487217FisherRSBlumDEDiVenturaBSeizure diaries for clinical research and practice: limitations and future prospectsEpilepsy Behav20122430431022652423Supporting InformationFigure S1. Patient disposition.Appendix S1. The 304 study team.", 'title': 'Eslicarbazepine acetate as adjunctive therapy in patients with uncontrolled partial-onset seizures: Results of a phase III, double-blind, randomized, placebo-controlled trial.', 'date': '2014-12-23'}}
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Is the rate of study withdrawal due to adverse effects higher, lower, or the same when comparing eslicarbazepine acetate (ESL) of any dose to placebo?
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higher
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yes
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['20299189', '17319919', '19243424', '19832771', '25528898']
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{'20299189': {'article_id': '20299189', 'content': 'To investigate the efficacy and safety of once-daily eslicarbazepine acetate (ESL) when used as add-on treatment in adults with > or = 4 partial-onset seizures per 4-week despite treatment with 1 to 3 antiepileptic drugs (AEDs).\nThis double-blind, parallel-group, multicenter study consisted of an 8-week observational baseline period, after which patients were randomized to placebo (n=100) or once-daily ESL 400 mg (n=96), 800 mg (n=101), or 1200 mg (n=98). Patients then entered a 14-week double-blind treatment phase. All patients started on their full maintenance dose except for those in the ESL 1200 mg group who received once-daily ESL 800 mg for 2 weeks before reaching their full maintenance dose.\nSeizure frequency per 4-week (primary endpoint) over the 14-week double-blind treatment period was significantly lower than placebo in the ESL 800 mg and 1200 mg (p<0.001) groups. Responder rate (> or = 50% reduction in seizure frequency) was 13.0% (placebo), 16.7% (400 mg), 40.0% (800 mg, p<0.001), and 37.1% (1200 mg, p<0.001). Median relative reduction in seizure frequency was 0.8% (placebo), 18.7% (400 mg), 32.6% (800 mg, p<0.001), and 32.8% (1200 mg). Discontinuation rates due to adverse events (AEs) were 3.0% (placebo), 12.5% (400 mg), 18.8% (800 mg), and 26.5% (1200 mg). The most common (>5%) AEs in any group were dizziness, somnolence, headache, nausea, diplopia, abnormal coordination, vomiting, blurred vision, and fatigue. The majority of AEs were of mild or moderate severity.\nTreatment with once-daily eslicarbazepine acetate 800 mg and 1200 mg was more effective than placebo and generally well tolerated in patients with partial-onset seizures refractory to treatment with 1 to 3 concomitant AEDs.', 'title': 'Eslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsy.', 'date': '2010-03-20'}, '17319919': {'article_id': '17319919', 'content': 'To explore the efficacy and safety of eslicarbazepine acetate (BIA 2-093), a new antiepileptic drug, as adjunctive therapy in adult patients with partial epilepsy.\nA multicenter, double-blind, randomized, placebo-controlled study was conducted in 143 refractory patients aged 18-65 years with >or=4 partial-onset seizures/month. The study consisted of a 12-week treatment period followed by a 1-week tapering off. Patients were randomly assigned to one of three groups: treatment with eslicarbazepine acetate once daily (QD, n=50), twice daily (BID, n=46), or placebo (PL, n=47). The daily dose was titrated from 400 mg to 800 mg and to 1,200 mg at 4-week intervals. The proportion of responders (patients with a >or=50% seizure reduction) was the primary end point.\nThe percentage of responders versus baseline showed a statistically significant difference between QD and PL groups (54% vs. 28%; 90% CI =-infinity, -14; p=0.008). The difference between the BID (41%) and PL did not reach statistical significance (90% CI =-infinity, -1; p=0.12). A significantly higher proportion of responders in weeks 5-8 was found in the QD group than in the BID group (58% vs. 33%, respectively, p=0.022). At the end of the 12-week treatment, the number of seizure-free patients in the QD and BID groups was 24%, which was significantly different from the PL group. The incidence of adverse events was similar between the treatment groups and no drug-related serious adverse events occurred.\nEslicarbazepine acetate was efficacious and well tolerated as an adjunctive therapy of refractory epileptic patients.', 'title': 'Eslicarbazepine acetate: a double-blind, add-on, placebo-controlled exploratory trial in adult patients with partial-onset seizures.', 'date': '2007-02-27'}, '19243424': {'article_id': '19243424', 'content': 'To study the efficacy and safety of eslicarbazepine acetate (ESL) as adjunctive therapy for refractory partial seizures in adults with >or=4 partial-onset seizures (simple or complex, with or without secondary generalization) per 4 weeks despite treatment with 1-2 antiepileptic drugs (AEDs).\nThis multicenter, parallel-group study had an 8-week, single-blind, placebo baseline phase, after which patients were randomized to placebo (n = 102) or once-daily ESL 400 mg (n = 100), 800 mg (n = 98), or 1,200 mg (n = 102) in the double-blind treatment phase. ESL starting dose was 400 mg; thereafter, ESL was titrated at weekly 400-mg steps to the full maintenance dose (12 weeks).\nSeizure frequency adjusted per 4 weeks over the maintenance period (primary endpoint) was significantly lower than placebo in the ESL 1,200-mg (p = 0.0003) and 800-mg (p = 0.0028) groups [analysis of covariance (ANCOVA) of log-transformed seizure frequency]. Responder rate was 20% (placebo), 23% (400 mg), 34% (800 mg), and 43% (1,200 mg). Median relative reduction in seizure frequency was 16% (placebo), 26% (400 mg), 36% (800 mg), and 45% (1,200 mg). The most frequent concomitant AEDs were carbamazepine (56-62% of patients), lamotrigine (25-27%), and valproic acid (22-28%). Similar efficacy results were obtained in patients administered ESL with or without carbamazepine as concomitant AED. Discontinuation rates caused by adverse events (AEs) were 3.9% (placebo), 4% (400 mg), 8.2% (800 mg), and 19.6% (1,200 mg). AEs in >10% of any group were dizziness, headache, and diplopia. Most AEs were mild or moderate.\nESL, 800 and 1,200 mg once-daily, was well tolerated and more effective than placebo in patients who were refractory to treatment with one or two concomitant AEDs.', 'title': 'Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures: a randomized, double-blind, placebo-controlled, parallel-group phase III study.', 'date': '2009-02-27'}, '19832771': {'article_id': '19832771', 'content': 'To evaluate the efficacy and safety of eslicarbazepine acetate (ESL) as adjunctive therapy in adults with partial-onset seizures.\nDouble-blind, placebo-controlled, parallel-group, multicenter study consisting of an 8-week baseline period, after which patients were randomized to placebo (n = 87) or once-daily ESL 800 mg (n = 85) or 1200 mg (n = 80). Patients received half dose during 2 weeks preceding a 12-week maintenance period.\nSeizure frequency over the maintenance period was significantly (P < 0.05) lower than placebo in both ESL groups. Responder rate was 23% (placebo), 35% (800 mg), and 38% (1200 mg). Median relative reduction in seizure frequency was 17% (placebo), 38% (800 mg), and 42% (1200 mg). The most common adverse events (AEs) (>10%) were dizziness, somnolence, headache, and nausea. The majority of AEs were of mild or moderate severity.\nOnce-daily treatment with ESL 800 and 1200 mg was effective and generally well tolerated.', 'title': 'Efficacy and safety of 800 and 1200 mg eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures.', 'date': '2009-10-17'}, '25528898': {'article_id': '25528898', 'content': "EpilepsiaEpilepsiaepiEpilepsia0013-95801528-1167BlackWell Publishing LtdOxford, UK25528898435426010.1111/epi.12894Full-Length Original ResearchEslicarbazepine acetate as adjunctive therapy in patients with uncontrolled partial-onset seizures: Results of a phase III, double-blind, randomized, placebo-controlled trialSperlingMichael R**Abou-KhalilBassel†HarveyJay‡RoginJoanne B§BirabenArnaud¶GalimbertiCarlo A#KowacsPedro A**HongSeung Bong††ChengHailong‡‡BlumDavid‡‡NunesTeresa§§Soares-da-SilvaPatrício§§¶¶on behalf of the 304 Study Team*Thomas Jefferson UniversityPhiladelphia, Pennsylvania, U.S.A†Vanderbilt University Medical CenterNashville, Tennessee, U.S.A‡Texas Epilepsy GroupDallas, Texas, U.S.A§Midwest Center for Seizure Disorders, Minneapolis Clinic of NeurologyGolden Valley, Minnesota, U.S.A¶C.H.U. de RennesRennes, France#I.R.C.C.S., C. Mondino National Neurological InstitutePavia, Italy**Curitiba Neurological InstituteCuritiba, Brazil††Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of MedicineSeoul, South Korea‡‡Sunovion Pharmaceuticals Inc.Marlborough, Massachusetts, U.S.A§§BIAL-Portela & Ca S.A.S. Mamede do Coronado, Portugal¶¶MedInUP – Center for Drug Discovery and Innovative Medicines, University of PortoPorto, Portugal\nAddress correspondence to Michael Sperling, Thomas Jefferson University, Philadelphia, PA, U.S.A. E-mail: michael.sperling@jefferson.edu220152212201456224425312112014© 2014 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.2014This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.ObjectiveTo evaluate the efficacy and safety of adjunctive eslicarbazepine acetate (ESL) in patients with refractory partial-onset seizures.MethodsThis randomized, placebo-controlled, double-blind, parallel-group, phase III study was conducted at 173 centers in 19 countries, including the United States and Canada. Eligible patients were aged ≥16\xa0years and had uncontrolled partial-onset seizures despite treatment with 1–2 antiepileptic drugs (AEDs). After an 8-week baseline period, patients were randomized to once-daily placebo (n\xa0=\xa0226), ESL 800\xa0mg (n\xa0=\xa0216), or ESL 1,200\xa0mg (n\xa0=\xa0211). Following a 2-week titration period, patients received ESL 800 or 1,200\xa0mg once-daily for 12\xa0weeks. Seizure data were captured and documented using event-entry or daily entry diaries.ResultsStandardized seizure frequency (SSF) during the maintenance period (primary end point) was reduced with ESL 1,200\xa0mg (p\xa0=\xa00.004), and there was a trend toward improvement with ESL 800\xa0mg (p\xa0=\xa00.06), compared with placebo. When data for titration and maintenance periods were combined, ESL 800\xa0mg (p\xa0=\xa00.001) and 1,200\xa0mg (p\xa0<\xa00.001) both reduced SSF. There were no statistically significant interactions between treatment response and geographical region (p\xa0=\xa00.38) or diary version (p\xa0=\xa00.76). Responder rate (≥50% reduction in SSF) was significantly higher with ESL 1,200\xa0mg (42.6%, p\xa0<\xa00.001) but not ESL 800\xa0mg (30.5%, p\xa0=\xa00.07) than placebo (23.1%). Incidence of treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation increased with ESL dose. The most common TEAEs were dizziness, somnolence, nausea, headache, and diplopia.SignificanceAdjunctive ESL 1,200\xa0mg once-daily was more efficacious than placebo in adult patients with refractory partial-onset seizures. The once-daily 800\xa0mg dose showed a marginal effect on SSF, but did not reach statistical significance. Both doses were well tolerated. Efficacy assessment was not affected by diary format used.Adjunctive therapyAntiepileptic drugsEslicarbazepine acetateNorth AmericaPartial-onset seizuresRefractory epilepsyEslicarbazepine acetate (ESL) is a new molecular entity belonging to the dibenzazepine carboxamide chemical class of antiepileptic drugs. ESL, carbamazepine (CBZ), and oxcarbazepine (OXC) all contain a dibenzazepine nucleus bearing a 5-carboxamide substitute, but ESL is structurally different at the 10,11 position.1,2 This molecular variation results in differences in metabolism and pharmacology. Following oral administration, ESL is rapidly and extensively converted to the major active metabolite, (S)-licarbazepine (eslicarbazepine) via hydrolytic first-pass metabolism;2,3 consequently, ESL is undetectable in plasma as early as 15\xa0min postdose.4 Approximately 95% of oral ESL exposure is accounted for by eslicarbazepine, and <1% by OXC.5 In contrast, the major metabolite of OXC is the monohydroxy derivative (MHD: a racemic mixture of 4:1 eslicarbazepine to (R)-licarbazepine);6 3% of OXC exposure is accounted for by residual oxcarbazepine.5 In contrast to CBZ, ESL is not metabolized to potentially toxic epoxide metabolites,3 and is not susceptible to metabolic autoinduction.7,8Eslicarbazepine is believed to act by stabilizing the inactivated state of voltage-gated sodium channels (VGSCs), and shows higher selectivity for the inactivated state of the channel versus the resting state3 (Ki[resting]/Ki[inactivated]\xa0=\xa060) than CBZ (Ki[r]/Ki[i]\xa0=\xa019), OXC (Ki[r]/Ki[i]\xa0=\xa044), and the enantiomer (R)-licarbazepine (Ki[r]/Ki[i]\xa0=\xa028).9 The greater selectivity of eslicarbazepine for the inactivated state of VGSCs is thought to confer a greater inhibitory effect on rapidly firing (or “epileptic”) neurons compared with neurons in the resting state.10Previous double-blind placebo-controlled studies demonstrated that ESL (800 or 1,200\xa0mg once-daily [QD]) is well-tolerated as adjunctive therapy and is significantly more effective than placebo in patients with partial-onset seizures refractory to treatment with between one and three concomitant antiepileptic drugs (AEDs).11,12 In these studies, ESL significantly reduced standardized seizure frequency (per 4\xa0weeks) during a maintenance period of 12\xa0weeks, and increased the rate of response (defined as the proportion of patients with ≥50% reduction in seizure frequency) compared with placebo.This article reports primary efficacy and safety data from an additional double-blind placebo-controlled trial (the trial is registered at ClinicalTrials.gov, number NCT00988429) that was undertaken to evaluate further the efficacy, safety, and tolerability of ESL as adjunctive therapy in patients aged ≥16 with refractory partial-onset (focal) seizures receiving one or two AEDs. The impact of an alternative seizure diary format on evaluation of ESL efficacy was also assessed. Previous trials of ESL made use of event-entry (EE) diaries (in which patients provide entries only when seizures occur); however, when using EE diaries, it is not possible to determine whether days with no entry reflect a true absence of seizures, or failure of the patient to make a diary entry. To address this issue, the current trial mainly used daily entry (DE) diaries, in which patients were instructed to document seizure data every day, irrespective of whether a seizure had occurred. To our knowledge, this is the first clinical trial to report efficacy data of an AED in patients with partial-onset seizures using either EE or DE diaries.MethodsStudy designThis randomized, placebo-controlled, double-blind, parallel-group study was conducted at 173 centers in 19 countries (Argentina, Australia, Brazil, Belgium, Canada, Cyprus, France, Germany, Greece, Hungary, India, Italy, Poland, Turkey, South Korea, Romania, South Africa, Ukraine, and the United States) between December 2008 and January 2012.Patients aged ≥16\xa0years were eligible for screening if they satisfied all of the following criteria: in general good health except for a documented diagnosis of epilepsy for a minimum of 12\xa0months; had ≥4 simple or complex partial-onset seizures (with or without secondary generalization) within the 4-week period prior to screening; treated with a stable dose of one to two AEDs (except OXC) for ≥1\xa0month prior to screening (vagus nerve stimulation therapy was not considered to be an AED and was permitted, as was vigabatrin, if the patients were stable and safety was monitored). Eligibility criteria for randomization included the following: ≥8 partial-onset seizures that were documented in a diary during the baseline period (with ≥3 seizures during each 4-week period and no seizure-free interval exceeding 28 consecutive days) and satisfactorily completed diaries.Criteria for exclusion included the following: simple partial seizures with no motor symptoms; primarily generalized seizures; known progressive neurologic disorder; status epilepticus or cluster seizures within 3\xa0months before screening, or seizures of nonepileptic or psychogenic origin within 2\xa0years; history of schizophrenia or suicide attempts; current treatment with OXC (Patients taking OXC were excluded from study participation to avoid the possibility of excessive exposure to eslicarbazepine.), or using benzodiazepines >2 times per week (except when used chronically as an AED); hypersensitivity to CBZ or CBZ derivatives; second- or third-degree atrioventricular blockade not corrected with a pacemaker; relevant clinical laboratory abnormalities; a positive major histocompatibility complex, class I, B*1502 test (for patients of Asian ancestry); at randomization, inadequate compliance to the study protocol during the baseline period.Following screening, patients entered an observational 8-week baseline period, during which they were instructed on how to complete their seizure diaries. Patients with at least eight seizures during the baseline period then entered a double-blind phase that comprised a 2-week titration period, a 12-week maintenance period, and a 2-week tapering-off period. At the start of the titration period, eligible patients were randomized in a 1:1:1 ratio to receive placebo, ESL 800\xa0mg, or ESL 1,200\xa0mg (all QD). Randomization and allocation to treatment group was performed using an interactive voice-response system. The randomization code was prepared by a third party using a computer-generated schedule, and followed a permuted-block design (block size\xa0=\xa08). Each patient was assigned a unique screening number that was used for identification purposes throughout the study. Investigators were provided with a sealed envelope for each patient containing the patient's unique randomization number but were blinded to study treatment. Treatment codes remained blinded throughout the study. During the titration period, patients in the ESL 800\xa0mg group started treatment at 400\xa0mg QD, and those in the ESL 1,200\xa0mg group started at 800\xa0mg QD (in each group, the dose was increased by 400\xa0mg at the end of the first week). Patients who completed the maintenance phase could enter a 1-year open-label extension study.When the study was first initiated, EE diaries were used to record seizures; patients (with or without assistance) recorded each seizure by date, type, and time of occurrence during the baseline and double-blind treatment phases. Following a protocol amendment, EE diaries were replaced with DE diaries. Patients who were already enrolled prior to the protocol amendment continued to use EE diaries for the duration of the study. Both types of diary were provided in printed form. Of the intent-to-treat (ITT) population, approximately 29% and 71% of patients used EE and DE diaries, respectively. EE and DE subgroups were well matched in terms of demographics and baseline clinical characteristics, although the proportion of patients using vagus nerve stimulation at baseline (8% vs. 0.3%) and the proportion of Asian patients (27% vs. 1.6%) were greater for the DE than for the EE group.Seizure types were classified according to the International League Against Epilepsy (ILAE) Revised Clinical and Electroencephalographic Classification of Epileptic Seizures (1981) into simple partial seizures, complex partial seizures, partial seizures evolving to secondarily generalized seizures, and unclassified.13 In addition, investigators could indicate “other” if the seizure type was unknown or not otherwise captured.AssessmentsEfficacyThe primary efficacy variable was seizure frequency, standardized per 4\xa0weeks (standardized seizure frequency). The primary assessment of efficacy was based on the least squares (LS) mean–adjusted seizure frequency during the maintenance period. For the primary end point, all patients with diaries (of either type) were considered. Secondary efficacy variables included the following: seizure frequency during the 2-week titration period and the maintenance period combined; proportion of responders (patients with ≥50% reduction in seizure frequency vs. baseline); reduction in seizure frequency from baseline; proportion of patients with exacerbations in seizure frequency ≥25% versus baseline; reduction in seizure frequency according to seizure type; proportion of seizure-free patients during the maintenance period; change in Clinical Global Impression (CGI) score from baseline;14 and change in Quality of Life in Epilepsy Inventory-31 (QOLIE-31) total score from baseline.15 CGI scores (global improvement [CGI-I], severity of illness [CGI-S], and therapeutic effect [CGI-efficacy]) and QOLIE-31 ratings were evaluated at randomization and the end of the maintenance period.Safety and tolerabilityAdverse events (AEs) were reported at each clinic visit (irrespective of whether they were considered to be related to the study drug) and coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 13.1. Treatment-emergent AEs (TEAEs) were defined as AEs that occurred on or after the first dose of study drug. Other safety assessments included the following: clinical laboratory tests; vital signs; 12-lead electrocardiography measurements; and Columbia Suicide Severity Rating Scale (C-SSRS) scores.Statistical analysesDetermination of sample sizeFor the primary efficacy analysis, the required sample size was calculated such that a treatment difference of 0.174 (standard deviation [SD]\xa0=\xa00.4) in the primary efficacy variable could be detected with 90% power (using DE diaries). Using Bonferroni adjustment for two comparisons of the two doses of active drug with placebo (α\xa0=\xa00.025 for each), 130\xa0patients would be required per group to achieve 89.4% power. Assuming a drop-out rate of 10% based on previous phase III studies,11,12 435 patients using DE diaries (145\xa0patients per group) were required. Therefore, a total enrollment of 615 patients was required (435 using DE diaries and 185 using EE diaries [the latter group was enrolled prior to the protocol amendment]).DefinitionsThe primary efficacy analysis was based on the ITT population (all randomized patients who received at least one dose of the study drug and had at least one post-baseline seizure frequency assessment). The ITT population included patients who used either EE or DE diaries. In addition, the EE and DE diary ITT populations were analyzed separately. Supportive analyses were performed in the per-protocol (PP) population (patients in the ITT population with no major protocol deviations/violations) and the DE diary ITT population. The safety population consisted of all randomized patients who received at least one dose of study drug.AnalysisFor the primary efficacy variable, the natural logarithm of seizure frequency was compared between groups using an analysis of covariance (ANCOVA), which models seizure frequency as a function of baseline seizure frequency and treatment (with diary type as an additional covariate). Estimates from the ANCOVA model were back-transformed using the exponential function. A two-stage gate-keeping multiple-testing procedure16 was used for comparisons between ESL treatment LS means and placebo LS means for the ITT and DE diary ITT populations in the primary analysis. p-values were subject to Bonferroni adjustment in the first stage; Dunnett's multiple comparison procedure was used in the second stage (p-values from other analyses were not corrected for multiplicity). The proportion of responders, the proportion of patients with exacerbations in seizure frequency ≥25%, and the proportion of patients who were seizure-free were analyzed using a Cochran-Mantel-Haenszel test. The group comparisons in the reduction in seizure frequency and the change in CGI score were analyzed by ANCOVA.This study (BIA 2-093-304) was approved by the appropriate institutional review boards, and was conducted in accordance with international and local regulations of the countries involved. Informed consent was obtained from each patient.ResultsPatientsThe number of patients randomized and their disposition (for the safety, ITT, and PP populations) are summarized in Figure S1. The placebo and active-treatment groups were well balanced in terms of demographics and baseline characteristics (Table1).Table 1Demographic and baseline characteristics (safety population)CharacteristicPlacebo (n\xa0=\xa0224)ESL 800\xa0mg (n\xa0=\xa0216)ESL 1,200\xa0mg (n\xa0=\xa0210)Age, years (median [range])39.0 (16–67)a38.5 (16–71)38.0 (16–69)Male, n (%)112 (50.0)109 (50.5)105 (50.0)Ethnicity, n (%)\u2003Caucasian142 (63.4)137 (63.4)134 (63.8)\u2003Black8 (3.6)8 (3.7)8 (3.8)\u2003Asian46 (20.5)41 (19.0)39 (18.6)\u2003Other28 (12.5)30 (13.9)29 (13.8)BMI, kg/m2b\u2003Mean\xa0±\xa0SD25.7\xa0±\xa05.826.3\xa0±\xa05.626.5\xa0±\xa07.0\u2003Median (range)24.8 (16.2–46.5)25.7 (16.0–55.2)25.4 (15.5–71.4)Duration of epilepsy (years)c\u2003Mean\xa0±\xa0SD21.3\xa0±\xa014.621.6\xa0±\xa013.021.2\xa0±\xa013.0\u2003Median (range)18.3 (1.1–63.4)19.6 (1.4–53.9)18.3 (1.1–57.3)Seizure frequency in the 4\xa0weeks prior to screeningd\u2003Mean\xa0±\xa0SD18.1\xa0±\xa028.718.0\xa0±\xa035.917.6\xa0±\xa030.2\u2003Median (range)8 (4–282)8 (1–420)9 (4–351)Seizure type in the 4\xa0weeks prior to screening,d,e n (%)f\u2003Simple partialg81 (36.8)84 (39.3)66 (32.2)\u2003Complex partialh175 (79.5)170 (79.4)170 (82.9)\u2003Partial evolving to secondarily generalizedi57 (25.9)59 (27.6)63 (30.7)\u2003Unclassifiable2 (0.9)03 (1.5)\u2003Other2 (0.9)1 (0.5)0\u2003Missing010Median (range) SSF during the baseline periodd,j9.0 (2.4–131.8)8.6 (2.0–412.3)8.9 (3.7–163.5)Number of AEDs used during the baseline period,k n (%)\u2003164 (28.6)60 (27.8)59 (28.1)\u20032158 (70.5)153 (70.8)151 (71.9)\u2003≥31 (0.4)00AEDs during baseline used by >15% of patients,l n (%)\u2003Carbamazepine77 (34.4)84 (38.9)89 (42.4)\u2003Levetiracetam66 (29.5)58 (26.9)43 (20.5)\u2003Lamotrigine57 (25.4)51 (23.6)57 (27.1)\u2003Valproic acid42 (18.8)46 (21.3)41 (19.5)AED, antiepileptic drug; BMI, body mass index; ESL, eslicarbazepine acetate; ILAE, International League Against Epilepsy; SD, standard deviation; SSF, standardized seizure frequency.an\xa0=\xa0223.bn\xa0=\xa0222, 215, and 208 for placebo, ESL 800\xa0mg, and ESL 1,200\xa0mg, respectively.cn\xa0=\xa0215 for ESL 800\xa0mg.dIntention-to-treat population.ePatients may have had more than one type of seizure.fn\xa0=\xa0220, 214, and 205 for placebo, ESL 800\xa0mg, and ESL 1,200\xa0mg, respectively.gFocal seizures without impairment of consciousness or awareness.hDyscognitive seizures.iFocal seizures evolving to bilateral convulsive seizures (2010 ILAE classification).17jn\xa0=\xa0220, 215, and 204 for placebo, ESL 800\xa0mg, and ESL 1,200\xa0mg, respectively.kAn AED was considered to be used at baseline if started any time prior to first dose of study drug and continued to the titration period. AEDs used as rescue medication at baseline are not included.lAs specified by the study protocol, none of the patients took OXC during the baseline period.EfficacySeizure frequencyIn the ITT population (Table2), during the 12-week maintenance period seizure frequency was significantly lower in the ESL 1,200\xa0mg group (LS mean: 6.00) than the placebo group (LS mean: 7.88; log difference: −0.26; p\xa0=\xa00.004). Seizure frequency was also numerically lower in the ESL 800\xa0mg group (LS mean: 6.54) than the placebo group (p\xa0=\xa00.06). In the PP population, similar statistically significant effects were observed during the 12-week maintenance period with ESL 1,200\xa0mg (LS\xa0mean 5.78, log difference: −0.29, p\xa0=\xa00.001), but not ESL 800\xa0mg (LS mean: 6.83; log difference: −0.13; p\xa0=\xa00.12) versus placebo (LS mean: 7.85).Table 2Analysis of covariance of standardized seizure frequency during the 12-week maintenance period (ITT population)Study populationPlacebo (n\xa0=\xa0220)ESL 800\xa0mg (n\xa0=\xa0215)ESL 1,200\xa0mg (n\xa0=\xa0205)Overall ITT population\u2003n212200184\u2003LS mean (95% CI)7.88 (6.98–8.90)6.54 (5.77–7.40)6.00 (5.26–6.84)\u2003Log difference in LS mean versus placebo–−0.18−0.26\u2003Bonferroni's procedure-adjusted p-valuea–0.060.004ITT population (daily entry diaries)\u2003n154137136\u2003LS mean (95% CI)7.54 (6.55–8.68)6.32 (5.44–7.35)5.96 (5.12–6.94)\u2003Log difference in LS mean versus placebo–−0.17−0.22\u2003Dunnett's procedure-adjusted p-valueb–0.170.05ITT population (event-entry diaries)\u2003N586348\u2003LS mean (95% CI)7.91 (6.43–9.72)6.33 (5.17–7.72)5.41 (4.28–6.81)\u2003Log difference in LS mean versus placebo–−0.21−0.36\u2003p-valuec–0.130.02CI, confidence interval; ESL, eslicarbazepine acetate; ITT, intention to treat; LS, least squares.aBonferroni's procedure was used to calculate the p-values and the 95% CIs for log differences.bDunnett's procedure was used to calculate the p-values (assessed at p\xa0=\xa00.025 level) and 97.5% CIs for log differences.cUnadjusted p-value for pairwise comparison with placebo.When analyzed for the titration and maintenance periods combined, seizure frequency was significantly lower for both the ESL 1,200\xa0mg group (LS mean: 6.31; log difference: −0.31; p\xa0<\xa00.001) and the ESL 800\xa0mg group (LS mean: 6.60; log difference: −0.26; p\xa0=\xa00.001) than for the placebo group (LS mean: 8.68).A separate ANCOVA demonstrated that there was no significant interaction between treatment and diary version used (p\xa0=\xa00.76); nevertheless the primary end point was analyzed separately in the EE and DE populations. Both diary groups showed similar trends across treatment groups (Table2). Although the influence of geographic region on treatment response was also not statistically significant (p\xa0=\xa00.38), seizure frequency was nevertheless analyzed separately for patients enrolled in North America (n\xa0=\xa0229) and the rest of the world (n\xa0=\xa0411). In the North American subgroup there was no statistically significant difference in seizure frequency between the ESL 1,200\xa0mg group (LS mean: 6.57; log difference: −0.18; p\xa0=\xa00.18) or the ESL 800\xa0mg group (LS mean: 7.63; log difference: −0.03; p\xa0=\xa00.79) and placebo (LS mean: 7.90). In the rest of the world subgroup, seizure frequency was significantly lower in both the ESL 1,200\xa0mg group (LS mean: 5.59; log difference: −0.32, p\xa0=\xa00.003) and the ESL 800\xa0mg group (LS mean: 5.87; log difference: −0.27; p\xa0=\xa00.010) than the placebo group (LS mean: 7.80).Responder rateThe responder rate in the ITT population during the maintenance phase was significantly higher in the ESL 1,200\xa0mg group (42.6%; p\xa0<\xa00.001) but not the ESL 800\xa0mg group (30.5%; p\xa0=\xa00.07) compared with the placebo group (23.1%; Fig.1). In patients taking ESL 1,200\xa0mg, a significantly greater response rate than placebo was observed in both DE (43.0% vs. 26.0%; p\xa0=\xa00.002) and EE (41.7% vs. 15.5%; p\xa0=\xa00.002) diary groups.Figure 1Responder rate (proportion of patients with ≥50% reduction in seizure frequency during the maintenance period versus baseline; ITT population). CI, confidence interval; ESL, eslicarbazepine acetate. *ESL group versus placebo.Reduction in seizure frequencyOverall, the median percent reduction in seizure frequency was 21.8% in the placebo group, 29.7% in the ESL 800\xa0mg group, and 35.6% in the ESL 1,200\xa0mg group. The difference from placebo was significant for the 1,200\xa0mg group (p\xa0=\xa00.02) but not for the ESL 800\xa0mg group (p\xa0=\xa00.07). A similar pattern was observed for different seizure types: simple partial seizures were reduced by 26.5%, 36.6%, and 34.1%; complex partial seizures were reduced by 17.2%, 28.2%, and 34.1%; and partial seizures evolving to secondarily generalized seizures were reduced by 18.7%, 35.9%, and 37.0% (for placebo, ESL 800\xa0mg, and ESL 1,200\xa0mg, respectively). A ≥25% increase in seizure frequency occurred in 31 (14.6%), 26 (13.0%), and 24 (13.1%) patients (placebo, ESL 800\xa0mg, and ESL 1,200\xa0mg, respectively); differences between treatment groups were not statistically significant in the subgroup analyses.Seizure freedomSeizure freedom (during the maintenance period) was achieved by 0.9% of placebo-treated patients, and 2.0% and 2.2% of ESL 800- and 1,200\xa0mg-treated patients, respectively.CGI and QOLIE-31 scoresThe proportions of patients with improvements on the CGI-I and the CGI efficacy scales are shown in Table3, as are the changes in CGI-S and QOLIE-31 scores between baseline and the end of the maintenance period. There were somewhat greater reductions in CGI-S scores with ESL 800\xa0mg and ESL 1,200\xa0mg than with placebo, although the differences were not statistically significant. Overall, 35.3% of patients taking ESL were rated either “very much improved” or “much improved” on the CGI-I scale, versus 20.7% of those taking placebo. Similarly, 44.7% of patients overall who were taking ESL had a “marked” or “moderate” improvement according to the CGI efficacy index, versus 27.8% of those on placebo. Treatment with ESL 1,200\xa0mg and ESL 800\xa0mg led to an increase in total QOLIE-31 scores of approximately five points between baseline and the end of the maintenance period.Table 3CGI and QOLIE-31 scores (ITT population)Placebo (n\xa0=\xa0220)ESL 800\xa0mg (n\xa0=\xa0215)ESL 1,200\xa0mg (n\xa0=\xa0205)CGI-S (change from baseline)a,b\u2003LS mean (95% CI)−0.3 (−0.4, −0.1)−0.5 (−0.6, −0.3)−0.4 (−0.6, −0.3)\u2003Unadjusted p-value0.0540.13CGI-Ia,c\u2003Very much improved, % (n)4.2 (9)6.9 (14)6.1 (12)\u2003Much improved, % (n)16.5 (35)27.5 (56)30.1 (59)CGI efficacy index (therapeutic effect)a,d\u2003Marked improvement, % (n)4.4 (9)9.8 (19)10.5 (19)\u2003Moderate improvement, % (n)23.4 (48)32.6 (63)36.5 (66)QOLIE-31 total score (change from baseline)a\u2003Mean\xa0±\xa0SD2.16\xa0±\xa025.45.35\xa0±\xa023.84.64\xa0±\xa025.7CGI, Clinical Global Impressions; CGI-I, CGI-Improvement; CGI-S, CGI-Severity of illness; CI, confidence interval; ESL, eslicarbazepine acetate; LS, least squares; QOLIE-31, Quality of Life Epilepsy Inventory-31; SD, standard deviation.aBased on last assessment at the end of the maintenance period. Note that not all subjects had evaluable data; percentages are based on evaluable subjects.bn\xa0=\xa0213, 205, and 198 for placebo, ESL 800\xa0mg, and ESL 1,200\xa0mg, respectively.cn\xa0=\xa0212, 204, and 196 for placebo, ESL 800\xa0mg, and ESL 1,200\xa0mg, respectively.dn\xa0=\xa0205, 193, and 181 for placebo, ESL 800\xa0mg, and ESL 1,200\xa0mg, respectively.SafetyTEAEsThe incidence of TEAEs (Table4), TEAEs considered potentially related to treatment, and TEAEs leading to discontinuation increased with ESL dose. The majority of TEAEs were of mild or moderate severity, the most common being dizziness, somnolence, nausea, headache, and diplopia (Table4). The percentage of patients who had at least one severe TEAE was 6.7% for placebo, 11.1% for ESL 800\xa0mg, and 14.8% for ESL 1,200\xa0mg. TEAEs classed as severe and reported in ≥2% of patients were dizziness (1.3%, 1.9%, and 3.8%) and vertigo (0%, 0.5%, and 2.9%) for placebo, ESL 800\xa0mg, and ESL 1,200\xa0mg, respectively. TEAEs leading to discontinuation in ≥2% of patients taking ESL (either dose) were dizziness, nausea, vomiting, ataxia, dysarthria, and somnolence (Table4). TEAEs of special interest included depression (reported in 2.7%, 2.3%, and 2.4% of the placebo, ESL 800\xa0mg, and ESL 1,200\xa0mg groups, respectively) and rash (reported in 1.8%, 1.4%, and 2.4% of the placebo, ESL 800\xa0mg, and ESL 1,200\xa0mg groups, respectively).Table 4TEAEs affecting ≥5% of patients, TEAEs leading to discontinuation in ≥2% of patients, all serious TEAEs, and deaths (safety population)Number (%) of patientsPlacebo(n\xa0=\xa0224)ESL 800\xa0mg(n\xa0=\xa0216)ESL 1,200\xa0mg(n\xa0=\xa0210)Any TEAE125 (55.8)145 (67.1)163 (77.6)\u2003Dizziness19 (8.5)34 (15.7)55 (26.2)\u2003Somnolence12 (5.4)16 (7.4)36 (17.1)\u2003Nausea11 (4.9)16 (7.4)32 (15.2)\u2003Headache17 (7.6)20 (9.3)24 (11.4)\u2003Vomiting3 (1.3)6 (2.8)23 (11.0)\u2003Diplopia4 (1.8)14 (6.5)22 (10.5)\u2003Vertigo1 (0.4)6 (2.8)15 (7.1)\u2003Fatigue6 (2.7)8 (3.7)11 (5.2)Potentially related TEAE83 (37.1)111 (51.4)140 (66.7)TEAEs leading to discontinuation18 (8)26 (12.0)54 (25.7)\u2003Dizziness1 (0.4)11 (5.1)19 (9.0)\u2003Nausea03 (1.4)13 (6.2)\u2003Vomiting008 (3.8)\u2003Ataxia01 (0.5)8 (3.8)\u2003Dysarthria005 (2.4)\u2003Somnolence2 (0.9)2 (0.9)5 (2.4)Serious TEAEs7 (3.1)14 (6.5)3 (1.4)Deathsa1 (0.4)1 (0.5)0ESL, eslicarbazepine acetate; TEAE, treatment-emergent adverse event.aData are based on the double-blind, placebo-controlled period.DeathsOne death occurred during the baseline period of a patient who had not received the study drug. Two deaths occurred during the double-blind period: a 29-year-old Caucasian woman randomized to placebo died of acute respiratory failure after being diagnosed with pneumonia; and a 27-year-old Caucasian man randomized to ESL 800\xa0mg was found dead in bed with a bitten tongue (during the titration phase, while receiving 400\xa0mg ESL). The cause of death according to the autopsy report was status epilepticus.Serious adverse eventsThere were no notable differences in the types of serious TEAEs between treatment groups, and no dose-related trends (the incidence of serious TEAEs was 3.1% for placebo, 6.5% for ESL 800\xa0mg, and 1.4% for ESL 1,200\xa0mg). One patient with a history of suicidal tendencies had a suicide attempt but, as she had responded to the study drug, she was allowed to continue on ESL 800\xa0mg; no other psychiatric symptoms were reported. One serious cutaneous event (leukocytoclastic vasculitis) leading to discontinuation of treatment was reported in a patient taking ESL 800\xa0mg.Clinical laboratory assessmentsOverall, changes in clinical laboratory parameters (other than serum sodium) were not substantially different between the three groups. Data for reductions in serum sodium concentrations are shown in Table5. Overall, 5.1% of patients taking ESL had a reduction in serum sodium of >10\xa0mEq/L, compared with 0.9% of those taking placebo, whereas hyponatremia (serum sodium <125\xa0mEq/L) occurred in 1.5% and 0% of patients, respectively. Between baseline and week 8 of treatment (week 6 of the maintenance period), there were greater reductions in mean serum sodium with ESL 800\xa0mg (−1.6\xa0mEq/L) and ESL 1,200\xa0mg (−2.2\xa0mEq/L) than with placebo (0.1\xa0mEq/L); the reductions tended to stabilize after approximately 2\xa0months of treatment. Hyponatremia was reported as an adverse event (AE) leading to discontinuation in three patients taking ESL 1,200\xa0mg (1.4%), but no patients taking placebo or ESL 800\xa0mg. Vital signs, body weight, and electrocardiography parameters were not substantially different across visits for the placebo and ESL groups. ESL 800 and 1,200\xa0mg had no notable effect on C-SSRS scores.Table 5Serum sodium levels (safety population)No. (%) of patientsa,bPlacebo (n\xa0=\xa0224)ESL 800\xa0mg (n\xa0=\xa0216)ESL 1,200\xa0mg (n\xa0=\xa0210)Total ESL (n\xa0=\xa0426)Serum sodium <125\xa0mEq/L01 (0.5)5 (2.5)6 (1.5)Reduction from baseline in serum sodium of >10\xa0mEq/L2 (0.9)9 (4.3)12 (5.9)21 (5.1)ESL, eslicarbazepine acetate; mEq/L, milliequivalent/liter.aData are for patients in the safety population with at least one post-baseline sodium assessment. Note that not all subjects had evaluable data; percentages are based on evaluable subjects.bn\xa0=\xa0220, 209, 204, and 413 for placebo, ESL 800\xa0mg and ESL 1,200\xa0mg, and Total ESL, respectively.DiscussionESL was developed to enhance the yield of the pharmacologically desirable metabolite eslicarbazepine, while reducing exposure to the less pharmacologically desirable metabolites (R)-licarbazepine and OXC.The present study confirms and extends the findings of efficacy and safety of ESL as adjunctive treatment of partial-onset seizures as reported in two prior randomized placebo-controlled trials.11,12 Once-daily ESL was effective as adjunctive therapy and was generally well tolerated in patients with refractory partial-onset (focal) seizures. During the 12-week maintenance period, seizure frequency was significantly reduced in the ESL 1,200\xa0mg group compared with placebo (p\xa0=\xa00.004), and there was a trend toward improvement in the ESL 800\xa0mg group compared with placebo (p\xa0=\xa00.06). No statistically significant interactions between ESL treatment and geographical region or ESL treatment and diary version (DE or EE) were detected. For the majority of secondary efficacy end points, including response rate and reduction in seizure frequency, there were statistically significant differences between ESL 1,200\xa0mg and placebo, and similar trends occurred with ESL 800\xa0mg. We noted relatively high 50% responder rates in placebo-treated patients, approximating rates reported in other studies of similar design (e.g., perampanel, 19.3%;18 lacosamide, 23.0%;19 and OXC, 28.1%20). This poses a challenge in interpreting the magnitude of effect of new AEDs. Nonetheless, substantially more patients taking ESL were rated at least “much improved” on the CGI-I scale, or had at least “moderate improvement” according to the CGI efficacy scale compared with placebo-treated patients. Patients taking ESL had improvements in QOLIE-31 scores of approximately five points (i.e., comparable to the minimal clinically important improvement described by Borghs et\xa0al.),21 indicating that treatment with ESL led to clinically meaningful improvements in quality of life.In this study, seizure frequency was the primary efficacy end point. Similar clinical trials22,23 previously used either the median percentage change in seizure frequency from baseline, or the responder rate as the primary outcome measure. These measures are susceptible to bias when the distribution of seizure frequencies is not normally distributed. In such circumstances, the log-transformed seizure frequency is a more robust measure, as discussed in an analysis by Siddiqui and Hershkowitz.24The current safety and tolerability findings are consistent with those reported previously for ESL.11,12 The most commonly reported TEAEs were dizziness, somnolence, nausea, headache, vomiting, diplopia, vertigo, and fatigue. Rash was reported in 1.4% and 2.4% of patients, and hyponatremia in 0% and 1.5% of patients (taking ESL 800 and 1,200\xa0mg, respectively). Too few cases occurred to draw conclusions regarding dose and incidence of symptomatic hyponatremia. In previous studies of OXC, rash was reported in 6% of patients25 and hyponatremia in 3.8% of adult patients.26 The incidence of TEAEs and TEAEs leading to discontinuations was higher in the ESL 1,200\xa0mg group than the ESL 800\xa0mg group. However, somewhat more patients in the 1,200\xa0mg group than the 800\xa0mg group were taking other concomitant AEDs with the same mode of action as ESL (sodium channel blockers, i.e., CBZ, lamotrigine). It has been reported that combining sodium channel blockers may lead to increased toxicity.27As in previous ESL trials, these findings indicate that ESL is effective as adjunctive therapy in patients with a long history of partial seizures and poor seizure control, who are taking one or two concomitant AEDs. ESL demonstrated efficacy in patients who previously had continued to have frequent seizures, despite treatment with AEDs including CBZ, levetiracetam, lamotrigine and valproic acid. The current trial is generally consistent with previous trials11,12 in which once-daily ESL (800 and/or 1,200\xa0mg) was efficacious and well-tolerated in patients with refractory partial-onset seizures. In the current trial, the ESL 800\xa0mg dose did not reach statistical significance. It is not clear why this occurred, however, the trends toward improvements were consistent with results in previous studies. Too few patients (n\xa0=\xa036) in the entire ESL development program were taking three concomitant AEDs to assess efficacy as a function of number of AEDs.One important methodologic difference between this trial and previous studies was the use of DE diaries to ensure that seizure data were recorded on every day of the trial, regardless of whether seizures had occurred. Reliability of seizure recording is a key issue in epilepsy trials,28 but to date no formal comparisons of seizure diaries of different designs are available. In the present study, the interaction between the effect of treatment and diary version was not significant (p\xa0=\xa00.76). The results obtained with DE diaries were consistent with those obtained with EE diaries. Selection of diary type was based on time of enrollment, rather than by randomization, which represents a limitation in the method.ConclusionsIn this phase III study, daily dosing with adjunctive ESL was effective in reducing seizures in patients with refractory partial-onset (focal) seizures, and was generally well tolerated. The effect of ESL 1,200\xa0mg on seizure frequency was significantly greater than that of placebo; whereas ESL 800\xa0mg also reduced seizure frequency, the difference versus placebo was not statistically significant. The DE and EE diary methods produced similar results with regard to seizure outcomes; this is the first clinical trial providing efficacy data in patients with partial-onset seizures who used two different diary designs. ESL is a useful addition to current AED pharmacotherapy for the treatment of refractory partial-onset (focal) seizures, on the basis of clinical activity, convenient once-daily dosing, and good tolerability.The authors would like to acknowledge the writing assistance of Tracey Baskerville of FireKite, part of the Knowledge Point 360 Group, an Ashfield company, for support in drafting this manuscript. Medical writing support was funded by Sunovion Pharmaceuticals Inc.Dr. Michael R. Sperling, is Baldwin Keyes Professor of Neurology at Thomas Jefferson University.Disclosure of Conflict of InterestMichael Sperling has received consultancy honoraria from UCB Pharma, ElectroCore, and Accorda Therapeutics and honoraria from Wiley Blackwell for serving as an associate editor for Epilepsia, and has received grants from National Institute of Neurological Disorders and Stroke (NINDS), UCB Pharma, Sunovion Pharmaceuticals Inc., Eisai, SK Life Science, Upsher-Smith, Medtronics, Lundbeck, Visualase, and Brain Sentinel. Bassel Abou-Khalil has received research grants paid to Vanderbilt University Medical Center from Sunovion Pharmaceuticals Inc., UCB Pharma, Pfizer, GlaxoSmithKline, Upsher-Smith, and SK Life Science. Jay Harvey has received financial support for research from Sunovion Pharmaceuticals Inc., UCB Pharma, Upsher-Smith, Marinus, SK Life Science, Cyberonics, Brain Sentinel, and Eisai, and speaker fees from Sunovion Pharmaceuticals Inc. and UCB Pharma. Joanne Rogin has received financial support for research from GlaxoSmithKline, Eisai, Pfizer, UCB Pharma, Sunovion Pharmaceuticals Inc., and Marinus; speaker's fees from GlaxoSmithKline, Pfizer, UCB Pharma, and Supernus; and consultancy honoraria from Pfizer and Sunovion Pharmaceuticals Inc. Arnaud Biraben serves as a member on a corporate scientific board and receives honoraria from GlaxoSmithKline, Eisai, and UCB Pharma. Carlo A. Galimberti received a grant from the Italian Ministry of Health, financial support for research from UCB Pharma, Eisai, and Bial-Portela & Ca S.A.; and speaker's fees from GlaxoSmithKline and UCB Pharma. Pedro A. Kowacs has received consultancy honoraria from Abbott, GlaxoSmithKline, and Cyberonics and financial support for research from Bial-Portela & Ca S.A. Seung Bong Hong has no potential conflicts of interest to disclose. Hailong Cheng and David Blum are paid employees of Sunovion Pharmaceuticals Inc. Teresa Nunes and Patrício Soares-da-Silva are paid employees of Bial-Portela & Ca S.A. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.ReferencesBenesJParadaAFigueiredoAAAnticonvulsant and sodium channel-blocking properties of novel 10,11-dihydro-5H-dibenz[b, f]azepine-5-carboxamide derivativesJ Med Chem1999422582258710411478AlmeidaLPotgieterJHMaiaJPharmacokinetics of eslicarbazepine acetate in patients with moderate hepatic impairmentEur J Clin Pharmacol20086426727318157705HebeisenSBradyKKonradDInhibitory effects of eslicarbazepine acetate and its metabolites against neuronal voltage-gated sodium channelsEpilepsia201152257258AlmeidaLSoares-da-SilvaPSafety, tolerability and pharmacokinetic profile of BIA 2-093, a novel putative antiepileptic agent, during first administration to humansDrugs R D2003426928412952496NunesTRochaJFFalcaoASteady-state plasma and cerebrospinal fluid pharmacokinetics and tolerability of eslicarbazepine acetate and oxcarbazepine in healthy volunteersEpilepsia20135410811622812691StahlSMStahl's essential psychopharmacology – the prescriber's guide2011New YorkCambridge University PressBialerMSoares-da-SilvaPPharmacokinetics and drug interactions of eslicarbazepine acetateEpilepsia20125393594622612290AlmeidaLBialerMSoares-da-SilvaPShorvonSPeruccaEEngelJEslicarbazepine acetateThe treatment of epilepsy20093rd EdOxfordBlackwell Publishing485498Marlborough, MASunovion Pharmaceuticals IncData on fileRagsdaleDSScheuerTCatterallWAFrequency and voltage-dependent inhibition of type IIA Na+ channels, expressed in a mammalian cell line, by local anaesthetic, antiarrhythmic, and anticonvulsant drugsMol Pharmacol1991407567651658608ElgerCHalaszPMaiaJEfficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures: a randomized, double-blind, placebo-controlled, parallel-group Phase III studyEpilepsia20095045446319243424Ben-MenachemEGabbaiAAHufnagelAEslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsyEpilepsy Res20108927828520299189Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the Commission on Classification and Terminology of the International League Against EpilepsyEpilepsia1981224895016790275National Institute of Mental HealthGuyWBonatoRRCGI: clinical global impressionManual for the ECDEU assessment battery19702nd Revised EdChevy Chase, MDNational Institute of Mental Health12-112-6CramerJAPerrineKDevinskyODevelopment and cross-cultural translation of a 31-item quality of life questionnaire (QOLIE-31)Epilepsia19983981889578017DmitrienkoATamhaneACWiensBLGeneral multistage gatekeeping proceduresBiom J20085066767718932130BergATBerkovicSFBrodieMJRevised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009Epilepsia20105167668520196795Perampanel (FYCOMPA)2013US prescribing information. Eisai Inc. Available at: http://www.fycompa.com/sites/all/themes/fycompa/pdf/Fycompa_Prescribing_Information.pdf. Accessed June 23, 2014Lacosamide (VIMPA)2013EPAR – summary for the public. European medicines Agency 710648, 2012. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000863/WC500050339.pdf. Accessed June 23, 2014Oxcarbazepine (Oxtellar®)2012FDA medical review. Available at: http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM328320.pdf. Accessed 23 June, 2014BorghsSde la LogeCCramerJADefining minimally important change in QOLIE-31 scores: estimates from three placebo-controlled lacosamide trials in patients with partial-onset seizuresEpilepsy Behav20122323023422341962BrodieMJLercheHGil-NagelAEfficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsyNeurology2010751817182420944074FrenchJAKraussGLSteinhoffBJEvaluation of adjunctive perampanel in patients with refractory partial-onset seizures: results of randomized global Phase III study 305Epilepsia20135411712522905857SiddiquiOHershkowitzNPrimary efficacy endpoint in clinical trials of antiepileptic drugs: change or percentage changeDrug Inf J201044343350MarsonAGAl-KharusiAMAlwaidhMThe SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trialLancet20073691000101517382827SachdeoRWassersteinAMesenbrinkPOxcarbazepine (Trileptal): effect on serum sodiumEpilepsia199940Suppl. 72.074 AbstractPeruccaEClinically relevant drug interactions with antiepileptic drugsBr J Clin Pharmacol20066124625516487217FisherRSBlumDEDiVenturaBSeizure diaries for clinical research and practice: limitations and future prospectsEpilepsy Behav20122430431022652423Supporting InformationFigure S1. Patient disposition.Appendix S1. The 304 study team.", 'title': 'Eslicarbazepine acetate as adjunctive therapy in patients with uncontrolled partial-onset seizures: Results of a phase III, double-blind, randomized, placebo-controlled trial.', 'date': '2014-12-23'}}
| 0.2
|
Psychiatry & Neurology
|
54
|
Is the overall cervical dystonia improvement higher, lower, or the same when comparing botulinum toxin type A (BtA) to botulinum toxin type B (BtB)?
|
higher
|
low
|
no
|
['16275831', '18098274']
| 27,782,297
| 2,016
|
{'16275831': {'article_id': '16275831', 'content': 'To directly compare two serotypes of botulinum toxin (BoNTA and BoNTB) in cervical dystonia (CD) using a randomized, double-blind, parallel-arm study design.\nSubjects with CD who had a previous response from BoNTA were randomly assigned to BoNTA or BoNTB and evaluated in a blinded fashion at baseline, 4 weeks, 8 weeks, and 2-week intervals thereafter until loss of 80% of clinical effect or completion of 20 weeks of observation. CD severity was measured with the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), and adverse events were assessed by structured interview. Statistical analysis included Wilcoxon rank sum test, log rank tests, and Kaplan-Meier survival curves for duration of effect.\nA total of 139 subjects (BoNTA, n = 74; BoNTB, n = 65) were randomized at 19 study sites. Improvement in TWSTRS score was found at 4 weeks after injection and did not differ between serotypes. Dysphagia and dry mouth were more frequent with BoNTB (dysphagia: BoNTA 19% vs BoNTB 48%, p = 0.0005; dry mouth (BoNTA 41% vs BoNTB 80%, p < 0.0001). In clinical responders, BoNT A had a modestly longer duration of benefit (BoNTA 14 weeks, BoNTB 12.1 weeks, p = 0.033).\nBoth serotypes of botulinum toxin (BoNTA and BoNTB) had equivalent benefit in subjects with cervical dystonia at 4 weeks. BoNTA had fewer adverse events and a marginally longer duration of effect in subjects showing a clinical response.', 'title': 'Comparison of botulinum toxin serotypes A and B for the treatment of cervical dystonia.', 'date': '2005-11-09'}, '18098274': {'article_id': '18098274', 'content': 'The objective of this study was to compare efficacy, safety, and duration of botulinum toxin type A (BoNT-A) and type B (BoNT-B) in toxin-naïve cervical dystonia (CD) subjects. BoNT-naïve CD subjects were randomized to BoNT-A or BoNT-B and evaluated in a double-blind trial at baseline and every 4-weeks following one treatment. The primary measure was the change in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) from baseline to week 4 post-injection. Secondary measures included change in TWSTRS-subscale scores, pain, global impressions, and duration of response and safety assessments. The study was designed as a noninferiority trial of BoNT-B to BoNT-A. 111 subjects were randomized (55 BoNT-A; 56 BoNT-B). Improvement in TWSTRS-total scores 4 weeks after BoNT-B was noninferior to BoNT-A (adjusted means 11.0 (SE 1.2) and 8.8 (SE 1.2), respectively; per-protocol-population (PPP)). The median duration of effect of BoNT-A and BoNT-B was not different (13.1 vs. 13.7 weeks, respectively; P-value = 0.833; PPP). There were no significant differences in the occurrence of injection site pain and dysphagia. Mild dry mouth was more frequent with BoNT-B but there were no differences for moderate/severe dry mouth. In this study, both BoNT-A and B were shown to be effective and safe for the treatment of toxin-naive CD subjects.', 'title': 'Botulinum toxin type B vs. type A in toxin-naïve patients with cervical dystonia: Randomized, double-blind, noninferiority trial.', 'date': '2007-12-22'}}
| 0
|
Psychiatry & Neurology
|
55
|
Is the rate of dysphagia higher, lower, or the same when comparing botulinum toxin type A (BtA) to botulinum toxin type B (BtB)?
|
no difference
|
low
|
no
|
['16275831', '18098274', '16157918']
| 27,782,297
| 2,016
|
{'16275831': {'article_id': '16275831', 'content': 'To directly compare two serotypes of botulinum toxin (BoNTA and BoNTB) in cervical dystonia (CD) using a randomized, double-blind, parallel-arm study design.\nSubjects with CD who had a previous response from BoNTA were randomly assigned to BoNTA or BoNTB and evaluated in a blinded fashion at baseline, 4 weeks, 8 weeks, and 2-week intervals thereafter until loss of 80% of clinical effect or completion of 20 weeks of observation. CD severity was measured with the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), and adverse events were assessed by structured interview. Statistical analysis included Wilcoxon rank sum test, log rank tests, and Kaplan-Meier survival curves for duration of effect.\nA total of 139 subjects (BoNTA, n = 74; BoNTB, n = 65) were randomized at 19 study sites. Improvement in TWSTRS score was found at 4 weeks after injection and did not differ between serotypes. Dysphagia and dry mouth were more frequent with BoNTB (dysphagia: BoNTA 19% vs BoNTB 48%, p = 0.0005; dry mouth (BoNTA 41% vs BoNTB 80%, p < 0.0001). In clinical responders, BoNT A had a modestly longer duration of benefit (BoNTA 14 weeks, BoNTB 12.1 weeks, p = 0.033).\nBoth serotypes of botulinum toxin (BoNTA and BoNTB) had equivalent benefit in subjects with cervical dystonia at 4 weeks. BoNTA had fewer adverse events and a marginally longer duration of effect in subjects showing a clinical response.', 'title': 'Comparison of botulinum toxin serotypes A and B for the treatment of cervical dystonia.', 'date': '2005-11-09'}, '18098274': {'article_id': '18098274', 'content': 'The objective of this study was to compare efficacy, safety, and duration of botulinum toxin type A (BoNT-A) and type B (BoNT-B) in toxin-naïve cervical dystonia (CD) subjects. BoNT-naïve CD subjects were randomized to BoNT-A or BoNT-B and evaluated in a double-blind trial at baseline and every 4-weeks following one treatment. The primary measure was the change in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) from baseline to week 4 post-injection. Secondary measures included change in TWSTRS-subscale scores, pain, global impressions, and duration of response and safety assessments. The study was designed as a noninferiority trial of BoNT-B to BoNT-A. 111 subjects were randomized (55 BoNT-A; 56 BoNT-B). Improvement in TWSTRS-total scores 4 weeks after BoNT-B was noninferior to BoNT-A (adjusted means 11.0 (SE 1.2) and 8.8 (SE 1.2), respectively; per-protocol-population (PPP)). The median duration of effect of BoNT-A and BoNT-B was not different (13.1 vs. 13.7 weeks, respectively; P-value = 0.833; PPP). There were no significant differences in the occurrence of injection site pain and dysphagia. Mild dry mouth was more frequent with BoNT-B but there were no differences for moderate/severe dry mouth. In this study, both BoNT-A and B were shown to be effective and safe for the treatment of toxin-naive CD subjects.', 'title': 'Botulinum toxin type B vs. type A in toxin-naïve patients with cervical dystonia: Randomized, double-blind, noninferiority trial.', 'date': '2007-12-22'}, '16157918': {'article_id': '16157918', 'content': 'To compare autonomic effects of botulinum toxin (BTX), we randomized patients with cervical dystonia to receive either BTX-A or BTX-B in a double-blind manner. Efficacy and physiologic questionnaire measures of autonomic function were assessed at baseline and 2 weeks after injection. Patients treated with BTX-B had less saliva production (p < 0.01) and greater severity of constipation (p = 0.037) than those treated with BTX-A, but did not differ in other tests of autonomic functions.', 'title': 'Autonomic function after botulinum toxin type A or B: a double-blind, randomized trial.', 'date': '2005-09-15'}}
| 0.333333
|
Psychiatry & Neurology
|
56
|
Is the risk of treatment‐related sore throat/dry mouth higher, lower, or the same when comparing botulinum toxin type A (BtA) to botulinum toxin type B (BtB)?
|
lower
|
moderate
|
no
|
['16275831', '18098274']
| 27,782,297
| 2,016
|
{'16275831': {'article_id': '16275831', 'content': 'To directly compare two serotypes of botulinum toxin (BoNTA and BoNTB) in cervical dystonia (CD) using a randomized, double-blind, parallel-arm study design.\nSubjects with CD who had a previous response from BoNTA were randomly assigned to BoNTA or BoNTB and evaluated in a blinded fashion at baseline, 4 weeks, 8 weeks, and 2-week intervals thereafter until loss of 80% of clinical effect or completion of 20 weeks of observation. CD severity was measured with the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), and adverse events were assessed by structured interview. Statistical analysis included Wilcoxon rank sum test, log rank tests, and Kaplan-Meier survival curves for duration of effect.\nA total of 139 subjects (BoNTA, n = 74; BoNTB, n = 65) were randomized at 19 study sites. Improvement in TWSTRS score was found at 4 weeks after injection and did not differ between serotypes. Dysphagia and dry mouth were more frequent with BoNTB (dysphagia: BoNTA 19% vs BoNTB 48%, p = 0.0005; dry mouth (BoNTA 41% vs BoNTB 80%, p < 0.0001). In clinical responders, BoNT A had a modestly longer duration of benefit (BoNTA 14 weeks, BoNTB 12.1 weeks, p = 0.033).\nBoth serotypes of botulinum toxin (BoNTA and BoNTB) had equivalent benefit in subjects with cervical dystonia at 4 weeks. BoNTA had fewer adverse events and a marginally longer duration of effect in subjects showing a clinical response.', 'title': 'Comparison of botulinum toxin serotypes A and B for the treatment of cervical dystonia.', 'date': '2005-11-09'}, '18098274': {'article_id': '18098274', 'content': 'The objective of this study was to compare efficacy, safety, and duration of botulinum toxin type A (BoNT-A) and type B (BoNT-B) in toxin-naïve cervical dystonia (CD) subjects. BoNT-naïve CD subjects were randomized to BoNT-A or BoNT-B and evaluated in a double-blind trial at baseline and every 4-weeks following one treatment. The primary measure was the change in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) from baseline to week 4 post-injection. Secondary measures included change in TWSTRS-subscale scores, pain, global impressions, and duration of response and safety assessments. The study was designed as a noninferiority trial of BoNT-B to BoNT-A. 111 subjects were randomized (55 BoNT-A; 56 BoNT-B). Improvement in TWSTRS-total scores 4 weeks after BoNT-B was noninferior to BoNT-A (adjusted means 11.0 (SE 1.2) and 8.8 (SE 1.2), respectively; per-protocol-population (PPP)). The median duration of effect of BoNT-A and BoNT-B was not different (13.1 vs. 13.7 weeks, respectively; P-value = 0.833; PPP). There were no significant differences in the occurrence of injection site pain and dysphagia. Mild dry mouth was more frequent with BoNT-B but there were no differences for moderate/severe dry mouth. In this study, both BoNT-A and B were shown to be effective and safe for the treatment of toxin-naive CD subjects.', 'title': 'Botulinum toxin type B vs. type A in toxin-naïve patients with cervical dystonia: Randomized, double-blind, noninferiority trial.', 'date': '2007-12-22'}}
| 0
|
Surgery
|
57
|
Is the overall survival rate higher, lower, or the same when comparing percutaneous ethanol injection (PEI) to percutaneous acetic acid injection (PAI)?
|
no difference
|
low
|
no
|
['9425919', '16009687']
| 25,620,061
| 2,015
|
{'9425919': {'article_id': '9425919', 'content': 'To assess whether ultrasound-guided percutaneous acetic acid injection is superior to percutaneous ethanol injection in the treatment of small hepatocellular carcinoma (HCC), 60 patients with one to four HCCs smaller than 3 cm were entered onto a randomized controlled trial. Thirty-one and 29 patients, respectively, were treated by percutaneous acetic acid injection using 50% acetic acid or by percutaneous ethanol injection using absolute ethanol. There were no significant differences in age, sex ratio, Child-Pugh class, size of tumors, or number of tumors between the two groups. When there was no evidence of viable HCC from biopsy, plain and helical dynamic computed tomography, or angiography, the treatment was considered successful and was discontinued. All original tumors were treated successfully by either therapy. However, 8% of 38 tumors treated with percutaneous acetic acid injection and 37% of 35 tumors treated with percutaneous ethanol injection developed a local recurrence (P < .001) during the follow-up periods of 29 +/- 8 months and 23 +/- 10 months, respectively. The 1- and 2-year survival rates were 100% and 92% in percutaneous acetic acid injection and 83% and 63% in percutaneous ethanol injection (P = .0017). A multivariate analysis of prognostic factors revealed that treatment was an independent predictor of survival. The risk ratio of percutaneous acetic acid injection versus percutaneous ethanol injection was 0.120 (range, 0.027-0.528; P = .0050). In conclusion, percutaneous acetic acid injection is superior to percutaneous ethanol injection in the treatment of small HCC.', 'title': 'Prospective randomized controlled trial comparing percutaneous acetic acid injection and percutaneous ethanol injection for small hepatocellular carcinoma.', 'date': '1998-01-13'}, '16009687': {'article_id': '16009687', 'content': 'The aim of this study was to compare the outcomes of radiofrequency thermal ablation (RFTA), percutaneous ethanol injection (PEI), and percutaneous acetic acid injection (PAI) in the treatment of hepatocellular carcinoma (HCC).\nA total of 187 patients with HCCs of 3 cm or less were randomly assigned to RFTA (n = 62), PEI (n = 62), or PAI (n = 63). Tumour recurrence and survival rates were assessed.\nOne, two, and three year local recurrence rates were 10%, 14%, and 14% in the RFTA group, 16%, 34%, and 34% in the PEI group, and 14%, 31%, and 31% in the PAI group (RFTA v PEI, p = 0.012; RFTA v PAI, p = 0.017). One, two, and three year survival rates were 93%, 81%, and 74% in the RFTA group, 88%, 66%, and 51% in the PEI group, and 90%, 67%, and 53% in the PAI group (RFTA v PEI, p = 0.031; RFTA v PAI, p = 0.038). One, two, and three year cancer free survival rates were 74%, 60%, and 43% in the RFTA group, 70%, 41%, and 21% in the PEI group, and 71%, 43%, and 23% in the PAI group (RFTA v PEI, p = 0.038; RFTA v PAI, p = 0.041). Tumour size, tumour differentiation, and treatment methods (RFTA v PEI and PAI) were significant factors for local recurrence, overall survival, and cancer free survival. Major complications occurred in 4.8% of patients (two with haemothorax, one gastric perforation) in the RFTA group and in none in two other groups (RFTA v PEI and PAI, p = 0.035).\nRFTA was superior to PEI and PAI with respect to local recurrence, overall survival, and cancer free survival rates, but RFTA also caused more major complications.', 'title': 'Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less.', 'date': '2005-07-13'}}
| 0
|
Oncology & Hematology
|
58
|
Is the overall survival rate higher, lower, or the same when comparing percutaneous ethanol injection (PEI) to surgery?
|
no difference
|
very low
|
no
|
['15973099']
| 25,620,061
| 2,015
|
{'15973099': {'article_id': '15973099', 'content': 'To compare disease recurrence and survival among patients with small hepatocellular carcinoma after surgical resection or percutaneous ethanol injection therapy, 2 treatments that have not been evaluated with a prospective study.\nA total of 76 patients were randomly assigned to 2 groups based on treatment; all had one or 2 tumors with diameter </=3 cm, with hepatitis without cirrhosis or Child class A or B cirrhosis without evident ascites or bleeding tendency.\nFollow-up ranged from 12 to 59 months. Among percutaneous injection patients, 18 had recurrence 1 to 37 months after treatment (true recurrence, 11; original safety margin inadequate, 3; limitation of imaging technology to detect tiny tumors, 4). Three injection therapy patients died of cancer 25, 37, and 57 months after treatment. For the surgical resection group, 15 had recurrence 2 to 54 months after treatment (true recurrence, 12; limitation of imaging, 2; neck metastasis, 1). Five resection patients died of cancer at 11, 20, 23, 26, and 52 months, respectively. By Cox regression model and Kaplan-Meier survival analysis, there is no statistical significance for recurrence and survival between treatment groups. However, tumor size larger than 2 cm and alpha-fetoprotein over 200 ng/mL correlated with higher recurrence rate, and Child class B liver cirrhosis correlated with shorter survival.\nPercutaneous ethanol injection therapy appears to be as safe and effective as resection, and both treatments can be considered first-line options for small hepatocellular carcinoma.', 'title': 'Percutaneous ethanol injection versus surgical resection for the treatment of small hepatocellular carcinoma: a prospective study.', 'date': '2005-06-24'}}
| 1
|
Surgery
|
221
|
Is the overall survival rate higher, lower, or the same when comparing percutaneous acetic acid injection (PAI) to sham intervention?
|
insufficient data
| null |
no
|
['9425919', '16009687', '15973099']
| 25,620,061
| 2,015
|
{'9425919': {'article_id': '9425919', 'content': 'To assess whether ultrasound-guided percutaneous acetic acid injection is superior to percutaneous ethanol injection in the treatment of small hepatocellular carcinoma (HCC), 60 patients with one to four HCCs smaller than 3 cm were entered onto a randomized controlled trial. Thirty-one and 29 patients, respectively, were treated by percutaneous acetic acid injection using 50% acetic acid or by percutaneous ethanol injection using absolute ethanol. There were no significant differences in age, sex ratio, Child-Pugh class, size of tumors, or number of tumors between the two groups. When there was no evidence of viable HCC from biopsy, plain and helical dynamic computed tomography, or angiography, the treatment was considered successful and was discontinued. All original tumors were treated successfully by either therapy. However, 8% of 38 tumors treated with percutaneous acetic acid injection and 37% of 35 tumors treated with percutaneous ethanol injection developed a local recurrence (P < .001) during the follow-up periods of 29 +/- 8 months and 23 +/- 10 months, respectively. The 1- and 2-year survival rates were 100% and 92% in percutaneous acetic acid injection and 83% and 63% in percutaneous ethanol injection (P = .0017). A multivariate analysis of prognostic factors revealed that treatment was an independent predictor of survival. The risk ratio of percutaneous acetic acid injection versus percutaneous ethanol injection was 0.120 (range, 0.027-0.528; P = .0050). In conclusion, percutaneous acetic acid injection is superior to percutaneous ethanol injection in the treatment of small HCC.', 'title': 'Prospective randomized controlled trial comparing percutaneous acetic acid injection and percutaneous ethanol injection for small hepatocellular carcinoma.', 'date': '1998-01-13'}, '16009687': {'article_id': '16009687', 'content': 'The aim of this study was to compare the outcomes of radiofrequency thermal ablation (RFTA), percutaneous ethanol injection (PEI), and percutaneous acetic acid injection (PAI) in the treatment of hepatocellular carcinoma (HCC).\nA total of 187 patients with HCCs of 3 cm or less were randomly assigned to RFTA (n = 62), PEI (n = 62), or PAI (n = 63). Tumour recurrence and survival rates were assessed.\nOne, two, and three year local recurrence rates were 10%, 14%, and 14% in the RFTA group, 16%, 34%, and 34% in the PEI group, and 14%, 31%, and 31% in the PAI group (RFTA v PEI, p = 0.012; RFTA v PAI, p = 0.017). One, two, and three year survival rates were 93%, 81%, and 74% in the RFTA group, 88%, 66%, and 51% in the PEI group, and 90%, 67%, and 53% in the PAI group (RFTA v PEI, p = 0.031; RFTA v PAI, p = 0.038). One, two, and three year cancer free survival rates were 74%, 60%, and 43% in the RFTA group, 70%, 41%, and 21% in the PEI group, and 71%, 43%, and 23% in the PAI group (RFTA v PEI, p = 0.038; RFTA v PAI, p = 0.041). Tumour size, tumour differentiation, and treatment methods (RFTA v PEI and PAI) were significant factors for local recurrence, overall survival, and cancer free survival. Major complications occurred in 4.8% of patients (two with haemothorax, one gastric perforation) in the RFTA group and in none in two other groups (RFTA v PEI and PAI, p = 0.035).\nRFTA was superior to PEI and PAI with respect to local recurrence, overall survival, and cancer free survival rates, but RFTA also caused more major complications.', 'title': 'Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less.', 'date': '2005-07-13'}, '15973099': {'article_id': '15973099', 'content': 'To compare disease recurrence and survival among patients with small hepatocellular carcinoma after surgical resection or percutaneous ethanol injection therapy, 2 treatments that have not been evaluated with a prospective study.\nA total of 76 patients were randomly assigned to 2 groups based on treatment; all had one or 2 tumors with diameter </=3 cm, with hepatitis without cirrhosis or Child class A or B cirrhosis without evident ascites or bleeding tendency.\nFollow-up ranged from 12 to 59 months. Among percutaneous injection patients, 18 had recurrence 1 to 37 months after treatment (true recurrence, 11; original safety margin inadequate, 3; limitation of imaging technology to detect tiny tumors, 4). Three injection therapy patients died of cancer 25, 37, and 57 months after treatment. For the surgical resection group, 15 had recurrence 2 to 54 months after treatment (true recurrence, 12; limitation of imaging, 2; neck metastasis, 1). Five resection patients died of cancer at 11, 20, 23, 26, and 52 months, respectively. By Cox regression model and Kaplan-Meier survival analysis, there is no statistical significance for recurrence and survival between treatment groups. However, tumor size larger than 2 cm and alpha-fetoprotein over 200 ng/mL correlated with higher recurrence rate, and Child class B liver cirrhosis correlated with shorter survival.\nPercutaneous ethanol injection therapy appears to be as safe and effective as resection, and both treatments can be considered first-line options for small hepatocellular carcinoma.', 'title': 'Percutaneous ethanol injection versus surgical resection for the treatment of small hepatocellular carcinoma: a prospective study.', 'date': '2005-06-24'}}
| 1
|
Oncology & Hematology
|
222
|
Is the overall survival rate higher, lower, or the same when comparing percutaneous ethanol injection (PEI) to sham intervention?
|
insufficient data
| null |
no
|
['9425919', '16009687', '15973099']
| 25,620,061
| 2,015
|
{'9425919': {'article_id': '9425919', 'content': 'To assess whether ultrasound-guided percutaneous acetic acid injection is superior to percutaneous ethanol injection in the treatment of small hepatocellular carcinoma (HCC), 60 patients with one to four HCCs smaller than 3 cm were entered onto a randomized controlled trial. Thirty-one and 29 patients, respectively, were treated by percutaneous acetic acid injection using 50% acetic acid or by percutaneous ethanol injection using absolute ethanol. There were no significant differences in age, sex ratio, Child-Pugh class, size of tumors, or number of tumors between the two groups. When there was no evidence of viable HCC from biopsy, plain and helical dynamic computed tomography, or angiography, the treatment was considered successful and was discontinued. All original tumors were treated successfully by either therapy. However, 8% of 38 tumors treated with percutaneous acetic acid injection and 37% of 35 tumors treated with percutaneous ethanol injection developed a local recurrence (P < .001) during the follow-up periods of 29 +/- 8 months and 23 +/- 10 months, respectively. The 1- and 2-year survival rates were 100% and 92% in percutaneous acetic acid injection and 83% and 63% in percutaneous ethanol injection (P = .0017). A multivariate analysis of prognostic factors revealed that treatment was an independent predictor of survival. The risk ratio of percutaneous acetic acid injection versus percutaneous ethanol injection was 0.120 (range, 0.027-0.528; P = .0050). In conclusion, percutaneous acetic acid injection is superior to percutaneous ethanol injection in the treatment of small HCC.', 'title': 'Prospective randomized controlled trial comparing percutaneous acetic acid injection and percutaneous ethanol injection for small hepatocellular carcinoma.', 'date': '1998-01-13'}, '16009687': {'article_id': '16009687', 'content': 'The aim of this study was to compare the outcomes of radiofrequency thermal ablation (RFTA), percutaneous ethanol injection (PEI), and percutaneous acetic acid injection (PAI) in the treatment of hepatocellular carcinoma (HCC).\nA total of 187 patients with HCCs of 3 cm or less were randomly assigned to RFTA (n = 62), PEI (n = 62), or PAI (n = 63). Tumour recurrence and survival rates were assessed.\nOne, two, and three year local recurrence rates were 10%, 14%, and 14% in the RFTA group, 16%, 34%, and 34% in the PEI group, and 14%, 31%, and 31% in the PAI group (RFTA v PEI, p = 0.012; RFTA v PAI, p = 0.017). One, two, and three year survival rates were 93%, 81%, and 74% in the RFTA group, 88%, 66%, and 51% in the PEI group, and 90%, 67%, and 53% in the PAI group (RFTA v PEI, p = 0.031; RFTA v PAI, p = 0.038). One, two, and three year cancer free survival rates were 74%, 60%, and 43% in the RFTA group, 70%, 41%, and 21% in the PEI group, and 71%, 43%, and 23% in the PAI group (RFTA v PEI, p = 0.038; RFTA v PAI, p = 0.041). Tumour size, tumour differentiation, and treatment methods (RFTA v PEI and PAI) were significant factors for local recurrence, overall survival, and cancer free survival. Major complications occurred in 4.8% of patients (two with haemothorax, one gastric perforation) in the RFTA group and in none in two other groups (RFTA v PEI and PAI, p = 0.035).\nRFTA was superior to PEI and PAI with respect to local recurrence, overall survival, and cancer free survival rates, but RFTA also caused more major complications.', 'title': 'Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less.', 'date': '2005-07-13'}, '15973099': {'article_id': '15973099', 'content': 'To compare disease recurrence and survival among patients with small hepatocellular carcinoma after surgical resection or percutaneous ethanol injection therapy, 2 treatments that have not been evaluated with a prospective study.\nA total of 76 patients were randomly assigned to 2 groups based on treatment; all had one or 2 tumors with diameter </=3 cm, with hepatitis without cirrhosis or Child class A or B cirrhosis without evident ascites or bleeding tendency.\nFollow-up ranged from 12 to 59 months. Among percutaneous injection patients, 18 had recurrence 1 to 37 months after treatment (true recurrence, 11; original safety margin inadequate, 3; limitation of imaging technology to detect tiny tumors, 4). Three injection therapy patients died of cancer 25, 37, and 57 months after treatment. For the surgical resection group, 15 had recurrence 2 to 54 months after treatment (true recurrence, 12; limitation of imaging, 2; neck metastasis, 1). Five resection patients died of cancer at 11, 20, 23, 26, and 52 months, respectively. By Cox regression model and Kaplan-Meier survival analysis, there is no statistical significance for recurrence and survival between treatment groups. However, tumor size larger than 2 cm and alpha-fetoprotein over 200 ng/mL correlated with higher recurrence rate, and Child class B liver cirrhosis correlated with shorter survival.\nPercutaneous ethanol injection therapy appears to be as safe and effective as resection, and both treatments can be considered first-line options for small hepatocellular carcinoma.', 'title': 'Percutaneous ethanol injection versus surgical resection for the treatment of small hepatocellular carcinoma: a prospective study.', 'date': '2005-06-24'}}
| 1
|
Oncology & Hematology
|
223
|
Is the overall survival rate higher, lower, or the same when comparing percutaneous acetic acid injection (PAI) to no intervention?
|
insufficient data
| null |
no
|
['9425919', '16009687', '15973099']
| 25,620,061
| 2,015
|
{'9425919': {'article_id': '9425919', 'content': 'To assess whether ultrasound-guided percutaneous acetic acid injection is superior to percutaneous ethanol injection in the treatment of small hepatocellular carcinoma (HCC), 60 patients with one to four HCCs smaller than 3 cm were entered onto a randomized controlled trial. Thirty-one and 29 patients, respectively, were treated by percutaneous acetic acid injection using 50% acetic acid or by percutaneous ethanol injection using absolute ethanol. There were no significant differences in age, sex ratio, Child-Pugh class, size of tumors, or number of tumors between the two groups. When there was no evidence of viable HCC from biopsy, plain and helical dynamic computed tomography, or angiography, the treatment was considered successful and was discontinued. All original tumors were treated successfully by either therapy. However, 8% of 38 tumors treated with percutaneous acetic acid injection and 37% of 35 tumors treated with percutaneous ethanol injection developed a local recurrence (P < .001) during the follow-up periods of 29 +/- 8 months and 23 +/- 10 months, respectively. The 1- and 2-year survival rates were 100% and 92% in percutaneous acetic acid injection and 83% and 63% in percutaneous ethanol injection (P = .0017). A multivariate analysis of prognostic factors revealed that treatment was an independent predictor of survival. The risk ratio of percutaneous acetic acid injection versus percutaneous ethanol injection was 0.120 (range, 0.027-0.528; P = .0050). In conclusion, percutaneous acetic acid injection is superior to percutaneous ethanol injection in the treatment of small HCC.', 'title': 'Prospective randomized controlled trial comparing percutaneous acetic acid injection and percutaneous ethanol injection for small hepatocellular carcinoma.', 'date': '1998-01-13'}, '16009687': {'article_id': '16009687', 'content': 'The aim of this study was to compare the outcomes of radiofrequency thermal ablation (RFTA), percutaneous ethanol injection (PEI), and percutaneous acetic acid injection (PAI) in the treatment of hepatocellular carcinoma (HCC).\nA total of 187 patients with HCCs of 3 cm or less were randomly assigned to RFTA (n = 62), PEI (n = 62), or PAI (n = 63). Tumour recurrence and survival rates were assessed.\nOne, two, and three year local recurrence rates were 10%, 14%, and 14% in the RFTA group, 16%, 34%, and 34% in the PEI group, and 14%, 31%, and 31% in the PAI group (RFTA v PEI, p = 0.012; RFTA v PAI, p = 0.017). One, two, and three year survival rates were 93%, 81%, and 74% in the RFTA group, 88%, 66%, and 51% in the PEI group, and 90%, 67%, and 53% in the PAI group (RFTA v PEI, p = 0.031; RFTA v PAI, p = 0.038). One, two, and three year cancer free survival rates were 74%, 60%, and 43% in the RFTA group, 70%, 41%, and 21% in the PEI group, and 71%, 43%, and 23% in the PAI group (RFTA v PEI, p = 0.038; RFTA v PAI, p = 0.041). Tumour size, tumour differentiation, and treatment methods (RFTA v PEI and PAI) were significant factors for local recurrence, overall survival, and cancer free survival. Major complications occurred in 4.8% of patients (two with haemothorax, one gastric perforation) in the RFTA group and in none in two other groups (RFTA v PEI and PAI, p = 0.035).\nRFTA was superior to PEI and PAI with respect to local recurrence, overall survival, and cancer free survival rates, but RFTA also caused more major complications.', 'title': 'Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less.', 'date': '2005-07-13'}, '15973099': {'article_id': '15973099', 'content': 'To compare disease recurrence and survival among patients with small hepatocellular carcinoma after surgical resection or percutaneous ethanol injection therapy, 2 treatments that have not been evaluated with a prospective study.\nA total of 76 patients were randomly assigned to 2 groups based on treatment; all had one or 2 tumors with diameter </=3 cm, with hepatitis without cirrhosis or Child class A or B cirrhosis without evident ascites or bleeding tendency.\nFollow-up ranged from 12 to 59 months. Among percutaneous injection patients, 18 had recurrence 1 to 37 months after treatment (true recurrence, 11; original safety margin inadequate, 3; limitation of imaging technology to detect tiny tumors, 4). Three injection therapy patients died of cancer 25, 37, and 57 months after treatment. For the surgical resection group, 15 had recurrence 2 to 54 months after treatment (true recurrence, 12; limitation of imaging, 2; neck metastasis, 1). Five resection patients died of cancer at 11, 20, 23, 26, and 52 months, respectively. By Cox regression model and Kaplan-Meier survival analysis, there is no statistical significance for recurrence and survival between treatment groups. However, tumor size larger than 2 cm and alpha-fetoprotein over 200 ng/mL correlated with higher recurrence rate, and Child class B liver cirrhosis correlated with shorter survival.\nPercutaneous ethanol injection therapy appears to be as safe and effective as resection, and both treatments can be considered first-line options for small hepatocellular carcinoma.', 'title': 'Percutaneous ethanol injection versus surgical resection for the treatment of small hepatocellular carcinoma: a prospective study.', 'date': '2005-06-24'}}
| 1
|
Oncology & Hematology
|
224
|
Is the overall survival rate higher, lower, or the same when comparing percutaneous ethanol injection (PEI) to no intervention?
|
insufficient data
| null |
no
|
['9425919', '16009687', '15973099']
| 25,620,061
| 2,015
|
{'9425919': {'article_id': '9425919', 'content': 'To assess whether ultrasound-guided percutaneous acetic acid injection is superior to percutaneous ethanol injection in the treatment of small hepatocellular carcinoma (HCC), 60 patients with one to four HCCs smaller than 3 cm were entered onto a randomized controlled trial. Thirty-one and 29 patients, respectively, were treated by percutaneous acetic acid injection using 50% acetic acid or by percutaneous ethanol injection using absolute ethanol. There were no significant differences in age, sex ratio, Child-Pugh class, size of tumors, or number of tumors between the two groups. When there was no evidence of viable HCC from biopsy, plain and helical dynamic computed tomography, or angiography, the treatment was considered successful and was discontinued. All original tumors were treated successfully by either therapy. However, 8% of 38 tumors treated with percutaneous acetic acid injection and 37% of 35 tumors treated with percutaneous ethanol injection developed a local recurrence (P < .001) during the follow-up periods of 29 +/- 8 months and 23 +/- 10 months, respectively. The 1- and 2-year survival rates were 100% and 92% in percutaneous acetic acid injection and 83% and 63% in percutaneous ethanol injection (P = .0017). A multivariate analysis of prognostic factors revealed that treatment was an independent predictor of survival. The risk ratio of percutaneous acetic acid injection versus percutaneous ethanol injection was 0.120 (range, 0.027-0.528; P = .0050). In conclusion, percutaneous acetic acid injection is superior to percutaneous ethanol injection in the treatment of small HCC.', 'title': 'Prospective randomized controlled trial comparing percutaneous acetic acid injection and percutaneous ethanol injection for small hepatocellular carcinoma.', 'date': '1998-01-13'}, '16009687': {'article_id': '16009687', 'content': 'The aim of this study was to compare the outcomes of radiofrequency thermal ablation (RFTA), percutaneous ethanol injection (PEI), and percutaneous acetic acid injection (PAI) in the treatment of hepatocellular carcinoma (HCC).\nA total of 187 patients with HCCs of 3 cm or less were randomly assigned to RFTA (n = 62), PEI (n = 62), or PAI (n = 63). Tumour recurrence and survival rates were assessed.\nOne, two, and three year local recurrence rates were 10%, 14%, and 14% in the RFTA group, 16%, 34%, and 34% in the PEI group, and 14%, 31%, and 31% in the PAI group (RFTA v PEI, p = 0.012; RFTA v PAI, p = 0.017). One, two, and three year survival rates were 93%, 81%, and 74% in the RFTA group, 88%, 66%, and 51% in the PEI group, and 90%, 67%, and 53% in the PAI group (RFTA v PEI, p = 0.031; RFTA v PAI, p = 0.038). One, two, and three year cancer free survival rates were 74%, 60%, and 43% in the RFTA group, 70%, 41%, and 21% in the PEI group, and 71%, 43%, and 23% in the PAI group (RFTA v PEI, p = 0.038; RFTA v PAI, p = 0.041). Tumour size, tumour differentiation, and treatment methods (RFTA v PEI and PAI) were significant factors for local recurrence, overall survival, and cancer free survival. Major complications occurred in 4.8% of patients (two with haemothorax, one gastric perforation) in the RFTA group and in none in two other groups (RFTA v PEI and PAI, p = 0.035).\nRFTA was superior to PEI and PAI with respect to local recurrence, overall survival, and cancer free survival rates, but RFTA also caused more major complications.', 'title': 'Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less.', 'date': '2005-07-13'}, '15973099': {'article_id': '15973099', 'content': 'To compare disease recurrence and survival among patients with small hepatocellular carcinoma after surgical resection or percutaneous ethanol injection therapy, 2 treatments that have not been evaluated with a prospective study.\nA total of 76 patients were randomly assigned to 2 groups based on treatment; all had one or 2 tumors with diameter </=3 cm, with hepatitis without cirrhosis or Child class A or B cirrhosis without evident ascites or bleeding tendency.\nFollow-up ranged from 12 to 59 months. Among percutaneous injection patients, 18 had recurrence 1 to 37 months after treatment (true recurrence, 11; original safety margin inadequate, 3; limitation of imaging technology to detect tiny tumors, 4). Three injection therapy patients died of cancer 25, 37, and 57 months after treatment. For the surgical resection group, 15 had recurrence 2 to 54 months after treatment (true recurrence, 12; limitation of imaging, 2; neck metastasis, 1). Five resection patients died of cancer at 11, 20, 23, 26, and 52 months, respectively. By Cox regression model and Kaplan-Meier survival analysis, there is no statistical significance for recurrence and survival between treatment groups. However, tumor size larger than 2 cm and alpha-fetoprotein over 200 ng/mL correlated with higher recurrence rate, and Child class B liver cirrhosis correlated with shorter survival.\nPercutaneous ethanol injection therapy appears to be as safe and effective as resection, and both treatments can be considered first-line options for small hepatocellular carcinoma.', 'title': 'Percutaneous ethanol injection versus surgical resection for the treatment of small hepatocellular carcinoma: a prospective study.', 'date': '2005-06-24'}}
| 1
|
Oncology & Hematology
|
59
|
Is the risk of seizure recurrence higher, lower, or the same when comparing six months of treatment to 12-24 months treatment?
|
no difference
|
low
|
no
|
['16441247', '12134175', '12134176']
| 31,608,991
| 2,019
|
{'16441247': {'article_id': '16441247', 'content': 'The duration of antiepileptic drug (AED) therapy in cases of solitary cerebral cysticercus granuloma (SCCG) presents a major dilemma and the efficacy of short-term (6 months) vs long-term (2 years) AED therapy has been studied.\nProspective randomized study of short-term vs long-term AED treatment with SCCG has been undertaken. A total of 206 subjects with new onset seizures with SCCG were randomized into two groups: group A (98 patients) were treated for 6 months and group B (108 patients) were treated for 2 years with AED therapy. The patients were evaluated periodically during and at least 18 months after the tapering of drugs.\nPartial seizures with or without secondary generalization has been found to be the commonest manifestation occurring in 80.6% of patients with SCCG. In group A 66.3% and in group B 57.4% patients showed complete resolution of computerized tomographic lesion and rest had punctated residual calcification. Statistically, no significant difference in the recurrence of seizures was found in two groups with disappearance of lesion but the difference between calcified residua and complete resolution subset was significant. In patients having residual calcification, 42.2% in group A and 21.7% in group B had recurrence of seizures and the difference was statistically significant (Z = 1.97, P < 0.05).\nThe study revealed that SCCG with epilepsy is a benign self-limiting disease. A longer duration of therapy is not warranted in patients having total resolution of lesion. Calcified lesion was found to be the most common cause of recurrence of seizures. Higher recurrence rate was observed in short-term therapy in patients having calcified lesions and may require long-term AED treatment.', 'title': 'Outcome of short-term antiepileptic treatment in patients with solitary cerebral cysticercus granuloma.', 'date': '2006-01-31'}, '12134175': {'article_id': '12134175', 'content': 'The duration of anti epileptic drug therapy for single small enhancing CT lesions (SSECTL) presents a major dilemma. We studied the efficacy of short duration (6 months) antiepileptic drug therapy as compared to long duration (2 years) drug therapy. Seventy three patients presenting with seizures and showing SSECTL on cranial CT scans (plain and contrast) were randomized into group A (6 months therapy) and group B (2 years therapy). There were 47 patients in group A and 26 patients in group B. Patients were followed up for one year after withdrawal of anti epileptic drugs. CT Head (plain and contrast) was repeated after 3 months, or earlier in cases of recurrence to rule out reinfection. 53.2% in group A and 53.8% in group B showed complete resolution and were seizure free on one year follow up. Punctate residual calcification was seen in 46.8% in group A and 46.2% in group B. Eight patients (17%) in group A and three (11.5%) in group B had a recurrence. The difference in recurrence of seizure between the two groups was not statistically significant (p<0.77) in the calcified lesion subset. Since none of the patients in total resolution subset showed recurrence, the difference between calcified and total resolution subset was highly significant. The study shows that a short duration (6 months) AED therapy in patients with total resolution of lesion on follow up scan, may be adequate in comparison to those who have calcific speck as a residue. However, a longer duration of therapy in case of calcific group probably does not alter their chances of recurrence.', 'title': 'Acute symptomatic seizures due to single CT lesions: how long to treat with antiepileptic drugs?', 'date': '2002-07-23'}, '12134176': {'article_id': '12134176', 'content': 'The study was conducted in 81 patients of epilepsy with small single enhancing CT (SSECT) lesion in brain to determine the clinical profile and duration of antiepileptic drugs (AEDs) treatment. The patients were randomly divided into group A (41 cases) and group B (40 cases). Group A patients were treated for 6 months and group B for 1 year with AEDS without cysticidal drugs. The most common mode of presentation was simple partial motor seizures with secondary generalization in both the groups. Repeat imaging of brain (CT/MRI) at 6 months showed disappearance of lesion in 82.94% in group A and 87% in group B, while persistence of lesion was present only in 4.87% in group A and 5% in group B. 87.81% patients in group A and 87.17% in group B were seizure free. The recurrence of seizure occurred in 12.19% cases in group A, and 12.82% in group B. 80% of these patients had calcified lesion in both the groups. This study reveals that SSECT lesion with epilpesy is a benign self-limiting disease. It also reveals that 6 months AED treatment is as effective as one year treatment. Patients having calcified lesion or persistence of lesion might require long term AED treatment.', 'title': 'Randomized prospective study of outcome of short term antiepileptic treatment in small single enhancing CT lesion in brain.', 'date': '2002-07-23'}}
| 0.666667
|
Psychiatry & Neurology
|
60
|
Is the risk of seizure recurrence higher, lower, or the same when comparing 6-12 months of treatment to 24 months of treatment?
|
no difference
|
low
|
no
|
['16441247', '14604159', '12134175']
| 31,608,991
| 2,019
|
{'16441247': {'article_id': '16441247', 'content': 'The duration of antiepileptic drug (AED) therapy in cases of solitary cerebral cysticercus granuloma (SCCG) presents a major dilemma and the efficacy of short-term (6 months) vs long-term (2 years) AED therapy has been studied.\nProspective randomized study of short-term vs long-term AED treatment with SCCG has been undertaken. A total of 206 subjects with new onset seizures with SCCG were randomized into two groups: group A (98 patients) were treated for 6 months and group B (108 patients) were treated for 2 years with AED therapy. The patients were evaluated periodically during and at least 18 months after the tapering of drugs.\nPartial seizures with or without secondary generalization has been found to be the commonest manifestation occurring in 80.6% of patients with SCCG. In group A 66.3% and in group B 57.4% patients showed complete resolution of computerized tomographic lesion and rest had punctated residual calcification. Statistically, no significant difference in the recurrence of seizures was found in two groups with disappearance of lesion but the difference between calcified residua and complete resolution subset was significant. In patients having residual calcification, 42.2% in group A and 21.7% in group B had recurrence of seizures and the difference was statistically significant (Z = 1.97, P < 0.05).\nThe study revealed that SCCG with epilepsy is a benign self-limiting disease. A longer duration of therapy is not warranted in patients having total resolution of lesion. Calcified lesion was found to be the most common cause of recurrence of seizures. Higher recurrence rate was observed in short-term therapy in patients having calcified lesions and may require long-term AED treatment.', 'title': 'Outcome of short-term antiepileptic treatment in patients with solitary cerebral cysticercus granuloma.', 'date': '2006-01-31'}, '14604159': {'article_id': '14604159', 'content': 'The duration of anti-epileptic drug (AED) therapy in children with seizures due to single small enhancing CT lesions (SSECTL) is controversial. We sought to determine whether there is any difference in the rate of seizure recurrence after 1 vs. 2 years of AED therapy and to identify the factors predictive of seizure recurrence. A total of 115 consecutive children with seizures and SSECTL were randomly assigned to two groups. Group A received AED(s) for 1 year and Group B for 2 years seizure-free interval. CT scan and EEG were done prior to AED withdrawal and children were followed-up for seizure recurrence for at least 1 year. Association between seizure recurrence and clinical and CT characteristics was analysed. Groups A and B consisted of 55 and 51 children, respectively (nine were lost to follow-up). There were 61 boys and 45 girls; mean age 9.33 years. Most (93 per cent) had focal seizures: 36 per cent complex partial, 22 per cent simple partial, 35 per cent partial with secondary generalization; 21 per cent had status epilepticus. The two groups were comparable in clinical, EEG and CT characteristics. CT scan and EEG prior to AED withdrawal were abnormal in 44 per cent and 33 per cent respectively. Six children, three from each group had seizure recurrence. Significant association was found between seizure recurrence and abnormal CT (persistence/calcification of lesion) and abnormal EEG prior to AED withdrawal (p < 0.01). The relative risk of seizure recurrence in a child with abnormal CT and EEG prior to AED withdrawal was 26.2 (95 per cent confidence interval 3.3-210.2, p = 0.0003). No association was found between seizure recurrence and any of the other variables. There was no difference in seizure recurrence after 1 vs. 2 years of AED therapy. Combination of persistent/calcified CT lesion and abnormal EEG prior to AED withdrawal was the best predictor of seizure recurrence.', 'title': 'One vs. two years of anti-epileptic therapy in children with single small enhancing CT lesions.', 'date': '2003-11-08'}, '12134175': {'article_id': '12134175', 'content': 'The duration of anti epileptic drug therapy for single small enhancing CT lesions (SSECTL) presents a major dilemma. We studied the efficacy of short duration (6 months) antiepileptic drug therapy as compared to long duration (2 years) drug therapy. Seventy three patients presenting with seizures and showing SSECTL on cranial CT scans (plain and contrast) were randomized into group A (6 months therapy) and group B (2 years therapy). There were 47 patients in group A and 26 patients in group B. Patients were followed up for one year after withdrawal of anti epileptic drugs. CT Head (plain and contrast) was repeated after 3 months, or earlier in cases of recurrence to rule out reinfection. 53.2% in group A and 53.8% in group B showed complete resolution and were seizure free on one year follow up. Punctate residual calcification was seen in 46.8% in group A and 46.2% in group B. Eight patients (17%) in group A and three (11.5%) in group B had a recurrence. The difference in recurrence of seizure between the two groups was not statistically significant (p<0.77) in the calcified lesion subset. Since none of the patients in total resolution subset showed recurrence, the difference between calcified and total resolution subset was highly significant. The study shows that a short duration (6 months) AED therapy in patients with total resolution of lesion on follow up scan, may be adequate in comparison to those who have calcific speck as a residue. However, a longer duration of therapy in case of calcific group probably does not alter their chances of recurrence.', 'title': 'Acute symptomatic seizures due to single CT lesions: how long to treat with antiepileptic drugs?', 'date': '2002-07-23'}}
| 0.666667
|
Psychiatry & Neurology
|
61
|
Is the duration of mechanical ventilation higher, lower, or the same when comparing bispectral index (BIS) monitoring to clinical assessment for sedation?
|
no difference
|
low
|
no
|
['17444309', '21473824']
| 29,464,690
| 2,018
|
{'17444309': {'article_id': '17444309', 'content': 'The aim of this prospective randomised controlled trial was to assess the effectiveness of the Bispectral Index (BIS) monitor in supporting clinical sedation management decisions in mechanically ventilated intensive care unit patients. Fifty adult mechanically ventilated surgical and general intensive care unit patients receiving sedative infusions of morphine and midazolam were randomly allocated to receive BIS monitoring (n=25) or standard sedation management (n=25). In the BIS group, sedation was titrated to maintain a BIS value of greater than 70. In the standard management group, sedative needs were titrated based on subjective assessment and clinical signs. There was no statistically significant difference in the amount of sedation administered (morphine P = 0.67 and midazolam P = 0.85). However, there was a statistically significant difference in sedation administration over time. Patients in the BIS group received increasing amounts of sedation over time whilst those in the control group received decreasing amounts of sedation over time. The same inverse relationship existed for both sedative agents (morphine P = 0.005, midazolam P = 0.03). Duration of mechanical ventilation was comparable in the two groups. We conclude that the use of BIS monitoring did not reduce the amount of sedation used, the length of mechanical ventilation time or the length of ICU stay.', 'title': 'The impact of bispectral index monitoring on sedation administration in mechanically ventilated patients.', 'date': '2007-04-21'}, '21473824': {'article_id': '21473824', 'content': 'To compare the value of bispectral index (BIS) monitoring and sedation agitation scale (SAS) in guiding intensive care unit (ICU) sedation therapy for the patients undergoing short term mechanical ventilation.\nOne hundred and five patients aged 18-60 years after operation receiving mechanical ventilation for longer than 12 hours in ICU were enrolled in this study. The patients were randomly divided into two groups: BIS guided group (n=42) and SAS guided group (n=63). All of them received protocolized continuous sedation and analgesia by using fentanyl for analgesia and propofol plus midazolam to sedate intravenously. The effect of sedation was assessed every hour till BIS reaching 50-70 or SAS reaching grade 3-4. Sedatives and analgesics were suspended at 6:00 am on next day after ICU admission , and BIS and the SAS were recorded every hour, sedation time, time to wake up, duration of mechanical ventilation, daily dosage of midazolam and propofol, and the incidence of adverse events including restlessness after suction, endotracheal tube resistance, pain tolerance during sedation, and delirium after extubation were all recorded accordingly.\nDosages of midazolam and propofol were found higher in BIS guided group than the SAS guided group [midazolam (mg×kg(-1) ×h(-1) ): 0.10±0.02 vs. 0.09±0.02, propofol (mg×kg(-1) ×h(-1) ): 0.95±0.23 vs. 0.86±0.20, both P<0.05]. The total time (D t) of patients under sedative control was significantly longer in BIS guided group compared with SAS guided group, and also in first three hours [D 1, D 2, D 3, D t: 75.2% (507) vs. 52.8% (421), D 1: 78.6% (33) vs. 22.2% (14), D 2: 88.1% (37) vs. 20.6% (13), D 3: 81.0% (34) vs. 31.7% (20), all P<0.01]. The time to wake up (minutes) was significantly shorter in BIS guided group compared with SAS guided group [0 (0, 20) vs. 15 (0, 47), P<0.05]. No significant difference in acute physiology and chronic health evaluation II (APACHE II) score (3.57±2.60 vs. 4.19±2.30), duration of mechanical ventilation [hours: 16.5 (14.5, 19.0) vs. 17.0 (15.0, 19.0)], sedation time [hours: 14.0 (12.9, 17.1) vs. 16.0 (13.0, 18.0)] and incidence of adverse events including restlessness after suction (81.0% vs. 79.4%), endotracheal tube resistance (71.4% vs. 74.6%), pain tolerance during sedation (92.8% vs. 93.6%) and delirium after extubation (4.8% vs. 1.6%) was found between BIS guided group and SAS guided group (all P>0.05).\nBIS monitoring is better in sedative control than SAS assessment for ICU patients undergoing short term mechanical ventilation.', 'title': '[A comparison of bispectral index and sedation agitation scale in guiding sedation therapy: a randomized controlled study in patients undergoing short term mechanical ventilation].', 'date': '2011-04-09'}}
| 1
|
Emergency Medicine & Critical Care
|
62
|
Is the incidence of restlessness after suction higher, lower, or the same when comparing bispectral index (BIS) monitoring to clinical assessment for sedation?
|
uncertain effect
|
very low
|
no
|
['21473824']
| 29,464,690
| 2,018
|
{'21473824': {'article_id': '21473824', 'content': 'To compare the value of bispectral index (BIS) monitoring and sedation agitation scale (SAS) in guiding intensive care unit (ICU) sedation therapy for the patients undergoing short term mechanical ventilation.\nOne hundred and five patients aged 18-60 years after operation receiving mechanical ventilation for longer than 12 hours in ICU were enrolled in this study. The patients were randomly divided into two groups: BIS guided group (n=42) and SAS guided group (n=63). All of them received protocolized continuous sedation and analgesia by using fentanyl for analgesia and propofol plus midazolam to sedate intravenously. The effect of sedation was assessed every hour till BIS reaching 50-70 or SAS reaching grade 3-4. Sedatives and analgesics were suspended at 6:00 am on next day after ICU admission , and BIS and the SAS were recorded every hour, sedation time, time to wake up, duration of mechanical ventilation, daily dosage of midazolam and propofol, and the incidence of adverse events including restlessness after suction, endotracheal tube resistance, pain tolerance during sedation, and delirium after extubation were all recorded accordingly.\nDosages of midazolam and propofol were found higher in BIS guided group than the SAS guided group [midazolam (mg×kg(-1) ×h(-1) ): 0.10±0.02 vs. 0.09±0.02, propofol (mg×kg(-1) ×h(-1) ): 0.95±0.23 vs. 0.86±0.20, both P<0.05]. The total time (D t) of patients under sedative control was significantly longer in BIS guided group compared with SAS guided group, and also in first three hours [D 1, D 2, D 3, D t: 75.2% (507) vs. 52.8% (421), D 1: 78.6% (33) vs. 22.2% (14), D 2: 88.1% (37) vs. 20.6% (13), D 3: 81.0% (34) vs. 31.7% (20), all P<0.01]. The time to wake up (minutes) was significantly shorter in BIS guided group compared with SAS guided group [0 (0, 20) vs. 15 (0, 47), P<0.05]. No significant difference in acute physiology and chronic health evaluation II (APACHE II) score (3.57±2.60 vs. 4.19±2.30), duration of mechanical ventilation [hours: 16.5 (14.5, 19.0) vs. 17.0 (15.0, 19.0)], sedation time [hours: 14.0 (12.9, 17.1) vs. 16.0 (13.0, 18.0)] and incidence of adverse events including restlessness after suction (81.0% vs. 79.4%), endotracheal tube resistance (71.4% vs. 74.6%), pain tolerance during sedation (92.8% vs. 93.6%) and delirium after extubation (4.8% vs. 1.6%) was found between BIS guided group and SAS guided group (all P>0.05).\nBIS monitoring is better in sedative control than SAS assessment for ICU patients undergoing short term mechanical ventilation.', 'title': '[A comparison of bispectral index and sedation agitation scale in guiding sedation therapy: a randomized controlled study in patients undergoing short term mechanical ventilation].', 'date': '2011-04-09'}}
| 0
|
Surgery
|
63
|
Is the incidence of delirium after extubation higher, lower, or the same when comparing bispectral index (BIS) monitoring to clinical assessment for sedation?
|
uncertain effect
|
very low
|
no
|
['21473824']
| 29,464,690
| 2,018
|
{'21473824': {'article_id': '21473824', 'content': 'To compare the value of bispectral index (BIS) monitoring and sedation agitation scale (SAS) in guiding intensive care unit (ICU) sedation therapy for the patients undergoing short term mechanical ventilation.\nOne hundred and five patients aged 18-60 years after operation receiving mechanical ventilation for longer than 12 hours in ICU were enrolled in this study. The patients were randomly divided into two groups: BIS guided group (n=42) and SAS guided group (n=63). All of them received protocolized continuous sedation and analgesia by using fentanyl for analgesia and propofol plus midazolam to sedate intravenously. The effect of sedation was assessed every hour till BIS reaching 50-70 or SAS reaching grade 3-4. Sedatives and analgesics were suspended at 6:00 am on next day after ICU admission , and BIS and the SAS were recorded every hour, sedation time, time to wake up, duration of mechanical ventilation, daily dosage of midazolam and propofol, and the incidence of adverse events including restlessness after suction, endotracheal tube resistance, pain tolerance during sedation, and delirium after extubation were all recorded accordingly.\nDosages of midazolam and propofol were found higher in BIS guided group than the SAS guided group [midazolam (mg×kg(-1) ×h(-1) ): 0.10±0.02 vs. 0.09±0.02, propofol (mg×kg(-1) ×h(-1) ): 0.95±0.23 vs. 0.86±0.20, both P<0.05]. The total time (D t) of patients under sedative control was significantly longer in BIS guided group compared with SAS guided group, and also in first three hours [D 1, D 2, D 3, D t: 75.2% (507) vs. 52.8% (421), D 1: 78.6% (33) vs. 22.2% (14), D 2: 88.1% (37) vs. 20.6% (13), D 3: 81.0% (34) vs. 31.7% (20), all P<0.01]. The time to wake up (minutes) was significantly shorter in BIS guided group compared with SAS guided group [0 (0, 20) vs. 15 (0, 47), P<0.05]. No significant difference in acute physiology and chronic health evaluation II (APACHE II) score (3.57±2.60 vs. 4.19±2.30), duration of mechanical ventilation [hours: 16.5 (14.5, 19.0) vs. 17.0 (15.0, 19.0)], sedation time [hours: 14.0 (12.9, 17.1) vs. 16.0 (13.0, 18.0)] and incidence of adverse events including restlessness after suction (81.0% vs. 79.4%), endotracheal tube resistance (71.4% vs. 74.6%), pain tolerance during sedation (92.8% vs. 93.6%) and delirium after extubation (4.8% vs. 1.6%) was found between BIS guided group and SAS guided group (all P>0.05).\nBIS monitoring is better in sedative control than SAS assessment for ICU patients undergoing short term mechanical ventilation.', 'title': '[A comparison of bispectral index and sedation agitation scale in guiding sedation therapy: a randomized controlled study in patients undergoing short term mechanical ventilation].', 'date': '2011-04-09'}}
| 0
|
Emergency Medicine & Critical Care
|
64
|
Is the incidence of endotracheal tube resistance higher, lower, or the same when comparing bispectral index (BIS) monitoring to clinical assessment for sedation?
|
uncertain effect
|
very low
|
no
|
['21473824']
| 29,464,690
| 2,018
|
{'21473824': {'article_id': '21473824', 'content': 'To compare the value of bispectral index (BIS) monitoring and sedation agitation scale (SAS) in guiding intensive care unit (ICU) sedation therapy for the patients undergoing short term mechanical ventilation.\nOne hundred and five patients aged 18-60 years after operation receiving mechanical ventilation for longer than 12 hours in ICU were enrolled in this study. The patients were randomly divided into two groups: BIS guided group (n=42) and SAS guided group (n=63). All of them received protocolized continuous sedation and analgesia by using fentanyl for analgesia and propofol plus midazolam to sedate intravenously. The effect of sedation was assessed every hour till BIS reaching 50-70 or SAS reaching grade 3-4. Sedatives and analgesics were suspended at 6:00 am on next day after ICU admission , and BIS and the SAS were recorded every hour, sedation time, time to wake up, duration of mechanical ventilation, daily dosage of midazolam and propofol, and the incidence of adverse events including restlessness after suction, endotracheal tube resistance, pain tolerance during sedation, and delirium after extubation were all recorded accordingly.\nDosages of midazolam and propofol were found higher in BIS guided group than the SAS guided group [midazolam (mg×kg(-1) ×h(-1) ): 0.10±0.02 vs. 0.09±0.02, propofol (mg×kg(-1) ×h(-1) ): 0.95±0.23 vs. 0.86±0.20, both P<0.05]. The total time (D t) of patients under sedative control was significantly longer in BIS guided group compared with SAS guided group, and also in first three hours [D 1, D 2, D 3, D t: 75.2% (507) vs. 52.8% (421), D 1: 78.6% (33) vs. 22.2% (14), D 2: 88.1% (37) vs. 20.6% (13), D 3: 81.0% (34) vs. 31.7% (20), all P<0.01]. The time to wake up (minutes) was significantly shorter in BIS guided group compared with SAS guided group [0 (0, 20) vs. 15 (0, 47), P<0.05]. No significant difference in acute physiology and chronic health evaluation II (APACHE II) score (3.57±2.60 vs. 4.19±2.30), duration of mechanical ventilation [hours: 16.5 (14.5, 19.0) vs. 17.0 (15.0, 19.0)], sedation time [hours: 14.0 (12.9, 17.1) vs. 16.0 (13.0, 18.0)] and incidence of adverse events including restlessness after suction (81.0% vs. 79.4%), endotracheal tube resistance (71.4% vs. 74.6%), pain tolerance during sedation (92.8% vs. 93.6%) and delirium after extubation (4.8% vs. 1.6%) was found between BIS guided group and SAS guided group (all P>0.05).\nBIS monitoring is better in sedative control than SAS assessment for ICU patients undergoing short term mechanical ventilation.', 'title': '[A comparison of bispectral index and sedation agitation scale in guiding sedation therapy: a randomized controlled study in patients undergoing short term mechanical ventilation].', 'date': '2011-04-09'}}
| 0
|
Surgery
|
65
|
Is improvement in depression symptoms higher, lower, or the same when comparing SSRIs to placebo?
|
no difference
|
very low
|
no
|
['25308771', '17136950']
| 30,566,235
| 2,018
|
{'25308771': {'article_id': '25308771', 'content': "There is a lack of randomized controlled trials to assess the effects of pharmacological treatments in patients with stable chronic obstructive pulmonary disease (COPD) complicated with moderate or severe depression.\nTo assess the efficacy of sertraline hydrochloride on improving the quality of life of patients with stable COPD complicated with depression.\nThis randomized controlled trial, conducted from May to November 2013 in the Huai'an Second Hospital, Huai'an, China, enrolled 120 patients with stable COPD who had moderate or severe depression. Patients were randomly assigned to control and interventional groups (n\u2009=\u200960 in each group). In addition to the treatment for COPD, interventional group also received sertraline hydrochloride tablets 50\u2009mg/day for 6\u2009weeks, while the control group received placebo. The primary end point included COPD assessment test (CAT) scores and the secondary endpoint included 6-min walk distance and 17-item Hamilton Depression Rating Scale (HAMD-17) scores. Parameters of spirometry and adverse events were also observed.\nThere was no significant difference in improvements in the parameters of spirometry tests before and after the treatment with sertraline hydrochloride tablets between the placebo and interventional groups (P\u2009>\u20090.05). Patients in the sertraline hydrochloride group showed more changes in the HAMD-17 scores and CAT scores after treatment (P\u2009<\u20090.05) and travelled longer distances in the 6-min walk test than in the placebo group (P\u2009<\u20090.05).\nAntidepressant treatment can improve the quality of life and exercise capacity of patients with depression, and it can also improve depression scores, but not lung function.", 'title': 'Sertraline hydrochloride treatment for patients with stable chronic obstructive pulmonary disease complicated with depression: a randomized controlled trial.', 'date': '2014-10-14'}, '17136950': {'article_id': '17136950', 'content': "The aim of this study was to determine whether treating concomitant depression improves quality of life and exercise tolerance in COPD patients. Out-patients with moderate to severe, stable COPD completed Hospital Anxiety-Depression (HAD) and General Health questionnaires. A psychiatrist interviewed those with high scores. In a randomised, double-blind fashion, 28 depressed COPD patients took a selective serotonin re-uptake inhibitor, Paroxetine 20 mg daily, or matched placebo for 6 weeks. Subsequently, all patients took un-blinded Paroxetine for 3 months. From these questionnaires, 35% of 135 patients had significant depression, but this was confirmed by psychiatric interview in only 21%. Throughout the study, there were no changes in laboratory lung function nor in home peak flow. Six weeks' treatment produced no significant differences between placebo and treatment group in either depression, quality of life scores or 6-minute walking distances, although overall improvements in depression, correlated with increases in walking distance. Three months of un-blinded treatment, significantly improved depression scores (self-complete HAD, Beck's Depression and psychiatrist-completed Montgomery-Asberg scores), walking distances (369 to 427 m, p = 0.0003) and St. George's Respiratory Questionnaire Total Scores (65 to 58, p = 0.033). Although self-complete questionnaires over-diagnose depression, the condition is nevertheless common in patients with moderately severe COPD. Six weeks of antidepressants is insufficient to improve either depression, quality of life or exercise tolerance. However, our study suggests that a longer course of treatment may be effective and that improvements in depression are associated with improvements in exercise tolerance. A larger, double blind study with a longer treatment period is indicated.", 'title': 'Effect of treating depression on quality-of-life and exercise tolerance in severe COPD.', 'date': '2006-12-02'}}
| 0.5
|
Psychiatry & Neurology
|
66
|
Is the risk of major postoperative bleeding requiring intervention higher, lower, or the same when comparing tranexamic acid (TXA) to placebo?
|
lower
|
moderate
|
no
|
['2648144', '8229393']
| 29,963,686
| 2,018
|
{'2648144': {'article_id': '2648144', 'content': 'We carried out a placebo-controlled, double-blind, randomized study of the hemostatic effect of tranexamic acid mouthwash after oral surgery in 39 patients receiving anticoagulant agents because of the presence of cardiac valvular stenosis, a prosthetic cardiac valve, or a vascular prosthesis. Surgery was performed with no change in the level of anticoagulant therapy, and treatment with the anticoagulant agent was continued after surgery. Before it was sutured, the operative field was irrigated in 19 patients with 10 ml of a 4.8 percent aqueous solution of tranexamic acid (an inhibitor of fibrinolysis) and in 20 patients with a placebo solution. For seven days thereafter, patients were instructed to rinse their mouths with 10 ml of the assigned solution for two minutes four times a day. There were no significant differences between the two treatment groups in base-line variables, including the level of anticoagulation at the time of surgery. Eight patients in the placebo group had a total of 10 postoperative bleeding episodes, whereas only 1 patient in the tranexamic acid group had a bleeding episode (P = 0.01). There were no systemic side effects. We conclude that local antifibrinolytic therapy is effective in preventing bleeding after oral surgery in patients who are being treated with anticoagulants.', 'title': 'Hemostatic effect of tranexamic acid mouthwash in anticoagulant-treated patients undergoing oral surgery.', 'date': '1989-03-30'}, '8229393': {'article_id': '8229393', 'content': 'The hemostatic effect of tranexamic acid solution (4.8%) used as a mouthwash was compared with a placebo solution in 93 patients on continuous, unchanged, oral anticoagulant treatment undergoing oral surgery. The investigation was a randomized, double-blind, placebo-controlled, multicenter study. Before suturing, the surgically treated region was irrigated with 10 mL of tranexamic acid (46 patients) or placebo (47 patients) solution. The patients then performed mouthwash with 10 mL of the solution for 2 minutes four times daily for 7 days. The treatment groups were comparable regarding age, smoking habits, and surgery. Laboratory variables measuring vitamin K-dependent coagulation factors were within therapeutic ranges (international normalized ratio 4.00 to 2.10). One of the clinics used a different method for these measurements and therefore the levels of coagulation factor X in plasma obtained for the three clinics were compared. No significant difference in the range at which surgery was performed was found between clinics. In the placebo group, 10 patients developed bleeding requiring treatment, while none of the patients treated with tranexamic acid solution had bleeding. This difference was statistically significant (P < .01). The treatment with mouthwash was well tolerated. It was concluded that patients on oral anticoagulants can undergo oral surgery within the therapeutic range without reducing the dosage of anticoagulants, provided that local antifibrinolytic treatment with tranexamic acid solution is instituted.', 'title': 'Prevention of postsurgical bleeding in oral surgery using tranexamic acid without dose modification of oral anticoagulants.', 'date': '1993-11-01'}}
| 1
|
Surgery
|
67
|
Is the risk of developing microbiologically confirmed tuberculosis higher, lower, or the same when comparing MVA85A added to BCG to BCG alone?
|
no difference
|
moderate
|
yes
|
['25726088', '23391465']
| 31,038,197
| 2,019
|
{'25726088': {'article_id': '25726088', 'content': "Lancet Respir MedLancet Respir MedThe Lancet. Respiratory Medicine2213-26002213-2619Elsevier257260884648060S2213-2600(15)00037-510.1016/S2213-2600(15)00037-5ArticlesSafety, immunogenicity, and efficacy of the candidate tuberculosis vaccine MVA85A in healthy adults infected with HIV-1: a randomised, placebo-controlled, phase 2 trialNdiayeBirahim PierreMDa*ThienemannFriedrichMDbd*OtaMartinFWACPeLandryBernard SMPHfCamaraMakhtarPhDaDièyeSiryMDaDieyeTandakha NdiayePhDaEsmailHanifMRCPbjGoliathReneBScbHuygenKrisPhDgJanuaryVanessabNdiayeIbrahimaMDaOniToluMDbcRaineMichaelBScfRomanoMartaPhDgSattiImanPhDiSuttonSharonBSfThiamAminataMDhWilkinsonKatalin APhDbdkMboupSouleymaneProfPhDaWilkinsonRobert JProfFRCPbdjk†McShaneHelenProfFRCPhelen.mcshane@ndm.ox.ac.uki*†for the MVA85A 030 trial investigators‡aLaboratoire de Bactériologie–Virologie, Centre Hospitalier Universitaire Le Dantec, Dakar, SenegalbClinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South AfricacDivision of Public Health Medicine, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South AfricadDepartment of Medicine, University of Cape Town, Cape Town, South AfricaeMedical Research Council Unit, Fajara, The GambiafAeras, Rockville, MD, USAgImmunology Service, Scientific Institute of Public Health (WIV-ISP), Brussels, BelgiumhCentre de Traitement Ambulatoire, Centre Hospitalier Universitaire de Fann, Dakar, SenegaliJenner Institute, University of Oxford, Oxford, UKjDepartment of Medicine, Imperial College London, London, UKkMRC National Institute for Medical Research, London, UK*Correspondence to: Prof Helen McShane, Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK helen.mcshane@ndm.ox.ac.uk*Joint first authors†Joint last authors‡Listed in appendix1320153201533190200© 2015 Ndiaye et al. Open Access article distributed under the terms of CC BY2015This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).SummaryBackgroundHIV-1 infection is associated with increased risk of tuberculosis and a safe and effective vaccine would assist control measures. We assessed the safety, immunogenicity, and efficacy of a candidate tuberculosis vaccine, modified vaccinia virus Ankara expressing antigen 85A (MVA85A), in adults infected with HIV-1.MethodsWe did a randomised, double-blind, placebo-controlled, phase 2 trial of MVA85A in adults infected with HIV-1, at two clinical sites, in Cape Town, South Africa and Dakar, Senegal. Eligible participants were aged 18–50 years, had no evidence of active tuberculosis, and had baseline CD4 counts greater than 350 cells per μL if they had never received antiretroviral therapy or greater than 300 cells per μL (and with undetectable viral load before randomisation) if they were receiving antiretroviral therapy; participants with latent tuberculosis infection were eligible if they had completed at least 5 months of isoniazid preventive therapy, unless they had completed treatment for tuberculosis disease within 3 years before randomisation. Participants were randomly assigned (1:1) in blocks of four by randomly generated sequence to receive two intradermal injections of either MVA85A or placebo. Randomisation was stratified by antiretroviral therapy status and study site. Participants, nurses, investigators, and laboratory staff were masked to group allocation. The second (booster) injection of MVA85A or placebo was given 6–12 months after the first vaccination. The primary study outcome was safety in all vaccinated participants (the safety analysis population). Safety was assessed throughout the trial as defined in the protocol. Secondary outcomes were immunogenicity and vaccine efficacy against Mycobacterium tuberculosis infection and disease, assessed in the per-protocol population. Immunogenicity was assessed in a subset of participants at day 7 and day 28 after the first and second vaccination, and M tuberculosis infection and disease were assessed at the end of the study. The trial is registered with ClinicalTrials.gov, number NCT01151189.FindingsBetween Aug 4, 2011, and April 24, 2013, 650 participants were enrolled and randomly assigned; 649 were included in the safety analysis (324 in the MVA85A group and 325 in the placebo group) and 645 in the per-protocol analysis (320 and 325). 513 (71%) participants had CD4 counts greater than 300 cells per μL and were receiving antiretroviral therapy; 136 (21%) had CD4 counts above 350 cells per μL and had never received antiretroviral therapy. 277 (43%) had received isoniazid prophylaxis before enrolment. Solicited adverse events were more frequent in participants who received MVA85A (288 [89%]) than in those given placebo (235 [72%]). 34 serious adverse events were reported, 17 (5%) in each group. MVA85A induced a significant increase in antigen 85A-specific T-cell response, which peaked 7 days after both vaccinations and was primarily monofunctional. The number of participants with negative QuantiFERON-TB Gold In-Tube findings at baseline who converted to positive by the end of the study was 38 (20%) of 186 in the MVA85A group and 40 (23%) of 173 in the placebo group, for a vaccine efficacy of 11·7% (95% CI −41·3 to 44·9). In the per-protocol population, six (2%) cases of tuberculosis disease occurred in the MVA85A group and nine (3%) occurred in the placebo group, for a vaccine efficacy of 32·8% (95% CI −111·5 to 80·3).InterpretationMVA85A was well tolerated and immunogenic in adults infected with HIV-1. However, we detected no efficacy against M tuberculosis infection or disease, although the study was underpowered to detect an effect against disease. Potential reasons for the absence of detectable efficacy in this trial include insufficient induction of a vaccine-induced immune response or the wrong type of vaccine-induced immune response, or both.FundingEuropean & Developing Countries Clinical Trials Partnership (IP.2007.32080.002), Aeras, Bill & Melinda Gates Foundation, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium.Research in contextEvidence before this studyOne previous study assessed the efficacy of several doses of the saprophyte Mycobacterium vaccae against tuberculosis disease in adults infected with HIV-1, and showed a decreased risk of protocol-defined pulmonary tuberculosis. A previous study with the MVA85A, the candidate vaccine under assessment here, has showed that boosting with MVA85A did not enhance protective efficacy in BCG-vaccinated infants. Adults infected with HIV-1 are an important target population for a new tuberculosis vaccine, and in earlier studies, vaccine-induced immunogenicity in adults infected with HIV-1 was higher than in infants.Added value of this studyThis is the first time that a candidate tuberculosis vaccine has been assessed for efficacy against Mycobacterium tuberculosis infection in people infected with HIV-1. The results show that vaccinating adults infected with HIV-1 with MVA85A is safe, but does not confer protection against infection with M tuberculosis.Implications of all the available evidenceThe safety of MVA85A in this large study population of adults with HIV infection is an important finding for tuberculosis vaccine development. The vector is safe to give to people without HIV testing; these safety data provide some generic reassurance that new candidate tuberculosis vaccines are safe in this higher risk population. Additionally, this study has shown that high-quality, multicentre tuberculosis vaccine trials in vulnerable populations are possible. The absence of efficacy despite immunogenicity in this and previous clinical trials of MVA85A suggests that the current parameters for selection of tuberculosis vaccine candidates are inadequate. Standardised preclinical animal models that better represent human infection and disease, and a greater understanding of immune mechanisms of protection in human tuberculosis are both urgently needed. Alternative approaches to vaccine development, including the delivery of candidate vaccines direct to the respiratory mucosa, merit assessment. Other lessons learnt from this trial include the characterisation of the epidemiology of M tuberculosis infection and disease associated with HIV-1 infection in a setting of antiretroviral therapy and isoniazid chemoprophylaxis.IntroductionTuberculosis is a substantial global cause of mortality and morbidity, with 9 million new cases of active tuberculosis and 1·5 million deaths occurring in 2013.1 One third of the world's population is infected with Mycobacterium tuberculosis.1 HIV-1 co-infection is one of the most important risk factors for both infection with M tuberculosis and active tuberculosis disease,2 with an estimated 1·1 million of all new tuberculosis cases in 2013 occurring in people co-infected with HIV-1.1 The WHO African region accounts for 80% of HIV-1-associated tuberculosis.1 Additionally, the growing incidence of drug-resistant tuberculosis is associated with poor treatment outcome and increased mortality.3 The global Stop TB Partnership aims to eliminate tuberculosis as a public health problem by 2050. An agreed major component to advance this aim would be an effective vaccine.4 BCG is the only licensed tuberculosis vaccine—it provides protection against severe childhood tuberculosis,5, 6 but the protection conferred against pulmonary tuberculosis in adults and adolescents is highly variable.7, 8At least 16 candidate tuberculosis vaccines have advanced to clinical testing.9 The modified vaccinia virus Ankara expressing the major M tuberculosis antigen 85A (MVA85A) is a clinically advanced candidate vaccine.10, 11, 12 MVA85A is well tolerated and immunogenic in adults infected and not infected with HIV-1, and in infants not exposed to HIV-1.10, 11, 12, 13, 14 MVA85A adds to BCG-induced protection against mycobacterial challenge in some preclinical animal models.15, 16, 17, 18, 19 However, boosting BCG with MVA85A in South African infants not infected with HIV-1 did not confer additional protection against tuberculosis disease or M tuberculosis infection.10Administration of several doses of the saprophyte Mycobacterium vaccae to adults infected with HIV-1 was associated with a decreased risk of protocol-defined pulmonary tuberculosis,20 suggesting that vaccination might be effective in people infected with HIV-1. Here we report the results of a multisite, randomised, placebo-controlled, phase 2 trial to assess the safety, immunogenicity, and efficacy of MVA85A in healthy adults infected with HIV-1.MethodsStudy design and participantsWe did a proof-of-concept, randomised, double-blind, placebo-controlled, phase 2 trial of MVA85A at two clinical sites, in Cape Town, South Africa and Dakar, Senegal. In Cape Town, participants were recruited in the community and from primary care clinics in Khayelitsha by use of radio and newspaper advertisements, flyers, pamphlets, and information campaigns at the clinics. Khayelitsha is a densely populated, low-income, peri-urban township. In 2010, antenatal HIV-1 prevalence was 33% and the tuberculosis case notification rate was at least 1500 per 100\u2008000 population per year.21 In Dakar, participants were recruited from public service HIV clinics at the Centre de Traitement Ambulatoire and the Centre de Recherche Clinique et de Formation, Centre Hospitalier Universitaire de Fann. Senegal had an estimated HIV-1 prevalence in adults of less than 1% in 2012, and a reported tuberculosis incidence rate of 0·14% in 2013.1 The annual rate of M tuberculosis infection has not previously been estimated at either site. Eligibility criteria included participants aged 18–50 years with no evidence of active tuberculosis, and baseline CD4 counts greater than 350 cells per μL if they were not receiving antiretroviral therapy, or greater than 300 cells per μL (and with undetectable viral load before randomisation) if they were receiving antiretroviral therapy. Participants with latent tuberculosis infection were eligible for enrolment if they had completed at least 5 months of isoniazid preventive therapy, unless they had completed treatment for tuberculosis disease within 3 years before randomisation. The complete inclusion criteria are listed in the study protocol (appendix).The trial adhered to International Conference on Harmonisation Good Clinical Practice guidelines, and was approved by the University of Cape Town's Faculty of Health Sciences Human Research Ethics Committee and the Medicines Control Council of South Africa; the Senegalese National Ethics Committee for Research in Health; and the Oxford University Tropical Research Ethics Committee. All participants provided written informed consent before any study procedure.Randomisation and maskingParticipants were randomly assigned (1:1) in blocks of four by a randomly generated sequence of participant identification numbers via an interactive voice response system to receive two intradermal injections of either 1\u2008×\u2008108 pfu MVA85A or placebo (Candida skin test antigen [Candin], Allermed Laboratories, San Diego, CA, USA). Randomisation was stratified by antiretroviral therapy status and study site. A statistician uninvolved with study analyses prepared the interactive voice response system randomisation schedule. Doses of vaccines were prepared and labelled in masked syringes by a pharmacist unmasked to group allocation. Participants, nurses (who were involved in assessment and follow-up), investigators, and laboratory staff were masked to group allocation. The second (booster) injection of MVA85A or placebo was given 6–12 months after the first vaccination and participants were actively followed up every 3 months until the last participant enrolled had completed 6 months of follow-up after the booster vaccination.ProceduresWe collected data for the incidence of solicited and unsolicited adverse events, including both local injection-site reactions and systemic reactions. Participants reported solicited adverse events on diary cards for 7 days after each vaccination and in response to direct questioning by trained study staff on days 7 and 28 after each injection. Phlebotomy for routine haematological and biochemical analysis was done at screening, before booster vaccination, and on days 7 and 28 after each vaccination. Peripheral CD4 cell count and HIV-1 viral load were also measured at these timepoints and every 3 months until 6 months after booster vaccination. Serious adverse events were monitored by active surveillance throughout and until the end of the trial. The site investigators and local medical monitors determined the severity and seriousness of adverse events and the relation of these to the vaccine. An independent data monitoring committee assessed masked group safety data after 200 participants had been enrolled and unmasked after 600 participants had been enrolled.In a prespecified subset of 70 participants (35 from each group), immunology samples were obtained before each vaccination and on days 7 and 28 after each vaccination. All immunology tests were done masked to group allocation. We assessed vaccine immunogenicity with three assays. First, ex vivo interferon γ enzyme-linked immunospot (ELISPOT) analysis was done on fresh peripheral blood mononuclear cells.22 Cells were stimulated overnight with a single pool of 66 peptides of the antigen 85A (Ag85A), ESAT-6, and CFP-10. Second, Ag85A-specific intracellular cytokine staining assay was done on whole blood.23 Stimulated fixed whole blood samples were stained for CD3-positive, CD4-positive, CD8-positive, CD14-positive, and CD19-positive cells, interferon γ, tumour necrosis factor α, interleukin 17, and interleukin 2. Third, Ag85A-specific antibody response was measured on plasma. Ag85A-specific immunoglobulin G (IgG) antibodies were measured by ELISA on eight serial two-fold dilutions of plasma (1:25–1:3200), by use of affinity purified recombinant, histidine-tagged Ag85A24 (microwell plates coated with 50 ng per well of recombinant Ag85A in borate buffer, overnight at 4°C). Alkaline phosphatase-labelled goat anti-human IgG (Sigma, St Louis, MO, USA) was used as secondary antibody at a dilution of 1:1000 and optical density was read at 405 nm after development with phosphatase substrate (Sigma). Results were expressed in arbitrary units per mL (AU/mL), as compared with values of an internal tuberculosis serum standard of 2500 AU/mL.Participants were screened to exclude active tuberculosis by symptom screen and chest radiography at both sites before enrolment. In Cape Town, participants also underwent sputum collection for tuberculosis smear microscopy, GeneXpert MTB/RIF (Cepheid, Sunnyvale, CA, USA), and mycobacterial liquid culture (MGIT; Becton Dickinson, Sparks, MD, USA) because of previously documented high frequencies of asymptomatic disease at this site.25 Latent M tuberculosis infection was defined as either a positive QuantiFERON-TB Gold In-Tube (QFT) test or a tuberculin purified protein derivative skin test (tuberculin skin test) reaction greater than 5 mm.Participants were monitored throughout the trial for possible tuberculosis. Tuberculosis investigations were done in participants who had been in contact with a known case of active tuberculosis, in those who presented with at least one of cough for more than 1 week, fever for more than 1 week, drenching night sweats, unintentional weight loss of more than 3 kg, pleuritic chest pains, haemoptysis, or shortness of breath; and in those who converted to a positive QFT or tuberculin skin test (≤5 mm to >5 mm). Investigations included clinical examination, chest radiography, and collection of at least two sputum samples on which tuberculosis smear microscopy, GeneXpert MTB/RIF, and mycobacterial liquid culture were done. Chest radiographs were reviewed by two physicians, with a third reading to achieve consensus in the event of disagreement. QFT and tuberculin skin tests were repeated at the final study visit.OutcomesTuberculosis disease endpoint 1 was defined as culture or GeneXpert MTB/RIF positivity; endpoint 2 included endpoint 1 and a composite clinical endpoint (which included a single acid-fast bacilli smear from a sterile body site; two smears from pulmonary and gastric sampling, and compatible clinical symptoms and radiological signs); and endpoint 3 was participant commencement on anti-tubercular chemotherapy (see the study protocol for more information; appendix). The M tuberculosis infection endpoint was defined as conversion from negative QFT at baseline to positive QFT at the final visit.The primary study outcome was the safety of MVA85A in all participants who received at least one dose of study vaccine or placebo (the safety analysis population) as determined by the numbers and percentages of adverse events (including solicited, unsolicited, and serious adverse events).The secondary outcome was the efficacy of MVA85A for the prevention of active tuberculosis in the per-protocol population (all randomly allocated participants who received at least one dose of study vaccine or placebo and had no major protocol deviations and no tuberculosis case definition endpoints within 28 days after study day 0 [first vaccination]), which was determined by the incidence of active tuberculosis meeting the definition of endpoint 1, calculated as the number of new cases of active tuberculosis with a date of diagnosis from 28 days after the first vaccination until the end of the study follow-up (May 19, 2014). An intention-to-treat analysis was also done for disease efficacy. In the per-protocol population, we also examined the efficacy of MVA85A by antiretroviral therapy status at the time of randomisation and by baseline isoniazid preventive therapy status.Other secondary outcomes were to assess CD4-positive lymphocyte counts and HIV-1 viral load before and after administration of MVA85A compared with placebo; to assess the immunogenicity of MVA85A compared with placebo as measured by the ex-vivo interferon γ ELISPOT assay; to assess the immunogenicity of MVA85A compared with placebo as measured by flow cytometric intracellular cytokine staining of CD4-positive and CD8-positive T cells after stimulation with a peptide pool of mycobacterial antigens; to identify potential immunological correlates of protection from tuberculosis in participants vaccinated with MVA85A and to assess the QFT conversion rate at final study assessment in MVA85A recipients compared with controls without a diagnosis of tuberculosis during the trial.Statistical analysisAll sample size calculations assumed a loss to follow-up and death rate of 2%. The initial planned sample size for this trial was 1400 adult participants, to be followed up for 2 years after the last participant was enrolled. This sample size provided 80% power to detect a vaccine efficacy of 60% against tuberculosis disease. However, after review of the phase 2 infant efficacy data,10 the trial design was revised with safety as the primary objective and a smaller sample size and shorter follow-up of a minimum of 6 months. The revised sample size for this study was selected as adequate for a review of the safety profile. With 325 participants assigned to receive MVA85A, the revised sample would have a 90% probability of detecting at least one adverse event occurring at a rate of 0·71%. Because of the expected effect of antiretroviral therapy on tuberculosis disease, an estimated tuberculosis disease incidence ranging between 1·5% and 2% per year was used to estimate the power of the revised sample size for efficacy. Calculations were based on a one-sided log-rank test at a significance level of 0·10 and assumed completion of enrolment in 21 months, a follow-up period of about 15 months for the last patient enrolled, and a maximum of 36 months for the first patient enrolled. If the true efficacy was about 70%, 325 patients per treatment group (650 patients total) provided 81% power to show positive efficacy given an incidence rate of 2·0% in the control group per year, or 71% power given an incidence rate of 1·5% in the control group per year. At a true efficacy of about 60%, 325 patients per treatment group provided 67% power to show positive efficacy given an incidence rate of 2·0% per year, or 57% power given an incidence rate of 1·5% per year. Vaccine efficacy to prevent infection was a secondary endpoint: the recorded QFT conversion rate in the study provided 80% power to detect a vaccine efficacy of 50%.Statistical analyses were done using SAS version 9.2. All analyses were prespecified in the statistical analysis plan before locking of the database. For the safety analysis, we compared the proportion of participants with at least one adverse event in the MVA85A group versus those in the placebo using Fisher's exact test. We also calculated two-sided 95% CIs for proportions of adverse events within treatment groups and the differences between groups.The main statistical method used in the analysis of tuberculosis disease endpoints 1–3 was vaccine efficacy, estimated as 1 minus the estimated hazard ratio, based on a Cox regression analysis of time (days) to initial tuberculosis diagnosis, based on the per-protocol population. As supportive confirmatory analysis, we used the conditional binomial (Clopper-Pearson) method to estimate vaccine efficacy and its corresponding two-sided 95% CIs and p values. Time to initial diagnosis for each endpoint was compared by use of a two-sided log-rank test, stratified by study site and antiretroviral therapy status at randomisation. Analyses were summarised by antiretroviral therapy and treatment group for participants in the per-protocol population. Vaccine efficacy against M tuberculosis infection and the corresponding 95% CI, and p value were calculated with the conditional binomial method (Clopper-Pearson), identical to the tuberculosis case definition endpoint analysis.Other secondary endpoints were analysed in various ways. Median CD4 cell counts and associated two-sided 95% CIs were summarised by antiretroviral therapy status at randomisation, study site, treatment group, and timepoint. HIV-1 viral load (copies per mL) was summarised with medians (and associated 95% CIs) by antiretroviral therapy status at randomisation, study site, and treatment group, at each available timepoint. Both the CD4 cell counts and HIV-1 viral load values were log-transformed before any analysis was done. We used Wilcoxon paired analysis to compare within group before and after vaccination responses.Quintiles (Blomfontein, South Africa) did the statistical analysis, and Aeras paid for this service. The trial was registered with ClinicalTrials.gov, number NCT01151189.Role of the funding sourceAeras was the trial sponsor and contributed to study design and data analysis. The other funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. BPN, FT, BSL, RJW, and HM had full access to all the data in the study. HM had final responsibility for the decision to submit for publication.ResultsBetween Aug 4, 2011, and April 24, 2013, 1233 adults infected with HIV-1 were screened and 650 were randomly assigned; 649 were included in the safety analysis and 645 in the per-protocol analysis (figure 1). 513 (71%) participants had CD4 counts greater than 300 cells per μL and were receiving antiretroviral therapy; 136 (21%) had CD4 counts above 350 cells per μL and had never received antiretroviral therapy. The results of the intention-to-treat analysis were not different and are not reported. 311 (96%) participants in the placebo group and 298 (92%) in the MVA85A group received the booster vaccination. One participant was randomly assigned to placebo but received MVA85A; this participant was included in the safety population for MVA85A but not in the per-protocol efficacy population. One participant was randomly assigned to MVA85A but withdrew consent before vaccination and was not vaccinated. This participant was excluded from both the safety and per-protocol populations. Baseline demographic characteristics were similar in the two study groups and across the two study sites (table 1; appendix). 625 participants completed the study; 14 participants were lost to follow-up (nine placebo, five MVA85A), five withdrew consent (two placebo, three MVA85A), and six died (four placebo, two MVA85A).In the per-protocol population, median follow-up was 655 days for the 320 recipients of MVA85A and 654 days for the 325 placebo participants. Other than the four participants shown in figure 1, all participants were included in the analysis.At least one adverse event was reported in 312 (96%) of placebo recipients and 321 (99%) of MVA85A recipients (table 2). Solicited adverse events were more common in participants who received MVA85A than placebo (table 2). Most of these events were local injection-site reactions; other solicited adverse events included mild influenza-like symptoms and regional lymphadenopathy. We noted no significant difference between study groups in the frequency of serious adverse events. 34 serious adverse events occurred during the study, 17 in the placebo group and 17 in the MVA85A group (table 2; appendix). All but one of these events were judged to be unrelated to vaccination; a case of probable tuberculous meningitis that occurred 6 days after vaccination was judged to be possibly related to vaccination. The data monitoring committee reviewed this case, did not request unmasking, and recommended continuing with the study. The participant was treated for tuberculous meningitis and made a full recovery. At study completion, this participant was identified as having received MVA85A. 13 serious adverse events in the infections and infestations category occurred during the study (the only category with more than five serious adverse events in either group), eight in the placebo group and five in the MVA85A group; this difference was not significant (Fisher's exact test, p=0·58).The frequency of severe adverse events did not differ significantly between study groups (table 2). We noted no significant changes in CD4 cell count or HIV-1 viral load throughout the course of the trial in either study group (data not shown). Routine haematological and biochemical test results did not differ between study groups (data not shown).ELISPOT responses to Ag85A were significantly higher in participants from Dakar than in those from Cape Town at baseline (p=0·0016), but at no other timepoint. This difference was not seen with the less sensitive whole blood intracellular cytokine staining assay. MVA85A induced an Ag85A-specific T-cell response that peaked 7 days after the first and booster vaccinations (median spots per million: day 0 [first vaccination], 9·0 [IQR 2·3–51·0]; day 7 [first vaccination], 337·0 [139·3–993·8]; day 0 [booster vaccination], 103·5 [14·8–223·8]; day 7 [booster vaccination], 426·0 [150·0–745·0]; figure 2). Responses at each timepoint after vaccination did not differ by study site or by antiretroviral therapy status. Medians in the placebo group did not exceed 20 spots per million at any timepoint.Whole blood intracellular cytokine staining showed the most commonly measured cytokine from CD4 T cells was interferon γ, in agreement with the ELISPOT data. Tumour necrosis factor α and low concentrations of interleukins 2 and 17 were also detected (table 3, figure 2). Overall, numbers of antigen-specific CD8 T cells were very low and were only positive for interferon γ and tumour necrosis factor α. Multiparameter flow-cytometric analysis showed that mainly monofunctional Ag85A-specific CD4 T cells were present before and after vaccination (figure 3). Ag85A-specific antibody responses were less than twice the baseline value after vaccination in all but three participants.In the per-protocol population, the overall number of tuberculosis cases and incidence during study follow-up of tuberculosis cases (endpoint 1) was six (2%) in the MVA85A group and nine (3%) in the placebo group, for a vaccine efficacy of 32·8% (95% CI −111·5 to 80·3; table 4). Figure 4 shows the Kaplan-Meier time-to-disease analysis for endpoint 1. Stratification by antiretroviral therapy status showed no significant difference between treatment groups. Eight of the 15 endpoint 1 cases were QFT positive at enrolment. No additional participants met endpoint 2 who did not already meet endpoint 1. Vaccine efficacy for endpoint 3 was 10·5% (−161·3 to 70.0). Disease incidence did not differ by site. Median time to diagnosis of endpoint 1 was 249 days in the MVA85A group and 236 days in the placebo group. 159 (50%) of 320 MVA85A recipients and 148 (46%) of 325 placebo recipients were investigated for tuberculosis during the study. The study was insufficiently powered to assess the efficacy of MVA85A for the prevention of tuberculosis disease in the subset of participants receiving antiretroviral therapy or isoniazid prophylaxis. The absence of efficacy also made it impossible to identify potential immunological correlates of protection from tuberculosis in participants vaccinated with MVA85A.The number of QFT-negative participants who converted to QFT positive by the end of the study was 38 (20%) in the MVA85A group and 40 (23%) in the placebo group, for a vaccine efficacy of 11·7% (95% CI −41·3 to 44·9). QFT conversion did not differ by antiretroviral therapy status (data not shown), but it did differ by site. In Cape Town, 41 (31%) of 132 participants converted, whereas in Dakar, 37 (16%) of 227 converted (χ2 10·89, p=0·001). Frequency of QFT reversion (participants who were positive at baseline and negative at end of study) was similar in the two treatment groups (17 [14%] of 124 for MVA85A and 27 [19%] of 139 for placebo; p=0·22), and did not differ by antiretroviral therapy status (data not shown). Tuberculin skin test conversion was not a prespecified endpoint and is not reported here, but will be the subject of further analysis.DiscussionThis phase 2 trial in 650 adult participants infected with HIV-1 showed that MVA85A was well tolerated and immunogenic, with safety and immunogenicity profiles similar to those reported elsewhere for other populations in which this candidate vaccine has been assessed.10, 11, 12, 13, 14 However, we did not identify any significant efficacy against tuberculosis disease or M tuberculosis infection.Both first and booster vaccination with MVA85A induced a significant increase in Ag85A-specific T cells. Responses did not differ by antiretroviral therapy status. A probable explanation for this finding is the high baseline median CD4 count (571 cells per mm3; table 1, appendix) in participants who had not received antiretroviral therapy. Unlike the previously reported infant efficacy trial of MVA85A,10 baseline ELISPOT responses were detected in this trial and were significantly higher in participants from Dakar than in those from Cape Town. This result might be due to greater exposure to environmental mycobacteria; and the finding is unlikely to be due to a technical issue because it was only recorded at this timepoint, and there was a robust quality control programme in place for these assays. Furthermore, the median response 7 days after vaccination in this trial exceeded that seen in the infant trial (337 vs 136 spots per million).10 Additionally, the functional phenotype of the dominant T-cell population in this trial was monofunctional by contrast with the infant trial, in which the dominant phenotype was polyfunctional.10 In both trials, the recorded response was insufficient to be associated with protection. It is not clear whether a quantitatively greater or a qualitatively different immune response is needed for protection. Alternative approaches, including the delivery of candidate vaccines direct to the respiratory mucosa, might be more potent routes of immunisation. For example, we have previously reported that delivery of MVA85A by aerosol to HIV-negative, BCG-vaccinated adults in the UK is well tolerated and induces potent mucosal and systemic immunity.26 Further assessment is needed before this route can be examined in countries with a high burden of tuberculosis. This approach, together with other strategies to improve the immunogenicity of MVA85A, are currently under investigation.The recorded annual incidence of tuberculosis (endpoint 1) was substantial (1·43% across treatment groups) and did not differ between sites. However, this incidence was lower than previously reported in Cape Town.27 The numbers of participants receiving antiretroviral therapy was greater than originally envisaged, because of the increased availability of this therapy during the study period and the change in national and international guidelines on the provision of antiretroviral therapy. These factors, combined with the redesign of this study upon availability of the infant trial results,10 led to a reduction in statistical power to detect a difference in tuberculosis disease incidence between treatment groups, leading to wide CIs for our estimates of vaccine efficacy.In this trial, the incidence of infection determined by QFT conversion was much higher than the incidence of tuberculosis disease, so CIs around the estimates of efficacy against infection are narrower. The overall recorded annual QFT conversion rate of about 12% meant that we had about 80% power to detect a vaccine efficacy of 50% against M tuberculosis infection. In view of the cost and complexity of human efficacy studies, there is now increased focus on infection as an endpoint rather than disease in proof-of-concept studies before progression to prevention-of-disease efficacy trials.9 However, this approach presupposes that the immune mechanisms needed to prevent infection and disease are similar. Our poor understanding of the biology underlying dynamic QFT conversion and reversion further complicates this shift in emphasis. The rate of QFT reversion was almost as high as the rate of conversion: whether this finding represents a true biological effect or technical variability in the assay cannot be determined from these data.In this study, we have shown that high-quality, multicentre tuberculosis vaccine trials are possible in Africa, and have succeeded in the characterisation of the epidemiology of tuberculosis associated with HIV-1 in two African cities. Nevertheless, the disappointing finding with respect to vaccine efficacy for MVA85A suggests the need for standardised preclinical animal models that better represent human disease and an improved understanding of immune mechanisms of protection in human tuberculosis. Such advances would greatly enhance the ability to efficiently translate clinical research capacity into the development and deployment of an effective vaccine.References1WHOGlobal tuberculosis report2014World Health OrganizationGeneva2WalkerNFMeintjesGWilkinsonRJHIV-1 and the immune response to TBFuture Virol820135780236536643FalzonDWeyerKRaviglioneMCDrug-resistant tuberculosis: latest advancesLancet Respir Med12013e910243218184BrennanMJTholeJTuberculosis vaccines: a strategic blueprint for the next decadeTuberculosis92suppl 12012S613224411605RodriguesLCDiwanVKWheelerJGProtective effect of BCG against tuberculous meningitis and miliary tuberculosis: a meta-analysisInt J Epidemiol2219931154115881442996TrunzBBFinePDyeCEffect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectivenessLancet367200611731180166165607MangtaniPAbubakarIAritiCProtection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trialsClin Infect Dis582014470480243369118ColditzGABrewerTFBerkeyCSEfficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literatureJAMA271199469870283090349HawnTRDayTAScribaTJTuberculosis vaccines and prevention of infectionMicrobiol Mol Biol Rev7820146506712542893810TamerisMDHatherillMLandryBSSafety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trialLancet3812013102110282339146511McShaneHPathanAASanderCRRecombinant modified vaccinia virus Ankara expressing antigen 85A boosts BCG-primed and naturally acquired antimycobacterial immunity in humansNat Med102004124012441550283912HawkridgeTScribaTJGelderbloemSSafety and immunogenicity of a new tuberculosis vaccine, MVA85A, in healthy adults in South AfricaJ Infect Dis19820085445521858219513SanderCRPathanAABeveridgeNESafety and immunogenicity of a new tuberculosis vaccine, MVA85A, in Mycobacterium tuberculosis-infected individualsAm J Respir Crit Care Med17920097247331915119114MinassianAMRowlandRBeveridgeNEA phase I study evaluating the safety and immunogenicity of MVA85A, a candidate TB vaccine, in HIV-infected adultsBMJ Open12011e00022315WilliamsAGoonetillekeNPMcShaneHBoosting with poxviruses enhances Mycobacterium bovis BCG efficacy against tuberculosis in guinea pigsInfect Immun732005381438161590842016VordermeierHMVillarreal-RamosBCocklePJViral booster vaccines improve Mycobacterium bovis BCG-induced protection against bovine tuberculosisInfect Immun772009336433731948747617VerreckFAVervenneRAKondovaIMVA.85A boosting of BCG and an attenuated, phoP deficient M. tuberculosis vaccine both show protective efficacy against tuberculosis in rhesus macaquesPLoS One42009e52641936733918GoonetillekeNPMcShaneHHannanCMAndersonRJBrookesRHHillAVEnhanced immunogenicity and protective efficacy against Mycobacterium tuberculosis of bacille Calmette–Guérin vaccine using mucosal administration and boosting with a recombinant modified vaccinia virus AnkaraJ Immunol1712003160216091287425519McShaneHWilliamsAA review of preclinical animal models utilised for TB vaccine evaluation in the context of recent human efficacy dataTuberculosis9420141051102436998620von ReynCFMteiLArbeitRDPrevention of tuberculosis in Bacille Calmette-Guérin-primed, HIV-infected adults boosted with an inactivated whole-cell mycobacterial vaccineAIDS2420106756852011876721CoxHHughesJDanielsJCommunity-based treatment of drug-resistant tuberculosis in Khayelitsha, South AfricaInt J Tuberc Lung Dis1820144414482467070022ScribaTJTamerisMMansoorNModified vaccinia Ankara-expressing Ag85A, a novel tuberculosis vaccine, is safe in adolescents and children, and induces polyfunctional CD4+ T cellsEur J Immunol4020102792902001718823HanekomWAHughesJMavinkurveMNovel application of a whole blood intracellular cytokine detection assay to quantitate specific T-cell frequency in field studiesJ Immunol Methods29120041851951534531624GartnerTBaetenMOtienoSRevetsHDe BaetselierPHuygenKMucosal prime-boost vaccination for tuberculosis based on TLR triggering OprI lipoprotein from Pseudomonas aeruginosa fused to mycolyl-transferase Ag85AImmunol Lett111200726351757053525RangakaMXGideonHPWilkinsonKAInterferon release does not add discriminatory value to smear-negative HIV-tuberculosis algorithmsEur Respir J3920121631712171948726SattiIMeyerJHarrisSASafety and immunogenicity of a candidate tuberculosis vaccine MVA85A delivered by aerosol in BCG-vaccinated healthy adults: a phase 1, double-blind, randomised controlled trialLancet Infect Dis1420149399462515122527RangakaMXWilkinsonRJBoulleAIsoniazid plus antiretroviral therapy to prevent tuberculosis: a randomised double-blind, placebo-controlled trialLancet384201468269024835842Supplementary MaterialSupplementary appendixAcknowledgmentsThe study was funded by the European & Developing Countries Clinical Trials Partnership (IP.07.32080.002), Aeras, Bill & Melinda Gates Foundation, the Wellcome Trust (095780, 084323, and 088316), and the Oxford-Emergent Tuberculosis Consortium. Quintiles (Bloemfontein, South Africa) were used for the statistical analysis, and Aeras paid for this service. The appendix includes a complete list of acknowledgments. We dedicate this study to the memory of Robyn Louw.ContributorsBPN, FT, SD, HE, RG, VJ, IN, TO, AT, MRa, BSL, SM, and RJW were responsible for implementation of the study and supervision at the study sites. MC, TND, KH, MRo, IS, and KAW did the immunological analysis. MO, RJW, SM, and HM raised the funding and wrote the protocol. All authors contributed to data analysis and contributed to the writing of the report.Declaration of interestsHM was previously a shareholder in the Oxford-Emergent Tuberculosis Consortium (OETC), a joint venture established for the development of MVA85A (OETC no longer exists). KH has a patent (US 5736524 A) related to the development of a DNA vaccine against Mycobacterium tuberculosis. RJW received grants from the European & Developing Countries Clinical Trials Partnership, the Wellcome Trust, the UK Medical Research Council, and the European Union during the conduct of the study, and personal fees from GlaxoSmithKline unrelated to this work. All other authors declare no competing interests.Figure 1Trial profileFigure 2Vaccine immunogenicity (both study sites combined)(A) Antigen 85A (Ag85A) interferon γ enzyme-linked immunospot analysis responses. Data are presented as spot-forming cells (SFC) per million peripheral blood mononuclear cells (PBMCs). p values were calculated with Wilcoxon matched-pair signed-rank tests. Box and whisker plots show median, IQR, and minimum and maximum values. (B) Whole blood intracellular cytokine staining assay of total cytokines. Data are presented as frequency of CD4 and CD8 T cells producing cytokines. Box and whisker plots show median, IQR, and minimum and maximum values. IFNγ=interferon γ. TNFα=tumour necrosis factor α. IL=interleukin. V1=vaccination 1. V2=vaccination 2.Figure 3Polyfunctional CD4 T cellsPlots show frequency of CD4 T cells producing combinations of the studied cytokines. Bars are median values and dots represent individual volunteers. IFNγ=interferon γ. TNFα=tumour necrosis factor α. IL=interleukin. V1=vaccination 1. V2=vaccination 2.Figure 4Cumulative incidence of diagnosis of tuberculosis endpoint 1 by treatment groupEndpoint 1 was defined as a positive finding from culture or GeneXpert MTB/RIF assay.Table 1Demographic and baseline characteristics (safety analysis population)Placebo (n=325)MVA85A (n=324)Median age, years (range)39·0 (22–41)38·0 (21–49)Women255 (78%)265 (82%)Ethnic originBlack304 (94%)302 (93%)Mixed21 (6%)22 (7%)QFT test resultPositive150 (46%)135 (42%)Negative173 (53%)188 (58%)Indeterminate2 (1%)1 (<1%)TST result>5 mm128 (39%)124 (38%)≤5 mm191 (59%)190 (59%)Missing data6 (2%)10 (3%)Latent tuberculosis infection178 (55%)164 (51%)5–6 months IPT before enrolment144 (44%)133 (41%)Receiving antiretroviral therapy256 (79%)257 (79%)CD4 count (cells per mm3)Participants not receiving antiretroviral therapy564 (169·8)571 (187·5)Participants receiving antiretroviral therapy599 (199·6)598 (220·7)HIV viral load (copies per mL)Participants not receiving antiretroviral therapy41\u2008371 (92\u2008456·9)62\u2008168 (166\u2008912·1)Participants receiving antiretroviral therapy29 (27·1)34 (63·7)Data are n (%) or mean (SD), unless otherwise stated. QFT=QuantiFERON-TB Gold In-Tube. TST=tuberculin skin test. IPT=isoniazid preventive therapy.Table 2Overview of adverse events (safety analysis population)OverallParticipants not receiving antiretroviral therapyParticipants receiving antiretroviral therapyPlacebo (n=325)MVA85A (n=324)Difference (MVA85A minus placebo) (95% CI)Placebo (n=69)MVA85A (n=67)Difference (MVA85A minus placebo) (95% CI)Placebo (n=256)MVA85A (n=257)Difference (MVA85A minus placebo) (95% CI)Any adverse event312 (96·0%; 93·3–97·7)321 (99·1%; 97·3–99·7)3·1 (0·7 to 5·4)67 (97·1%; 90·0–99·2)66 (98·5%; 92·0–99·7)1·4 (−3·5 to 6·3)245 (95·7%; 92·5–97·6)255 (99·2%; 97·2–99·8)3·5 (0·8 to 6·2)Solicited adverse event235 (72·3%; 67·2–76·9)288 (88·9%; 85·0–91·9)16·6 (10·6 to 22·5)50 (72·5%; 61·0–81·6)63 (94·0%; 85·6–97·7)21·6 (9·6 to 33·5)185 (72·3%; 66·5–77·4)225 (87·5%; 83·0–91·0)15·3 (8·5 to 22·1)Serious adverse event17 (5·2%; 3·9–8·2)17 (5·2%; 3·3–8·2)0·02 (−3·4 to 3·4)2 (2·9%; 0·8–10·0)9 (13·4%; 7·2–23·6)10·5 (1·5 to 19·6)15 (5·9%; 3·6–9·4)8 (3·1%; 1·6–6·0)−2·7 (−6·3 to 0·8)Related adverse event307 (94·5%; 91·4–96·5)318 (98·1%; 96·0–99·2)3·7 (0·8 to 6·6)66 (95·7%; 88·0–98·5)66 (98·5%; 92·0–99·7)2·9 (−2·8 to 8·5)241 (94·1%; 90·6–96·4)252 (98·1%; 95·5–99·1)3·9 (0·6 to 7·2)Severe adverse event84 (25·8%; 21·4–30·9)100 (30·9%; 26·1-36·1)5·0 (−1·9 to 11·9)15 (21·7%; 13·6–32·8)22 (32·8%; 22·8–44·8)11·1 (−3·8 to 26)69 (27·0%; 21·7–32·9)78 (30·4%; 25·1–36·2)3·4 (−4·4 to 11·2)Data are n (%; 95% CI), unless otherwise stated. Serious adverse events were coded with Medical Dictionary for Regulatory Activities version 14.0. Patients with multiple events in each category are counted only once in each category.Table 3Total intracellular cytokine response, presented as frequency of CD4 T cells and CD8 T cells producing specific cytokinesMVA85A (n=28)MVA85A timepoint comparisons (p values)Placebo (n=29)Day 0 (vaccination 1)Day 7 (vaccination 1)Day 0 (vaccination 2)Day 7 (vaccination 2)Day 0 (vaccination 1) vs day 7 (vaccination 1)Day 0 (vaccination 1) vs day 0 (vaccination 2)Day 0 (vaccination 1) vs day 7 (vaccination 2)Day 0 (vaccination 2) vs day 7 (vaccination 2)Day 0 (vaccination 1)Day 7 (vaccination 1)Day 0 (vaccination 2)Day 7 (vaccination 2)CD4 IFNγ0·01 (0–0·07)0·1 (0–1·12)0·03 (0–0·28)0·11 (0·02–0·82)<0·00010·0015<0·0001<0·00010·02 (0–0·12)0·01 (0–0·08)0 (0–0·08)0·01 (0–0·18)CD4 TNFα0·02 (0–0·12)0·11 (0–0·53)0·05 (0–0·57)0·11 (0–0·46)<0·00010·0403<0·0001<0·00010·02 (0–0·15)0·02 (0-0·14)0·02 (0–0·11)0·02 (0–0·23)CD4 IL-20·021 (0–0·11)0·07 (0–0·68)0·04 (0–0·27)0·1 (0·03–0·44)<0·00010·0421<0·0001<0·00010·02 (0–0·08)0·017 (0–0·08)0·02 (0–0·09)0·018 (0–0·06)CD4 IL-170·09 (0·01–0·28)0·12 (0·03–0·27)0·09 (0–0·37)0·1 (0·03–0·23)0·09460·54250·40470·28430·07 (0–0·27)0·06 (0·02–0·27)0·08 (0·01–0·26)0·078 (0–0·25)CD8 IFNγ0 (0–0·21)0·02 (0–0·94)0 (0–0·58)0·01 (0–0·3)0·01010·54990·22640·28970 (0–0·35)0 (0–0·19)0 (0–0·33)0 (0–0·24)CD8 TNFα0 (0–0·28)0 (0–0·24)0 (0–0·48)0 (0–0·05)0·45130·76150·73370·39530 (0–0·09)0 (0–0·38)0 (0–0·2)0 (0–0·13)Data are median (minimum to maximum) of total cytokines at each of the study timepoints, unless otherwise stated. Population is the immunology substudy (the first 70 participants), of which complete data were available for 57 participants. Statistical comparison of total cytokine responses in MVA85A study group used Wilcoxon matched-pairs signed-rank test. IL=interleukin. IFNγ=interferon γ. TNFα=tumour necrosis factor α.Table 4Primary and secondary efficacy results (per-protocol population)OverallParticipants not receiving antiretroviral therapyParticipants receiving antiretroviral therapyPlaceboMVA85AVaccine efficacy (95% CI)PlaceboMVA85AVaccine efficacy (95% CI)PlaceboMVA85AVaccine efficacy (95% CI)Disease endpoint 1 (primary efficacy endpoint)9/325 (2·8%)6/320 (1·9%)32·8%(−111·5 to 80·3)1/69 (1·4%)2/65 (3·1%)−114·1%(−12\u2008528·3 to 88·9)8/256 (3·1%)4/255 (1·6%)50·3%(−85·4 to 89·1)Disease endpoint 39/325 (2·8%)8/320 (2·5%)10·5%(−161·3 to 70·0)1/69 (1·4%)3/65 (4·6%)−224·7%(−16\u2008947·7 to 73·9)8/256 (3·1%)5/255 (2·0%)38·2%(−114·1 to 84·1)QFT positive conversion40/173 (23·1%)38/186 (20·4%)11·7%(−41·3 to 44·9)11/36 (30·6%)6/38 (15·8%)44·2%(−64·8 to 83·0)29/137 (21·2%)32/148 (21·6%)−0·1%(−71·5 to 41·4)Data are n/N (%), unless otherwise stated. Disease endpoint 1 was defined as culture or GeneXpert MTB/RIF positivity; disease endpoint 2 included endpoint 1 and a composite clinical endpoint; and disease endpoint 3 was commencement on anti-tubercular chemotherapy. No additional participants met endpoint 2 who did not already meet endpoint 1. QFT=QuantiFERON-TB Gold In-Tube.", 'title': 'Safety, immunogenicity, and efficacy of the candidate tuberculosis vaccine MVA85A in healthy adults infected with HIV-1: a randomised, placebo-controlled, phase 2 trial.', 'date': '2015-03-03'}, '23391465': {'article_id': '23391465', 'content': "LancetLancetLancet (London, England)0140-67361474-547XElsevier233914655424647S0140-6736(13)60177-410.1016/S0140-6736(13)60177-4ArticlesSafety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trialTamerisMichele DDrMBChBmichele.tameris@uct.ac.zaa**HatherillMarkFCPa*LandryBernard SMPHbScribaThomas JPhDaSnowdenMargaret AnnMPHbLockhartStephenDMcdSheaJacqueline EPhDcMcClainJ BruceMDbHusseyGregory DProfFFCHafHanekomWillem AProfFCPaMahomedHassanMMedag†McShaneHelenProfFRCPhelen.mcshane@ndm.ox.ac.uke†**the MVA85A 020 Trial Study TeamaSouth African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and School of Child and Adolescent Health, University of Cape Town, Cape Town, South AfricabAeras, Rockville, MD, USAcOxford-Emergent Tuberculosis Consortium, Wokingham, Berkshire, UKdEmergent Product Development UK, Wokingham, Berkshire, UKeJenner Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UKfVaccines for Africa, Institute of Infectious Disease and Molecular Medicine and Department of Medical Microbiology, University of Cape Town, Cape Town, South AfricagDepartment of Health, Western Cape and Division of Community Health, Stellenbosch University, Stellenbosch, South Africa*Correspondence to: Dr Michele D Tameris, South African Tuberculosis Vaccine Initiative (SATVI), Brewelskloof Hospital, Haarlem Street, Worcester 6850, South Africa michele.tameris@uct.ac.za**Prof Helen McShane, University of Oxford, Jenner Institute, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK helen.mcshane@ndm.ox.ac.uk*Contributed equally†Senior authors422013422013381987110211028© 2013 Published by Elsevier Ltd.2013Elsevier LtdSummaryBackgroundBCG vaccination provides incomplete protection against tuberculosis in infants. A new vaccine, modified Vaccinia Ankara virus expressing antigen 85A (MVA85A), was designed to enhance the protective efficacy of BCG. We aimed to assess safety, immunogenicity, and efficacy of MVA85A against tuberculosis and Mycobacterium tuberculosis infection in infants.MethodsIn our double-blind, randomised, placebo-controlled phase 2b trial, we enrolled healthy infants (aged 4–6 months) without HIV infection who had previously received BCG vaccination. We randomly allocated infants (1:1), according to an independently generated sequence with block sizes of four, to receive one intradermal dose of MVA85A or an equal volume of Candida skin test antigen as placebo at a clinical facility in a rural region near Cape Town, South Africa. We actively followed up infants every 3 months for up to 37 months. The primary study outcome was safety (incidence of adverse and serious adverse events) in all vaccinated participants, but we also assessed efficacy in a protocol-defined group of participants who received at least one dose of allocated vaccine. The primary efficacy endpoint was incident tuberculosis incorporating microbiological, radiological, and clinical criteria, and the secondary efficacy endpoint was M tuberculosis infection according to QuantiFERON TB Gold In-tube conversion (Cellestis, Australia). This trial was registered with the South African National Clinical Trials Register (DOH-27-0109-2654) and with ClinicalTrials.gov on July 31, 2009, number NCT00953927FindingsBetween July 15, 2009, and May 4, 2011, we enrolled 2797 infants (1399 allocated MVA85A and 1398 allocated placebo). Median follow-up in the per-protocol population was 24·6 months (IQR 19·2–28·1), and did not differ between groups. More infants who received MVA85A than controls had at least one local adverse event (1251 [89%] of 1399 MVA85A recipients and 628 [45%] of 1396 controls who received the allocated intervention) but the numbers of infants with systemic adverse events (1120 [80%] and 1059 [76%]) or serious adverse events (257 [18%] and 258 (18%) did not differ between groups. None of the 648 serious adverse events in these 515 infants was related to MVA85A. 32 (2%) of 1399 MVA85A recipients met the primary efficacy endpoint (tuberculosis incidence of 1·15 per 100 person-years [95% CI 0·79 to 1·62]; with conversion in 178 [13%] of 1398 infants [95% CI 11·0 to 14·6]) as did 39 (3%) of 1395 controls (1·39 per 100 person-years [1·00 to 1·91]; with conversion in 171 [12%] of 1394 infants [10·6 to 14·1]). Efficacy against tuberculosis was 17·3% (95% CI −31·9 to 48·2) and against M tuberculosis infection was −3·8% (–28·1 to 15·9).InterpretationMVA85A was well tolerated and induced modest cell-mediated immune responses. Reasons for the absence of MVA85A efficacy against tuberculosis or M tuberculosis infection in infants need exploration.FundingAeras, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium (OETC).IntroductionTuberculosis is a major global health problem, with an estimated 8·7 million cases and 1·4 million deaths in 2011.1 The Stop TB Partnership developed the Global Plan to Stop TB: 2006–2015, with a goal of tuberculosis elimination by 2050.2 One of the long-term strategies essential for control of the epidemic is effective vaccination. The existing BCG vaccine protects against disseminated tuberculosis in young children,3, 4 but protection against pulmonary tuberculosis is very variable.4, 5, 6 Efficacy against infection with Mycobacterium tuberculosis has only been reported in observational studies in low-burden settings.7 In endemic countries such as South Africa, the incidence of tuberculosis in infants and young children is very high despite high BCG coverage.8, 9 An improved infant tuberculosis vaccination regimen is urgently needed.12 candidate vaccines are being tested in clinical trials.10 MVA85A is a recombinant strain of modified Vaccinia Ankara virus expressing the immunodominant M tuberculosis protein, antigen 85A.11 MVA85A has been developed as a heterologous boost for BCG.11 Boosting BCG with MVA85A improved BCG-induced protection against mycobacterial challenge in animals.12, 13, 14, 15 MVA85A was well tolerated in clinical trials in infants.11, 16, 17 Furthermore, a BCG prime-MVA85A boost immunisation regimen in infants induced antigen-specific Th1 and Th17 cells,16 which are regarded as important in protection against tuberculosis.18, 19We aimed to further assess safety of MVA85A in HIV-negative infants who were previously vaccinated with BCG. As secondary endpoints, we also aimed to assess efficacy of MVA85A against tuberculosis and M tuberculosis infection beyond that of BCG alone, assess immunogenicity of MVA85A, and identify correlates of protection. To our knowledge, our investigation was the first infant efficacy trial of a new tuberculosis vaccine since BCG was last assessed in infants as part of the Chingleput-Madras trial that started in 1968.20MethodsStudy design and participantsWe undertook a parallel-group, randomised, placebo-controlled, double-blind phase 2b trial at the South African Tuberculosis Vaccine Initiative (SATVI) site in a rural region near Cape Town, South Africa. The region has a population of about 290\u2008000 people and an annual birth cohort of about 7000 babies. The overall incidence of tuberculosis in South Africa in 2011 was estimated to be almost 1% (993 per 100\u2008000 individuals).1 The incidence of tuberculosis in children younger than 2 years was about 3% at our trial site.21Parents of recently born infants were approached at local immunisation clinics or at home about study participation. We enrolled healthy infants, aged 4–6 months and who had received BCG (Danish 1331, Statens Serum Institut, Denmark) within 7 days of birth. Infants had to have received all age-appropriate routine immunisations, and two doses of pneumococcal conjugate vaccine at least 28 days before study vaccination (amended to 14 days during enrolment). All infants had to be HIV ELISA negative, QuantiFERON-TB Gold In-tube test (QFT; Cellestis, Australia) negative, and have had no substantial exposure to a patient with known tuberculosis. The appendix contains the study protocol.The trial was approved by the University of Cape Town Faculty of Health Sciences Human Research Ethics Committee, Oxford University Tropical Research Ethics Committee, and the Medicines Control Council of South Africa. Parents or legal guardians provided written, informed consent.Randomisation and maskingWe randomly allocated infants in a 1:1 ratio, with a block size of four, by use of an interactive voice/online response system to receive one intradermal dose of MVA85A (1×108 plaque-forming units in 0·06 mL) or an equal volume of Candida skin test antigen (Candin, AllerMed, USA) as placebo. Doses were prepared and labelled in masked syringes by an unmasked study pharmacist. An independent statistician prepared the randomisation schedule. The parents or legal guardians of study participants, study staff administering vaccinations or undertaking follow-up clinic assessments, and laboratory staff were masked to intervention group assignment.ProceduresThe study design included specific cohorts for specialised analyses, but all participants were followed up for assessment of efficacy and incidence of serious adverse events. Peripheral blood for routine haematological and biochemical tests was taken at screening and on day 7 and day 28 after vaccination in an initial safety cohort of at least 330 infants (study group 1). We assessed immunogenicity in three subsequent cohorts of up to 60 participants with an enzyme-linked immunosorbent spot analysis (study group 2), an intracellular cytokine staining (ICS) assay for peripheral blood mononuclear cell (PBMCs) counts (study group 3), and a whole blood ICS assay (study group 4). We enrolled remaining infants into a fifth cohort (study group 5). PBMCs obtained from all infants before and after vaccination were cryopreserved for future correlates analyses. We did QFT testing at screening, day 336, at the end of study visit, and for infants admitted to a dedicated study ward for investigation for tuberculosis.21We obtained data for incidence of solicited and unsolicited local (injection site) and systemic adverse events reported by parents or guardians on diary cards for 7 days after vaccination and by direct questioning by study staff for 28 days after vaccination. We also obtained data for serious adverse events throughout follow-up by active surveillance. Adverse events were assessed by the trial investigators and serious adverse events were assessed by the trial investigators and a local medical monitor, acting on behalf of the sponsor, to determine relation to vaccination. The trial investigators and local medical monitor were masked to intervention group throughout the trial. The safety monitoring committee (SMC) did not determine the association or severity of the adverse events. When the last infant in the safety cohort completed day 84, the SMC reviewed unmasked safety data to determine if a pattern of adverse events related to MVA85A or other safety concerns existed so as to advise on further enrolments. The SMC also conducted a second unmasked analysis-by-group safety and risk review after the 1000th infant completed their visit at study day 84.We actively followed up infants every 3 months to identify any signs, symptoms, or exposure that merited further investigation. Participants who had a persistent cough, failure to thrive, weight loss crossing a major centile band, QFT or tuberculin skin test conversion, household tuberculosis contact, or any other condition causing investigator concern were admitted to the study ward. Standardised investigations involved assessments with chest radiography, tuberculin skin test, QFT, HIV-ELISA, two consecutive early morning gastric lavage samples, and two induced sputa. Gastric lavage and sputum samples underwent auramine smear microscopy, GeneXpert MTB/RIF (Cepheid, USA; routinely from January, 2011, onwards), and MGIT (Becton Dickinson, Sparks, USA) liquid culture and sensitivity testing. Positive samples were speciated by PCR. We developed a hierarchy of three disease endpoint definitions. Endpoint 1 (panel 1) and endpoint 2 (appendix p 49) were based on the presence of specific clinical, radiological, and microbiological findings.22 Endpoint 2 (which included all infants who met endpoint 1 criteria) had marginally less stringent criteria to define tuberculosis infection and household exposure. Endpoint 3 included all participants placed on treatment for tuberculosis by a health professional. This approach allowed objective case classification without the need for an adjudication committee.The endpoint of infection with M tuberculosis was defined as conversion to a positive QFT test at any time during follow-up. We assessed rates of QFT conversion 1 year after vaccination and at end of study in those participants not previously started on anti-tuberculous treatment.We measured immunological sensitisation to M tuberculosis antigens, suggesting M tuberculosis infection, by QFT during screening, 1 year after vaccination, and at the close-out visit. We obtained blood samples from study groups 2–4 for immunogenicity analyses 7 days before vaccination and 7 days or 28 days after vaccination. We assessed immunogenicity with an ex-vivo interferon γ enzyme-linked immunosorbent spot assay, together with PBMC and whole blood ICS assays done as previously described.23 Further details of the methods are available in the appendix.Statistical analysesThe primary study outcome was safety in all vaccinated participants (safety population), including all solicited, unsolicited, and serious adverse events. We compared the proportion of participants with at least one such adverse event in the placebo and MVA85A groups with Fisher's exact test, and we calculated two-sided exact 95% CIs for proportions of individual events within treatment groups. We did immunogenicity analyses for all vaccinated participants enrolled in study groups 2–4. Statistical analyses were prespecified in a statistical analysis plan, signed off prior to study database lock and unmasking of data (appendix).The primary efficacy outcome was incidence of endpoint 1 and the secondary efficacy outcome was infection with M tuberculosis. Endpoints 2 and 3 were exploratory efficacy outcomes. All efficacy analyses were based on the per-protocol population, consisting of all randomly allocated participants who received at least one dose of study vaccine as randomised, and who had no major protocol deviations.The primary statistical method for analysis of endpoint 1 was vaccine efficacy, defined as 1 minus the estimated hazard ratio based on a Cox regression analysis of time to first diagnosis of endpoint 1. The Cox model contained one indicator variable for treatment group. To investigate the potential effect of variable follow-up times, we also did this analysis with a predefined cutoff of 2 years after vaccination. Analysis of endpoint 1 also included time (months) to initial tuberculosis diagnosis from day of vaccination in each treatment group with the Kaplan-Meier estimate of the survival function by treatment group, and the exact binomial method to estimate vaccine efficacy and its corresponding 95% CI (Clopper-Pearson with mid-p adjustment) conditional on the total number of events. We included participants with more than one diagnosis (eg, a diagnosis of tuberculosis endpoint 2 that was subsequently diagnosed as endpoint 1) in analyses separately for each diagnostic level. For the analysis of secondary and exploratory efficacy endpoints, no adjustment for multiplicity was done. We regarded a two-sided p value of less than 0·05 as significant. Summaries were presented for all cases reported during the study, and also, all cases with a diagnosis during the first 2 years of individual follow-up.For efficacy analyses, we based the sample size calculation on the primary efficacy endpoint of tuberculosis (endpoint 1). We assumed a cumulative tuberculosis incidence of 3% after a median of 18 months' follow-up in the placebo group,21 with an estimated 7·5% loss to follow-up.24 Thus, 1392 participants per intervention group would provide a 90% chance of detection of a 60% reduction between the intervention and control groups based on a two-sided log-rank test at a significance level of 0·05. We implemented a 6 month extension to the planned follow-up to achieve the target case accrual.For safety analyses, the sample size of 1392 participants receiving MVA85A would provide a greater than 75% chance of observing an adverse event that had an approximately one in 1000 actual rate of occurrence.The trial was registered with the South African National Clinical Trials Register on Nov, 4, 2008 (DOH-27-0109-2654), and with ClinicalTrials.gov on July 31, 2009, number NCT00953927.Role of the funding sourceAeras was the trial sponsor. Aeras and the Oxford-Emergent Tuberculosis Consortium (OETC) contributed to study design, data interpretation, and writing of the manuscript. MDT, MH, BSL, TJS, MAS, SL, HM, and HMcS had complete access to the data. HMcS had final responsibility for the decision to submit for publication.ResultsBetween July 15, 2009, and May 4, 2011, we obtained consent for 4754 infants. We enrolled 2797 infants who had completed screening when the enrolment target of 2784 was met (figure 1). Reasons for screening failure have been reported elsewhere.22 363 infants were entered into study group 1 (initial safety cohort; 182 in MVA85A group and 181 in the placebo group); 54 into group 2 (27 and 27), 54 into group 3 (27 and 27), and 39 into group 4 (19 and 20; immunogenicity groups); and 2287 in group 5 (1144 and 1143; correlates of protection). Follow-up was completed in October, 2012. The per-protocol population was 2794, excluding three participants from the intention-to-treat population (figure 1). The intention-to-treat analysis is not reported.Demographic and baseline clinical characteristics of the study participants were much the same between groups (table 1). In the per-protocol population, median follow-up for 1399 recipients of MVA85A was 24·6 months (range 0·2–37·3; IQR 19·2–27·8) and for 1395 controls was 24·6 months (0·3–37·3; 19·2–30·1). The number of participants discontinuing the study did not differ between the two treatment groups (figure 1). 126 infants (5%) were lost to follow-up, 11 died (<1%), and 62 (2%) had consent withdrawn.At least one local adverse event was reported in 628 (45%) of 1396 controls who received the allocated intervention and 1251 (89%) of 1399 recipients of MVA85A. At least one systemic adverse event was reported in 1059 (76%) controls and 1120 (80%) of recipients of MVA85A. At least one serious adverse event was reported in 258 (18%) controls and 257 (18%) recipients of MVA85A (appendix). No serious adverse events related to vaccine were reported in the MVA85A group, but one serious adverse event regarded as related to placebo occurred in the placebo group (short admission to hospital for fever 4 days after vaccination). 417 (64%) of 648 serious adverse events were acute lower-respiratory-tract infections or gastroenteritis (appendix). Seven (1%) infants died in the vaccine group (two from kwashiorkor, two from non-tuberculous meningitis, one from gastroenteritis, one from asphyxia due to drowning, and one from sudden death) and four (<1%) infants died in the placebo group (two from gastroenteritis, one from encephalitis, and one from a lower-respiratory-tract infection). During follow-up, 510 (37%) of 1395 recipients of placebo and 507 (36%) of 1399 recipients of MVA85A were admitted to the study ward for investigation.MVA85A induced an Ag85-specific T-cell response as measured by ex-vivo interferon γ enzyme-linked immunosorbent spot (median 136 spot-forming cells per million PBMCs, IQR 87–362; figure 2). Whole blood ICS showed that these cells were CD4-positive T cells predominantly expressing interferon γ, TNFα, and interleukin 2 (figure 2). We also detected CD4-positive interleukin 17-positive T cells (figure 2), some of which co-expressed Th1 cytokines (data not shown). These responses were not detected in recipients of placebo. No CD8-positive T-cell responses were detectable and no responses were detected with ICS completed on cryopreserved PBMCs (data not shown).Table 2 shows vaccine efficacy and numbers of infants who met endpoints 1, 2, or 3 by intervention group. For analysis with follow-up data truncated at 2 years after vaccination, vaccine efficacy was 23·9% (95% CI −27·9 to 54·7) for endpoint 1, −0·7% (–52·3 to 33·4) for endpoint 2, and −3·6% (–29·0 to 16·8) for endpoint 3. A post-hoc review of case distribution in the first year showed 16 recipients of placebo met endpoint 1 as did ten MVA85A recipients. Figure 3 shows the Kaplan-Meier survival analysis for endpoint 1.39 (3%) of 1395 infants assessed in the placebo group had incident tuberculosis (1·39 per 100 person-years [95% CI 1·00 to 1·91]) as did 32 (2%) of 1399 infants in the MVA85A group (1·15 per 100 person-years [0·79 to 1·62]). 171 (12% [95% CI 10·6 to 14·1]) infants assessed in the placebo group and 178 (13% [95% CI 11·0 to 14·6]) infants in the MVA85A group became infected with M tuberculosis as defined by QFT conversion during the course of the study. Vaccine efficacy against infection was −3·8% (95% CI −28·1 to 15·9). Efficacy was much the same when the comparison was restricted to QFT conversion at day 336 and end of study visit (data not shown).DiscussionWe report completion of a phase 2b safety and efficacy trial for infants with a new tuberculosis vaccine strategy (panel 2). In this trial, MVA85A was well tolerated and immunogenic in healthy infants who had previously been vaccinated with BCG, with a safety and immunogenicity profile consistent with that reported in other studies of infants.16, 17 However, we noted no significant efficacy against tuberculosis or M tuberculosis infection.This absence of efficacy was not consistent with findings from studies in animals, which suggested potential for efficacy,12, 13, 14, 15 and evidence of immunogenicity in previous clinical trials16, 17, 23 that measured immune responses regarded as important for protection.18, 19 Our results suggest that the CD4-positive T cells induced by MVA85A—at least at the modest frequencies noted in this trial—do not correlate with protection against tuberculosis or M tuberculosis infection. Frequencies of antigen-specific Th1 cells observed in infants with MVA85A were up to a tenth of the frequencies noted in adults.16, 25Our efficacy trial was undertaken in infants. However, this group is not responsible for most transmission of M tuberculosis. Thus, MVA85A could potentially protect adolescents or adults against pulmonary tuberculosis, in view of the fact that immunologically immature infants do not respond as well to this vaccine as adults do. MVA85A could also potentially have high efficacy in people of all ages against severe forms of tuberculosis, including pulmonary tuberculosis, without preventing infection or mild forms of disease. A high efficacy against severe disease could be masked in a trial that predominantly detects mild forms of tuberculosis. The sample size of a trial powered to detect only severe or disseminated disease would be prohibitively large. The safety and immunogenicity of MVA85A alone in infants exposed to HIV is currently being assessed.26 BCG-specific Th1 and Th17 responses were recently shown not to correlate with risk of tuberculosis in infants after BCG vaccination.27 Whether a substantially greater magnitude of response, a response that is qualitatively different, or a completely new immunological response would be necessary for protection is unclear. In our study, frequencies of BCG-primed Ag85A-specific T cells detected before MVA85A vaccination were very low or undetectable (figure 2). Conversely, adults and adolescents have significantly higher Ag85A-specific responses before vaccination,16 which might be an important factor in the stronger responses induced by MVA85A in older individuals. MVA85A was designed to boost BCG-primed responses, and the low frequencies of BCG-induced cells in infants might restrict the immunogenicity, and potentially the efficacy, of MVA85A in this age group. Ongoing assessment of study samples for potential correlates of risk might also yield important insights into why MVA85A did not confer protection in this trial and could add to the design and assessment of the next generation of tuberculosis vaccine candidates. Identification of immune correlates of protection would greatly aid vaccine design and assessment. However such correlates can only be identified in trials in which efficacy was shown. Identification and optimisation of animal models that accurately predict efficacy in human beings is also needed. Other efficacy trials of new HIV and malaria vaccines have reported early but waning efficacy.28, 29 In this trial, a post-hoc analysis of distribution of case accrual in the first year suggested a possible early effect on disease that merits further study of route of administration, regimen, and dosing strategies with MVA85A and other vaccines.Despite concerns about potential immunopathology induced by new tuberculosis vaccines,30 we noted no evidence for this effect. The high incidence of respiratory and gastrointestinal serious adverse events recorded in this trial reflects the known burden of childhood morbidity in this community.24 High numbers of unrelated serious adverse events should be expected in clinical trials in infant populations in developing countries. The high frequency of mild, self-limiting local reactions in MVA85A recipients is consistent with previous studies.16, 17 These local reactions were only partially controlled for by Candin, a placebo selected for its local reactogenicity profile. The overall safety profile supports modified Vaccinia Ankara virus as a suitable vector for infant vaccination strategies.The high incidence of disease noted in our study was comparable to the high rates noted in previous trials.21, 23 We noted no confirmed cases of disseminated tuberculosis (two cases of tuberculous meningitis met the definition for endpoint 2) and no deaths from tuberculosis, supporting our previous observation that disseminated and severe tuberculosis are uncommon in a setting of modern trials with active surveillance, effective isoniazid prophylaxis, and effective anti-tuberculous treatment.21 The high overall rate of M tuberculosis infection noted in this trial (349 [13%] of 2792) suggests a high level of exposure and transmission in this community. This infection burden suggests that M tuberculosis infection might be a suitable endpoint for future trials of new tuberculosis vaccines that aim to prevent infection and subsequent disease. Because BCG is regarded as less effective for prevention of infection than prevention of disease, our finding that MVA85A did not prevent infection is unsurprising and should be interpreted separately from the findings about efficacy against disease. We recognise that QFT has not been validated as a diagnostic test for M tuberculosis infection in infants and young children; however, a previous study31 done by our group showed good correlation between QFT and the tuberculin skin test.Our study showed that a large efficacy trial of a new tuberculosis vaccine in a high-burden setting is feasible with a stringent and objective case definition that incorporated the primary elements proposed in a recent consensus statement.32 We have also shown that standardised investigation for tuberculosis with multiple respiratory sampling, microbiological confirmation of disease, and masked expert panel review of digital radiograph images is feasible in a developing country setting where tuberculosis vaccine efficacy trials are likely to be done. We recognise that there is no gold standard definition of childhood tuberculosis,33 but we believe that the hierarchal endpoint definition used in this trial is robust and might be suitable for future tuberculosis vaccine trials.Cohort retention was very high in this trial, and no evidence was noted that the rate of loss to follow-up had a differential effect on case accrual. Similarly, exclusion of three enrolled infants in the per-protocol analysis did not affect the results.In conclusion, MVA85A was well tolerated, modestly immunogenic but unable to confer significant protection against tuberculosis or M tuberculosis infection. The information gained from the successful execution of this study will aid the planning of future trials and vaccination strategies. Substantial global efforts to develop an improved vaccine against tuberculosis must continue.References1WHOGlobal tuberculosis report 2012http://apps.who.int/iris/bitstream/10665/75938/1/9789241564502_eng.pdf(accessed Jan 2, 2013).2Stop TB PartnershipThe global plan to stop TB 2011–2015http://www.stoptb.org/global/plan/(accessed Jan 2, 2013).3TrunzBFinePDyeCEffect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectivenessLancet367200611731180166165604RodriguesLDiwanVWheelerJProtective effect of BCG against tuberculous meningitis and miliary tuberculosis: a meta-analysisInt J Epidemiol2219931154115881442995FinePVariation in protection by BCG: implications of and for heterologous immunityLancet34619951339134574757766ColditzGABerkeyCSMostellerFThe efficacy of bacillus Calmette-Guerin vaccination of newborns and infants in the prevention of tuberculosis: meta-analyses of the published literaturePediatrics961995293575967187Basu RoyRSotgiuGAltet-GomezNIdentifying predictors of interferon-gamma release assay results in pediatric latent tuberculosis: a protective role of bacillus Calmette-Guerin?: a pTB-NET collaborative studyAm J Respir Crit Care Med1862012378384227008628MahomedHKibelMHawkridgeTThe impact of a change in bacille Calmette-Guerin vaccine policy on tuberculosis incidence in children in Cape Town, South AfricaPediatr Infect Dis J25200611671172171331649MoyoSVerverSMahomedHAge-related tuberculosis incidence and severity in children under 5 years of age in Cape Town, South AfricaInt J Tuberc Lung Dis1420101491542007440410BrennanMJTholeJTuberculosis vaccines: a strategic blueprint for the next decadeTuberculosis (Edinb)92suppl 12012S6132244116011McShaneHPathanASanderCRecombinant modified vaccinia virus Ankara expressing antigen 85A boosts BCG-primed and naturally acquired antimycobacterial immunity in humansNat Med102004124012441550283912VordermeierHVillarreal-RamosBCocklePViral booster vaccines improve Mycobacterium bovis BCG-induced protection against bovine tuberculosisInfect Immun772009336433731948747613VerreckFVervenneRKondovaIMVA85A boosting of BCG and an attenuated, phoP deficient M tuberculosis vaccine both show protective efficacy against tuberculosis in rhesus macaquesPloS One42009e52641936733914GoonetillekeNMcShaneHHannanCAndersonRBrookesRHillAEnhanced immunogenicity and protective efficacy against Mycobacterium tuberculosis of bacille Calmette-Guerin vaccine using mucosal administration and boosting with a recombinant modified vaccinia virus AnkaraJ Immunol1712003160216091287425515WilliamsAGoonetillekeNPMcShaneHBoosting with poxviruses enhances Mycobacterium bovis BCG efficacy against tuberculosis in guinea pigsInfect Immun732005381438161590842016ScribaTJTamerisMMansoorNDose-finding study of the novel tuberculosis vaccine, MVA85A, in healthy BCG-vaccinated infantsJ Infect Dis2032011183218432160654217OtaMOdutolaAOwiafePImmunogenicity of the tuberculosis vaccine MVA85A is reduced by coadministration with EPI vaccines in a randomized controlled trial in Gambian infantsSci Transl Med3201188ra5618KaufmannSHFact and fiction in tuberculosis vaccine research: 10 years laterLancet Infect Dis1120116336402179846319HanekomWDockrellHOttenhoffTImmunological outcomes of new tuberculosis vaccine trials: WHO panel recommendationsPLoS Med52008e1451859755120BailyGVTuberculosis prevention trial, MadrasIndian J Med Res72suppl1980174700508621HawkridgeAHatherillMLittleFEfficacy of percutaneous versus intradermal BCG in the prevention of tuberculosis in South African infants: randomised trialBMJ33720081275128222Tameris M, McShane H, McClain J, et al. Lessons learnt from the first efficacy trial of a new infant tuberculosis vaccine since BCG. Tuberculosis (Edin) (in press).23ScribaTJTamerisMMansoorNModified vaccinia Ankara-expressing Ag85A, a novel tuberculosis vaccine, is safe in adolescents and children, and induces polyfunctional CD4+ T cellsEur J Immunol4020102792902001718823MoyoSVerverSHawkridgeATuberculosis case finding for vaccine trials in young children in high-incidence settings: a randomised trialInt J Tuberc Lung Dis1620121851912223691825MeyerJHarrisSSattiIComparing the safety and immunogenicity of a candidate TB vaccine MVA85A administered by intramuscular and intradermal deliveryVaccine312013102610332326634226HatherillMSafety and immunogenicity of MVA85A prime and bacille Calmette-Guérin boost vaccination (MVA(TB)029)http://www.clinicaltrials.gov/ct2/show/NCT1650389(accessed Jan 29, 2013).27KaginaBAbelBScribaTSpecific T cell frequency and cytokine expression profile do not correlate with protection against tuberculosis after bacillus Calmette-Guerin vaccination of newbornsAm J Resp Crit Care Med1822010107310792055862728Rerks-NgarmSPitisuttithumPNitayaphanSVaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in ThailandN Engl J Med3612009220922201984355729RtsSCTPAgnandjiSLellBA phase 3 trial of RTS,S/AS01 malaria vaccine in African infantsN Engl J Med3672012228422952313690930TaylorJTurnerOBasarabaRBelisleJHuygenKOrmeIPulmonary necrosis resulting from DNA vaccination against tuberculosisInfect Immun712003219221981265484131MoyoSIsaacsFGelderbloemSTuberculin skin test and QuantiFERON® assay in young children investigated for tuberculosis in South AfricaInt J Tuberc Lung Dis152011117611812194384132GrahamSAhmedTAmanullahFEvaluation of tuberculosis diagnostics in children: 1. Proposed clinical case definitions for classification of intrathoracic tuberculosis disease. Consensus from an expert panelJ Infect Dis205Suppl 22012S199S2082244802333HatherillMVerverSMahomedHConsensus statement on diagnostic end points for infant tuberculosis vaccine trialsClin Infect Dis54201249350122144538Supplementary MaterialSupplementary appendixAcknowledgmentsWe thank study participants and their families, the community of Cape Winelands East district, and South African Tuberculosis Vaccine Initiative (SATVI) personnel (Tony Hawkridge and Zainab Waggie [medical monitors]; Savvas Andronikou, Tracy Kilborn, and Nicky Wieselthaler [radiograph reviewers]; Andre Burger, Lizette Phillips, Danie Theron, Luise Lunnon [Cape Winelands Department of Health], staff of Cape Winelands East public health clinics and hospitals, Andrew Whitelaw and staff of National Health Laboratory Service, Groote Schuur Hospital, Cape Town; Jasur Ishmukhamedov, Sharon Sutton, Amy Lwin, Michael Raine, Christine Fattore, Wasima Rida, and E Martin Stals [Aeras]; and Andreas Diacon [Chair], James Balsley, Prakash Jeena, Neil Cameron, Alison Elliot, and Gil Price [safety monitoring committee]).ContributorsAll authors, on behalf of the MVA85A 020 Trial Study Team, contributed to study design, data analysis and interpretation, and writing and approval of the manuscript. MDT, MH, TJS, and HM contributed to the implementation of the study and supervision at the study site. MDT, GDH, and HM were the principal investigators. MAS designed and led the statistical analysis.The MVA85A 020 Trial Study TeamLinda Van Der Merwe, E Jane Hughes, Hennie Geldenhuys, Angelique K K Luabeya, Susan Rossouw, Erica Smit, Yolande Browne, Frances Ratangee, Cynthia Ontong, Marwou De Kock, Humphrey Mulenga, Ashley Veldsman, Stephanie Abrahim, Lilly Denation, Veronica Baartman, Amaryl Van Schalkwyk, Mariana Jacks, Colleen Krohn, Fazlin Kafaar, Marcia Steyn, Lebohang Makhete, Fatima Isaacs, Julia Noble, and Welile Sikhondze from the South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and School of Child and Adolescent Health, University of Cape Town, Cape Town, South Africa. Thomas Evans and Jerald Sadoff from Aeras, Rockville, MD, USA. Adrian V S Hill, Alison M Lawrie, Nathaniel J Brittain, and Samantha Vermaak from the Jenner Institute, Nuffield Department of Clinical Medicine, University of Oxford, UK.Conflicts of interestSL and JES are employees of Emergent BioSolutions and own shares and stock options in the company. HMcS is a shareholder in the Oxford-Emergent Tuberculosis Consortium (a joint venture between Emergent BioSolutions and the University of Oxford). All other authors declare that they have no conflicts of interest.Figure 1Trial profile*One infant developed gastroenteritis that precluded inclusion and one infant became ineligible after a randomisation error. QFT=QuantiFERON-TB Gold In-tube.Figure 2Vaccine immunogenicity(A) Frequencies of Ag85A-specific T cells measured by interferon-γ enzyme-linked immunosorbent spot assay in infants in study group 2 (27 infants in the MVA85A group and 27 infants in the placebo group) before administration of placebo or MVA85A (day 0) and 7 days after vaccination. (B) Frequencies of cytokine-expressing Ag85A-specific Th1 (CD4-positive T cells expressing IFN-γ, TNFα, or interleukin 2) and (C) frequencies of Ag85A-specific Th17 (CD4-positive T cells expressing interleukin 17) cells, measured by whole blood intracellular cytokine staining 28 days after administration of placebo or MVA85A to infants in study group four (17 infants in the MVA85A group and 19 infants in the placebo group). SFC=spot-forming cells. PBMC=peripheral blood mononuclear cell.Figure 3Cumulative incidence of diagnosis of tuberculosis endpoint 1Table 1Demographics and baseline characteristics of the per-protocol populationPlacebo (n=1395)MVA85A (n=1399)Overall (n=2794)Age, days145·7 (13·5)146·6 (14·3)146·2 (13·9)Sex, male714 (51%)708 (51%)1422 (51%)Ethnic groupBlack267 (19%)287 (21%)554 (20%)Mixed race1126 (81%)1107 (79%)2233 (80%)Asian1 (<1%)3 (<1%)4 (<1%)White1 (<1%)2 (<1%)3 (<1%)WeightInfants assessed1389 (>99%)1394 (>99%)2783 (>99%)Mean, kg6·47 (0·98)6·45 (0·99)6·46 (0·98)Full-term birth (≥38 weeks)983 (70%)1031 (74%)2014 (72%)Data are mean (SD) or n (%).Table 2Primary and secondary efficacy endpointsPlacebo (n=1395)MVA85A (n=1399)Vaccine efficacyEndpoint 1 (primary efficacy endpoint)39 (3%)32 (2%)17·3% (–31·9 to 48·2)Endpoint 2 (exploratory efficacy endpoint)52 (4%)55 (4%)–6·9% (–56·1 to 26·9)Endpoint 3 (exploratory efficacy endpoint)177 (13%)196 (14%)–12·1% (–37·4 to 8·5)Data are n (%) or % (95% CI). Participants with more than one diagnosis were analysed in each level of diagnosis attained. Vaccine efficacy and corresponding 95% CI was estimated with the Cox regression model (1 – estimated hazard ratio).Panel 1Definition of endpoint 1Any of the following criteria:•Isolation of Mycobacterium tuberculosis from any site•Identification of M tuberculosis by an approved molecular diagnostic technique from any site•Histopathology diagnostic for tuberculosis disease (eg, caseating granulomas)•Choroidal tubercle diagnosed by an ophthalmologist•Miliary pattern on chest radiograph in an HIV-negative infant•Clinical diagnosis of tuberculous meningitis (cerebrospinal fluid protein concentrations >0·6 g/L and pleocytosis of >50 cells per μL with >50% mononuclear cells) with features of basal meningeal enhancement and hydrocephalus on head CT•Vertebral spondylosis•One smear or histology specimen positive for auramine-positive bacilli from a normally sterile body site•One of each of the following:•Evidence of mycobacterial infection defined as two acid-fast positive smears (each from a separate collection) that were morphologically consistent with mycobacteria from either sputum or gastric aspirate that were not found to be non-tuberculous mycobacteria bacteria on culture; QuantiFERON-TB Gold In-tube test conversion from negative to positive; or tuberculin skin test ≥15 mmand•Radiographic findings compatible with tuberculosis defined as ≥1 of the following factors identified independently by at least two of three paediatric radiologists serving on a masked review panel: calcified Ghon focus, pulmonary cavity, hilar or mediastinal adenopathy, pleural effusion, or airspace opacificationand•Clinical manifestations compatible with tuberculosis defined as cough without improvement for >2 weeks; weight loss of >10% of bodyweight for >2 months; or failure to thrive, defined as crossing >1 complete major centile band (<97th–90th, <90th–75th, <75th–50th, <50th–25th, <25th–10th, and <10th–3rd weight-for-age centiles) downward for >2 monthsPanel 2Research in contextSystematic reviewTo our knowledge, our trial is the first efficacy study of a novel BCG booster tuberculosis vaccine in infants. A systematic review is not applicable.InterpretationThe safety of MVA85A reported in our large cohort is an important finding for tuberculosis vaccine development. However the absence of efficacy noted, despite studies in animals suggesting potential for efficacy and evidence of immunogenicity in previous clinical trials, was unexpected and suggests that the present parameters for selection of tuberculosis vaccine candidates might be inadequate. The relatively weak immunogenicity we noted in this study makes it difficult to conclude whether a higher magnitude response (ie, one that is qualitatively different or a completely new immunological mechanism) will be required for a protective vaccine. Lessons learnt from this trial, including trial design, execution, and vaccine selection, will be of enormous importance to the broader specialty of vaccine development.", 'title': 'In vivo detection of non-cavitated caries lesions on occlusal surfaces by visual inspection and quantitative light-induced fluorescence.', 'date': '2007-05-22'}}
| 0.5
|
Public Health, Epidemiology & Health Systems
|
68
|
Is the risk of developing latent tuberculosis higher, lower, or the same when comparing MVA85A added to BCG to BCG alone?
|
no difference
|
moderate
|
yes
|
['25726088', '23391465', '29028973']
| 31,038,197
| 2,019
|
{'25726088': {'article_id': '25726088', 'content': "Lancet Respir MedLancet Respir MedThe Lancet. Respiratory Medicine2213-26002213-2619Elsevier257260884648060S2213-2600(15)00037-510.1016/S2213-2600(15)00037-5ArticlesSafety, immunogenicity, and efficacy of the candidate tuberculosis vaccine MVA85A in healthy adults infected with HIV-1: a randomised, placebo-controlled, phase 2 trialNdiayeBirahim PierreMDa*ThienemannFriedrichMDbd*OtaMartinFWACPeLandryBernard SMPHfCamaraMakhtarPhDaDièyeSiryMDaDieyeTandakha NdiayePhDaEsmailHanifMRCPbjGoliathReneBScbHuygenKrisPhDgJanuaryVanessabNdiayeIbrahimaMDaOniToluMDbcRaineMichaelBScfRomanoMartaPhDgSattiImanPhDiSuttonSharonBSfThiamAminataMDhWilkinsonKatalin APhDbdkMboupSouleymaneProfPhDaWilkinsonRobert JProfFRCPbdjk†McShaneHelenProfFRCPhelen.mcshane@ndm.ox.ac.uki*†for the MVA85A 030 trial investigators‡aLaboratoire de Bactériologie–Virologie, Centre Hospitalier Universitaire Le Dantec, Dakar, SenegalbClinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South AfricacDivision of Public Health Medicine, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South AfricadDepartment of Medicine, University of Cape Town, Cape Town, South AfricaeMedical Research Council Unit, Fajara, The GambiafAeras, Rockville, MD, USAgImmunology Service, Scientific Institute of Public Health (WIV-ISP), Brussels, BelgiumhCentre de Traitement Ambulatoire, Centre Hospitalier Universitaire de Fann, Dakar, SenegaliJenner Institute, University of Oxford, Oxford, UKjDepartment of Medicine, Imperial College London, London, UKkMRC National Institute for Medical Research, London, UK*Correspondence to: Prof Helen McShane, Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK helen.mcshane@ndm.ox.ac.uk*Joint first authors†Joint last authors‡Listed in appendix1320153201533190200© 2015 Ndiaye et al. Open Access article distributed under the terms of CC BY2015This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).SummaryBackgroundHIV-1 infection is associated with increased risk of tuberculosis and a safe and effective vaccine would assist control measures. We assessed the safety, immunogenicity, and efficacy of a candidate tuberculosis vaccine, modified vaccinia virus Ankara expressing antigen 85A (MVA85A), in adults infected with HIV-1.MethodsWe did a randomised, double-blind, placebo-controlled, phase 2 trial of MVA85A in adults infected with HIV-1, at two clinical sites, in Cape Town, South Africa and Dakar, Senegal. Eligible participants were aged 18–50 years, had no evidence of active tuberculosis, and had baseline CD4 counts greater than 350 cells per μL if they had never received antiretroviral therapy or greater than 300 cells per μL (and with undetectable viral load before randomisation) if they were receiving antiretroviral therapy; participants with latent tuberculosis infection were eligible if they had completed at least 5 months of isoniazid preventive therapy, unless they had completed treatment for tuberculosis disease within 3 years before randomisation. Participants were randomly assigned (1:1) in blocks of four by randomly generated sequence to receive two intradermal injections of either MVA85A or placebo. Randomisation was stratified by antiretroviral therapy status and study site. Participants, nurses, investigators, and laboratory staff were masked to group allocation. The second (booster) injection of MVA85A or placebo was given 6–12 months after the first vaccination. The primary study outcome was safety in all vaccinated participants (the safety analysis population). Safety was assessed throughout the trial as defined in the protocol. Secondary outcomes were immunogenicity and vaccine efficacy against Mycobacterium tuberculosis infection and disease, assessed in the per-protocol population. Immunogenicity was assessed in a subset of participants at day 7 and day 28 after the first and second vaccination, and M tuberculosis infection and disease were assessed at the end of the study. The trial is registered with ClinicalTrials.gov, number NCT01151189.FindingsBetween Aug 4, 2011, and April 24, 2013, 650 participants were enrolled and randomly assigned; 649 were included in the safety analysis (324 in the MVA85A group and 325 in the placebo group) and 645 in the per-protocol analysis (320 and 325). 513 (71%) participants had CD4 counts greater than 300 cells per μL and were receiving antiretroviral therapy; 136 (21%) had CD4 counts above 350 cells per μL and had never received antiretroviral therapy. 277 (43%) had received isoniazid prophylaxis before enrolment. Solicited adverse events were more frequent in participants who received MVA85A (288 [89%]) than in those given placebo (235 [72%]). 34 serious adverse events were reported, 17 (5%) in each group. MVA85A induced a significant increase in antigen 85A-specific T-cell response, which peaked 7 days after both vaccinations and was primarily monofunctional. The number of participants with negative QuantiFERON-TB Gold In-Tube findings at baseline who converted to positive by the end of the study was 38 (20%) of 186 in the MVA85A group and 40 (23%) of 173 in the placebo group, for a vaccine efficacy of 11·7% (95% CI −41·3 to 44·9). In the per-protocol population, six (2%) cases of tuberculosis disease occurred in the MVA85A group and nine (3%) occurred in the placebo group, for a vaccine efficacy of 32·8% (95% CI −111·5 to 80·3).InterpretationMVA85A was well tolerated and immunogenic in adults infected with HIV-1. However, we detected no efficacy against M tuberculosis infection or disease, although the study was underpowered to detect an effect against disease. Potential reasons for the absence of detectable efficacy in this trial include insufficient induction of a vaccine-induced immune response or the wrong type of vaccine-induced immune response, or both.FundingEuropean & Developing Countries Clinical Trials Partnership (IP.2007.32080.002), Aeras, Bill & Melinda Gates Foundation, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium.Research in contextEvidence before this studyOne previous study assessed the efficacy of several doses of the saprophyte Mycobacterium vaccae against tuberculosis disease in adults infected with HIV-1, and showed a decreased risk of protocol-defined pulmonary tuberculosis. A previous study with the MVA85A, the candidate vaccine under assessment here, has showed that boosting with MVA85A did not enhance protective efficacy in BCG-vaccinated infants. Adults infected with HIV-1 are an important target population for a new tuberculosis vaccine, and in earlier studies, vaccine-induced immunogenicity in adults infected with HIV-1 was higher than in infants.Added value of this studyThis is the first time that a candidate tuberculosis vaccine has been assessed for efficacy against Mycobacterium tuberculosis infection in people infected with HIV-1. The results show that vaccinating adults infected with HIV-1 with MVA85A is safe, but does not confer protection against infection with M tuberculosis.Implications of all the available evidenceThe safety of MVA85A in this large study population of adults with HIV infection is an important finding for tuberculosis vaccine development. The vector is safe to give to people without HIV testing; these safety data provide some generic reassurance that new candidate tuberculosis vaccines are safe in this higher risk population. Additionally, this study has shown that high-quality, multicentre tuberculosis vaccine trials in vulnerable populations are possible. The absence of efficacy despite immunogenicity in this and previous clinical trials of MVA85A suggests that the current parameters for selection of tuberculosis vaccine candidates are inadequate. Standardised preclinical animal models that better represent human infection and disease, and a greater understanding of immune mechanisms of protection in human tuberculosis are both urgently needed. Alternative approaches to vaccine development, including the delivery of candidate vaccines direct to the respiratory mucosa, merit assessment. Other lessons learnt from this trial include the characterisation of the epidemiology of M tuberculosis infection and disease associated with HIV-1 infection in a setting of antiretroviral therapy and isoniazid chemoprophylaxis.IntroductionTuberculosis is a substantial global cause of mortality and morbidity, with 9 million new cases of active tuberculosis and 1·5 million deaths occurring in 2013.1 One third of the world's population is infected with Mycobacterium tuberculosis.1 HIV-1 co-infection is one of the most important risk factors for both infection with M tuberculosis and active tuberculosis disease,2 with an estimated 1·1 million of all new tuberculosis cases in 2013 occurring in people co-infected with HIV-1.1 The WHO African region accounts for 80% of HIV-1-associated tuberculosis.1 Additionally, the growing incidence of drug-resistant tuberculosis is associated with poor treatment outcome and increased mortality.3 The global Stop TB Partnership aims to eliminate tuberculosis as a public health problem by 2050. An agreed major component to advance this aim would be an effective vaccine.4 BCG is the only licensed tuberculosis vaccine—it provides protection against severe childhood tuberculosis,5, 6 but the protection conferred against pulmonary tuberculosis in adults and adolescents is highly variable.7, 8At least 16 candidate tuberculosis vaccines have advanced to clinical testing.9 The modified vaccinia virus Ankara expressing the major M tuberculosis antigen 85A (MVA85A) is a clinically advanced candidate vaccine.10, 11, 12 MVA85A is well tolerated and immunogenic in adults infected and not infected with HIV-1, and in infants not exposed to HIV-1.10, 11, 12, 13, 14 MVA85A adds to BCG-induced protection against mycobacterial challenge in some preclinical animal models.15, 16, 17, 18, 19 However, boosting BCG with MVA85A in South African infants not infected with HIV-1 did not confer additional protection against tuberculosis disease or M tuberculosis infection.10Administration of several doses of the saprophyte Mycobacterium vaccae to adults infected with HIV-1 was associated with a decreased risk of protocol-defined pulmonary tuberculosis,20 suggesting that vaccination might be effective in people infected with HIV-1. Here we report the results of a multisite, randomised, placebo-controlled, phase 2 trial to assess the safety, immunogenicity, and efficacy of MVA85A in healthy adults infected with HIV-1.MethodsStudy design and participantsWe did a proof-of-concept, randomised, double-blind, placebo-controlled, phase 2 trial of MVA85A at two clinical sites, in Cape Town, South Africa and Dakar, Senegal. In Cape Town, participants were recruited in the community and from primary care clinics in Khayelitsha by use of radio and newspaper advertisements, flyers, pamphlets, and information campaigns at the clinics. Khayelitsha is a densely populated, low-income, peri-urban township. In 2010, antenatal HIV-1 prevalence was 33% and the tuberculosis case notification rate was at least 1500 per 100\u2008000 population per year.21 In Dakar, participants were recruited from public service HIV clinics at the Centre de Traitement Ambulatoire and the Centre de Recherche Clinique et de Formation, Centre Hospitalier Universitaire de Fann. Senegal had an estimated HIV-1 prevalence in adults of less than 1% in 2012, and a reported tuberculosis incidence rate of 0·14% in 2013.1 The annual rate of M tuberculosis infection has not previously been estimated at either site. Eligibility criteria included participants aged 18–50 years with no evidence of active tuberculosis, and baseline CD4 counts greater than 350 cells per μL if they were not receiving antiretroviral therapy, or greater than 300 cells per μL (and with undetectable viral load before randomisation) if they were receiving antiretroviral therapy. Participants with latent tuberculosis infection were eligible for enrolment if they had completed at least 5 months of isoniazid preventive therapy, unless they had completed treatment for tuberculosis disease within 3 years before randomisation. The complete inclusion criteria are listed in the study protocol (appendix).The trial adhered to International Conference on Harmonisation Good Clinical Practice guidelines, and was approved by the University of Cape Town's Faculty of Health Sciences Human Research Ethics Committee and the Medicines Control Council of South Africa; the Senegalese National Ethics Committee for Research in Health; and the Oxford University Tropical Research Ethics Committee. All participants provided written informed consent before any study procedure.Randomisation and maskingParticipants were randomly assigned (1:1) in blocks of four by a randomly generated sequence of participant identification numbers via an interactive voice response system to receive two intradermal injections of either 1\u2008×\u2008108 pfu MVA85A or placebo (Candida skin test antigen [Candin], Allermed Laboratories, San Diego, CA, USA). Randomisation was stratified by antiretroviral therapy status and study site. A statistician uninvolved with study analyses prepared the interactive voice response system randomisation schedule. Doses of vaccines were prepared and labelled in masked syringes by a pharmacist unmasked to group allocation. Participants, nurses (who were involved in assessment and follow-up), investigators, and laboratory staff were masked to group allocation. The second (booster) injection of MVA85A or placebo was given 6–12 months after the first vaccination and participants were actively followed up every 3 months until the last participant enrolled had completed 6 months of follow-up after the booster vaccination.ProceduresWe collected data for the incidence of solicited and unsolicited adverse events, including both local injection-site reactions and systemic reactions. Participants reported solicited adverse events on diary cards for 7 days after each vaccination and in response to direct questioning by trained study staff on days 7 and 28 after each injection. Phlebotomy for routine haematological and biochemical analysis was done at screening, before booster vaccination, and on days 7 and 28 after each vaccination. Peripheral CD4 cell count and HIV-1 viral load were also measured at these timepoints and every 3 months until 6 months after booster vaccination. Serious adverse events were monitored by active surveillance throughout and until the end of the trial. The site investigators and local medical monitors determined the severity and seriousness of adverse events and the relation of these to the vaccine. An independent data monitoring committee assessed masked group safety data after 200 participants had been enrolled and unmasked after 600 participants had been enrolled.In a prespecified subset of 70 participants (35 from each group), immunology samples were obtained before each vaccination and on days 7 and 28 after each vaccination. All immunology tests were done masked to group allocation. We assessed vaccine immunogenicity with three assays. First, ex vivo interferon γ enzyme-linked immunospot (ELISPOT) analysis was done on fresh peripheral blood mononuclear cells.22 Cells were stimulated overnight with a single pool of 66 peptides of the antigen 85A (Ag85A), ESAT-6, and CFP-10. Second, Ag85A-specific intracellular cytokine staining assay was done on whole blood.23 Stimulated fixed whole blood samples were stained for CD3-positive, CD4-positive, CD8-positive, CD14-positive, and CD19-positive cells, interferon γ, tumour necrosis factor α, interleukin 17, and interleukin 2. Third, Ag85A-specific antibody response was measured on plasma. Ag85A-specific immunoglobulin G (IgG) antibodies were measured by ELISA on eight serial two-fold dilutions of plasma (1:25–1:3200), by use of affinity purified recombinant, histidine-tagged Ag85A24 (microwell plates coated with 50 ng per well of recombinant Ag85A in borate buffer, overnight at 4°C). Alkaline phosphatase-labelled goat anti-human IgG (Sigma, St Louis, MO, USA) was used as secondary antibody at a dilution of 1:1000 and optical density was read at 405 nm after development with phosphatase substrate (Sigma). Results were expressed in arbitrary units per mL (AU/mL), as compared with values of an internal tuberculosis serum standard of 2500 AU/mL.Participants were screened to exclude active tuberculosis by symptom screen and chest radiography at both sites before enrolment. In Cape Town, participants also underwent sputum collection for tuberculosis smear microscopy, GeneXpert MTB/RIF (Cepheid, Sunnyvale, CA, USA), and mycobacterial liquid culture (MGIT; Becton Dickinson, Sparks, MD, USA) because of previously documented high frequencies of asymptomatic disease at this site.25 Latent M tuberculosis infection was defined as either a positive QuantiFERON-TB Gold In-Tube (QFT) test or a tuberculin purified protein derivative skin test (tuberculin skin test) reaction greater than 5 mm.Participants were monitored throughout the trial for possible tuberculosis. Tuberculosis investigations were done in participants who had been in contact with a known case of active tuberculosis, in those who presented with at least one of cough for more than 1 week, fever for more than 1 week, drenching night sweats, unintentional weight loss of more than 3 kg, pleuritic chest pains, haemoptysis, or shortness of breath; and in those who converted to a positive QFT or tuberculin skin test (≤5 mm to >5 mm). Investigations included clinical examination, chest radiography, and collection of at least two sputum samples on which tuberculosis smear microscopy, GeneXpert MTB/RIF, and mycobacterial liquid culture were done. Chest radiographs were reviewed by two physicians, with a third reading to achieve consensus in the event of disagreement. QFT and tuberculin skin tests were repeated at the final study visit.OutcomesTuberculosis disease endpoint 1 was defined as culture or GeneXpert MTB/RIF positivity; endpoint 2 included endpoint 1 and a composite clinical endpoint (which included a single acid-fast bacilli smear from a sterile body site; two smears from pulmonary and gastric sampling, and compatible clinical symptoms and radiological signs); and endpoint 3 was participant commencement on anti-tubercular chemotherapy (see the study protocol for more information; appendix). The M tuberculosis infection endpoint was defined as conversion from negative QFT at baseline to positive QFT at the final visit.The primary study outcome was the safety of MVA85A in all participants who received at least one dose of study vaccine or placebo (the safety analysis population) as determined by the numbers and percentages of adverse events (including solicited, unsolicited, and serious adverse events).The secondary outcome was the efficacy of MVA85A for the prevention of active tuberculosis in the per-protocol population (all randomly allocated participants who received at least one dose of study vaccine or placebo and had no major protocol deviations and no tuberculosis case definition endpoints within 28 days after study day 0 [first vaccination]), which was determined by the incidence of active tuberculosis meeting the definition of endpoint 1, calculated as the number of new cases of active tuberculosis with a date of diagnosis from 28 days after the first vaccination until the end of the study follow-up (May 19, 2014). An intention-to-treat analysis was also done for disease efficacy. In the per-protocol population, we also examined the efficacy of MVA85A by antiretroviral therapy status at the time of randomisation and by baseline isoniazid preventive therapy status.Other secondary outcomes were to assess CD4-positive lymphocyte counts and HIV-1 viral load before and after administration of MVA85A compared with placebo; to assess the immunogenicity of MVA85A compared with placebo as measured by the ex-vivo interferon γ ELISPOT assay; to assess the immunogenicity of MVA85A compared with placebo as measured by flow cytometric intracellular cytokine staining of CD4-positive and CD8-positive T cells after stimulation with a peptide pool of mycobacterial antigens; to identify potential immunological correlates of protection from tuberculosis in participants vaccinated with MVA85A and to assess the QFT conversion rate at final study assessment in MVA85A recipients compared with controls without a diagnosis of tuberculosis during the trial.Statistical analysisAll sample size calculations assumed a loss to follow-up and death rate of 2%. The initial planned sample size for this trial was 1400 adult participants, to be followed up for 2 years after the last participant was enrolled. This sample size provided 80% power to detect a vaccine efficacy of 60% against tuberculosis disease. However, after review of the phase 2 infant efficacy data,10 the trial design was revised with safety as the primary objective and a smaller sample size and shorter follow-up of a minimum of 6 months. The revised sample size for this study was selected as adequate for a review of the safety profile. With 325 participants assigned to receive MVA85A, the revised sample would have a 90% probability of detecting at least one adverse event occurring at a rate of 0·71%. Because of the expected effect of antiretroviral therapy on tuberculosis disease, an estimated tuberculosis disease incidence ranging between 1·5% and 2% per year was used to estimate the power of the revised sample size for efficacy. Calculations were based on a one-sided log-rank test at a significance level of 0·10 and assumed completion of enrolment in 21 months, a follow-up period of about 15 months for the last patient enrolled, and a maximum of 36 months for the first patient enrolled. If the true efficacy was about 70%, 325 patients per treatment group (650 patients total) provided 81% power to show positive efficacy given an incidence rate of 2·0% in the control group per year, or 71% power given an incidence rate of 1·5% in the control group per year. At a true efficacy of about 60%, 325 patients per treatment group provided 67% power to show positive efficacy given an incidence rate of 2·0% per year, or 57% power given an incidence rate of 1·5% per year. Vaccine efficacy to prevent infection was a secondary endpoint: the recorded QFT conversion rate in the study provided 80% power to detect a vaccine efficacy of 50%.Statistical analyses were done using SAS version 9.2. All analyses were prespecified in the statistical analysis plan before locking of the database. For the safety analysis, we compared the proportion of participants with at least one adverse event in the MVA85A group versus those in the placebo using Fisher's exact test. We also calculated two-sided 95% CIs for proportions of adverse events within treatment groups and the differences between groups.The main statistical method used in the analysis of tuberculosis disease endpoints 1–3 was vaccine efficacy, estimated as 1 minus the estimated hazard ratio, based on a Cox regression analysis of time (days) to initial tuberculosis diagnosis, based on the per-protocol population. As supportive confirmatory analysis, we used the conditional binomial (Clopper-Pearson) method to estimate vaccine efficacy and its corresponding two-sided 95% CIs and p values. Time to initial diagnosis for each endpoint was compared by use of a two-sided log-rank test, stratified by study site and antiretroviral therapy status at randomisation. Analyses were summarised by antiretroviral therapy and treatment group for participants in the per-protocol population. Vaccine efficacy against M tuberculosis infection and the corresponding 95% CI, and p value were calculated with the conditional binomial method (Clopper-Pearson), identical to the tuberculosis case definition endpoint analysis.Other secondary endpoints were analysed in various ways. Median CD4 cell counts and associated two-sided 95% CIs were summarised by antiretroviral therapy status at randomisation, study site, treatment group, and timepoint. HIV-1 viral load (copies per mL) was summarised with medians (and associated 95% CIs) by antiretroviral therapy status at randomisation, study site, and treatment group, at each available timepoint. Both the CD4 cell counts and HIV-1 viral load values were log-transformed before any analysis was done. We used Wilcoxon paired analysis to compare within group before and after vaccination responses.Quintiles (Blomfontein, South Africa) did the statistical analysis, and Aeras paid for this service. The trial was registered with ClinicalTrials.gov, number NCT01151189.Role of the funding sourceAeras was the trial sponsor and contributed to study design and data analysis. The other funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. BPN, FT, BSL, RJW, and HM had full access to all the data in the study. HM had final responsibility for the decision to submit for publication.ResultsBetween Aug 4, 2011, and April 24, 2013, 1233 adults infected with HIV-1 were screened and 650 were randomly assigned; 649 were included in the safety analysis and 645 in the per-protocol analysis (figure 1). 513 (71%) participants had CD4 counts greater than 300 cells per μL and were receiving antiretroviral therapy; 136 (21%) had CD4 counts above 350 cells per μL and had never received antiretroviral therapy. The results of the intention-to-treat analysis were not different and are not reported. 311 (96%) participants in the placebo group and 298 (92%) in the MVA85A group received the booster vaccination. One participant was randomly assigned to placebo but received MVA85A; this participant was included in the safety population for MVA85A but not in the per-protocol efficacy population. One participant was randomly assigned to MVA85A but withdrew consent before vaccination and was not vaccinated. This participant was excluded from both the safety and per-protocol populations. Baseline demographic characteristics were similar in the two study groups and across the two study sites (table 1; appendix). 625 participants completed the study; 14 participants were lost to follow-up (nine placebo, five MVA85A), five withdrew consent (two placebo, three MVA85A), and six died (four placebo, two MVA85A).In the per-protocol population, median follow-up was 655 days for the 320 recipients of MVA85A and 654 days for the 325 placebo participants. Other than the four participants shown in figure 1, all participants were included in the analysis.At least one adverse event was reported in 312 (96%) of placebo recipients and 321 (99%) of MVA85A recipients (table 2). Solicited adverse events were more common in participants who received MVA85A than placebo (table 2). Most of these events were local injection-site reactions; other solicited adverse events included mild influenza-like symptoms and regional lymphadenopathy. We noted no significant difference between study groups in the frequency of serious adverse events. 34 serious adverse events occurred during the study, 17 in the placebo group and 17 in the MVA85A group (table 2; appendix). All but one of these events were judged to be unrelated to vaccination; a case of probable tuberculous meningitis that occurred 6 days after vaccination was judged to be possibly related to vaccination. The data monitoring committee reviewed this case, did not request unmasking, and recommended continuing with the study. The participant was treated for tuberculous meningitis and made a full recovery. At study completion, this participant was identified as having received MVA85A. 13 serious adverse events in the infections and infestations category occurred during the study (the only category with more than five serious adverse events in either group), eight in the placebo group and five in the MVA85A group; this difference was not significant (Fisher's exact test, p=0·58).The frequency of severe adverse events did not differ significantly between study groups (table 2). We noted no significant changes in CD4 cell count or HIV-1 viral load throughout the course of the trial in either study group (data not shown). Routine haematological and biochemical test results did not differ between study groups (data not shown).ELISPOT responses to Ag85A were significantly higher in participants from Dakar than in those from Cape Town at baseline (p=0·0016), but at no other timepoint. This difference was not seen with the less sensitive whole blood intracellular cytokine staining assay. MVA85A induced an Ag85A-specific T-cell response that peaked 7 days after the first and booster vaccinations (median spots per million: day 0 [first vaccination], 9·0 [IQR 2·3–51·0]; day 7 [first vaccination], 337·0 [139·3–993·8]; day 0 [booster vaccination], 103·5 [14·8–223·8]; day 7 [booster vaccination], 426·0 [150·0–745·0]; figure 2). Responses at each timepoint after vaccination did not differ by study site or by antiretroviral therapy status. Medians in the placebo group did not exceed 20 spots per million at any timepoint.Whole blood intracellular cytokine staining showed the most commonly measured cytokine from CD4 T cells was interferon γ, in agreement with the ELISPOT data. Tumour necrosis factor α and low concentrations of interleukins 2 and 17 were also detected (table 3, figure 2). Overall, numbers of antigen-specific CD8 T cells were very low and were only positive for interferon γ and tumour necrosis factor α. Multiparameter flow-cytometric analysis showed that mainly monofunctional Ag85A-specific CD4 T cells were present before and after vaccination (figure 3). Ag85A-specific antibody responses were less than twice the baseline value after vaccination in all but three participants.In the per-protocol population, the overall number of tuberculosis cases and incidence during study follow-up of tuberculosis cases (endpoint 1) was six (2%) in the MVA85A group and nine (3%) in the placebo group, for a vaccine efficacy of 32·8% (95% CI −111·5 to 80·3; table 4). Figure 4 shows the Kaplan-Meier time-to-disease analysis for endpoint 1. Stratification by antiretroviral therapy status showed no significant difference between treatment groups. Eight of the 15 endpoint 1 cases were QFT positive at enrolment. No additional participants met endpoint 2 who did not already meet endpoint 1. Vaccine efficacy for endpoint 3 was 10·5% (−161·3 to 70.0). Disease incidence did not differ by site. Median time to diagnosis of endpoint 1 was 249 days in the MVA85A group and 236 days in the placebo group. 159 (50%) of 320 MVA85A recipients and 148 (46%) of 325 placebo recipients were investigated for tuberculosis during the study. The study was insufficiently powered to assess the efficacy of MVA85A for the prevention of tuberculosis disease in the subset of participants receiving antiretroviral therapy or isoniazid prophylaxis. The absence of efficacy also made it impossible to identify potential immunological correlates of protection from tuberculosis in participants vaccinated with MVA85A.The number of QFT-negative participants who converted to QFT positive by the end of the study was 38 (20%) in the MVA85A group and 40 (23%) in the placebo group, for a vaccine efficacy of 11·7% (95% CI −41·3 to 44·9). QFT conversion did not differ by antiretroviral therapy status (data not shown), but it did differ by site. In Cape Town, 41 (31%) of 132 participants converted, whereas in Dakar, 37 (16%) of 227 converted (χ2 10·89, p=0·001). Frequency of QFT reversion (participants who were positive at baseline and negative at end of study) was similar in the two treatment groups (17 [14%] of 124 for MVA85A and 27 [19%] of 139 for placebo; p=0·22), and did not differ by antiretroviral therapy status (data not shown). Tuberculin skin test conversion was not a prespecified endpoint and is not reported here, but will be the subject of further analysis.DiscussionThis phase 2 trial in 650 adult participants infected with HIV-1 showed that MVA85A was well tolerated and immunogenic, with safety and immunogenicity profiles similar to those reported elsewhere for other populations in which this candidate vaccine has been assessed.10, 11, 12, 13, 14 However, we did not identify any significant efficacy against tuberculosis disease or M tuberculosis infection.Both first and booster vaccination with MVA85A induced a significant increase in Ag85A-specific T cells. Responses did not differ by antiretroviral therapy status. A probable explanation for this finding is the high baseline median CD4 count (571 cells per mm3; table 1, appendix) in participants who had not received antiretroviral therapy. Unlike the previously reported infant efficacy trial of MVA85A,10 baseline ELISPOT responses were detected in this trial and were significantly higher in participants from Dakar than in those from Cape Town. This result might be due to greater exposure to environmental mycobacteria; and the finding is unlikely to be due to a technical issue because it was only recorded at this timepoint, and there was a robust quality control programme in place for these assays. Furthermore, the median response 7 days after vaccination in this trial exceeded that seen in the infant trial (337 vs 136 spots per million).10 Additionally, the functional phenotype of the dominant T-cell population in this trial was monofunctional by contrast with the infant trial, in which the dominant phenotype was polyfunctional.10 In both trials, the recorded response was insufficient to be associated with protection. It is not clear whether a quantitatively greater or a qualitatively different immune response is needed for protection. Alternative approaches, including the delivery of candidate vaccines direct to the respiratory mucosa, might be more potent routes of immunisation. For example, we have previously reported that delivery of MVA85A by aerosol to HIV-negative, BCG-vaccinated adults in the UK is well tolerated and induces potent mucosal and systemic immunity.26 Further assessment is needed before this route can be examined in countries with a high burden of tuberculosis. This approach, together with other strategies to improve the immunogenicity of MVA85A, are currently under investigation.The recorded annual incidence of tuberculosis (endpoint 1) was substantial (1·43% across treatment groups) and did not differ between sites. However, this incidence was lower than previously reported in Cape Town.27 The numbers of participants receiving antiretroviral therapy was greater than originally envisaged, because of the increased availability of this therapy during the study period and the change in national and international guidelines on the provision of antiretroviral therapy. These factors, combined with the redesign of this study upon availability of the infant trial results,10 led to a reduction in statistical power to detect a difference in tuberculosis disease incidence between treatment groups, leading to wide CIs for our estimates of vaccine efficacy.In this trial, the incidence of infection determined by QFT conversion was much higher than the incidence of tuberculosis disease, so CIs around the estimates of efficacy against infection are narrower. The overall recorded annual QFT conversion rate of about 12% meant that we had about 80% power to detect a vaccine efficacy of 50% against M tuberculosis infection. In view of the cost and complexity of human efficacy studies, there is now increased focus on infection as an endpoint rather than disease in proof-of-concept studies before progression to prevention-of-disease efficacy trials.9 However, this approach presupposes that the immune mechanisms needed to prevent infection and disease are similar. Our poor understanding of the biology underlying dynamic QFT conversion and reversion further complicates this shift in emphasis. The rate of QFT reversion was almost as high as the rate of conversion: whether this finding represents a true biological effect or technical variability in the assay cannot be determined from these data.In this study, we have shown that high-quality, multicentre tuberculosis vaccine trials are possible in Africa, and have succeeded in the characterisation of the epidemiology of tuberculosis associated with HIV-1 in two African cities. Nevertheless, the disappointing finding with respect to vaccine efficacy for MVA85A suggests the need for standardised preclinical animal models that better represent human disease and an improved understanding of immune mechanisms of protection in human tuberculosis. Such advances would greatly enhance the ability to efficiently translate clinical research capacity into the development and deployment of an effective vaccine.References1WHOGlobal tuberculosis report2014World Health OrganizationGeneva2WalkerNFMeintjesGWilkinsonRJHIV-1 and the immune response to TBFuture Virol820135780236536643FalzonDWeyerKRaviglioneMCDrug-resistant tuberculosis: latest advancesLancet Respir Med12013e910243218184BrennanMJTholeJTuberculosis vaccines: a strategic blueprint for the next decadeTuberculosis92suppl 12012S613224411605RodriguesLCDiwanVKWheelerJGProtective effect of BCG against tuberculous meningitis and miliary tuberculosis: a meta-analysisInt J Epidemiol2219931154115881442996TrunzBBFinePDyeCEffect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectivenessLancet367200611731180166165607MangtaniPAbubakarIAritiCProtection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trialsClin Infect Dis582014470480243369118ColditzGABrewerTFBerkeyCSEfficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literatureJAMA271199469870283090349HawnTRDayTAScribaTJTuberculosis vaccines and prevention of infectionMicrobiol Mol Biol Rev7820146506712542893810TamerisMDHatherillMLandryBSSafety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trialLancet3812013102110282339146511McShaneHPathanAASanderCRRecombinant modified vaccinia virus Ankara expressing antigen 85A boosts BCG-primed and naturally acquired antimycobacterial immunity in humansNat Med102004124012441550283912HawkridgeTScribaTJGelderbloemSSafety and immunogenicity of a new tuberculosis vaccine, MVA85A, in healthy adults in South AfricaJ Infect Dis19820085445521858219513SanderCRPathanAABeveridgeNESafety and immunogenicity of a new tuberculosis vaccine, MVA85A, in Mycobacterium tuberculosis-infected individualsAm J Respir Crit Care Med17920097247331915119114MinassianAMRowlandRBeveridgeNEA phase I study evaluating the safety and immunogenicity of MVA85A, a candidate TB vaccine, in HIV-infected adultsBMJ Open12011e00022315WilliamsAGoonetillekeNPMcShaneHBoosting with poxviruses enhances Mycobacterium bovis BCG efficacy against tuberculosis in guinea pigsInfect Immun732005381438161590842016VordermeierHMVillarreal-RamosBCocklePJViral booster vaccines improve Mycobacterium bovis BCG-induced protection against bovine tuberculosisInfect Immun772009336433731948747617VerreckFAVervenneRAKondovaIMVA.85A boosting of BCG and an attenuated, phoP deficient M. tuberculosis vaccine both show protective efficacy against tuberculosis in rhesus macaquesPLoS One42009e52641936733918GoonetillekeNPMcShaneHHannanCMAndersonRJBrookesRHHillAVEnhanced immunogenicity and protective efficacy against Mycobacterium tuberculosis of bacille Calmette–Guérin vaccine using mucosal administration and boosting with a recombinant modified vaccinia virus AnkaraJ Immunol1712003160216091287425519McShaneHWilliamsAA review of preclinical animal models utilised for TB vaccine evaluation in the context of recent human efficacy dataTuberculosis9420141051102436998620von ReynCFMteiLArbeitRDPrevention of tuberculosis in Bacille Calmette-Guérin-primed, HIV-infected adults boosted with an inactivated whole-cell mycobacterial vaccineAIDS2420106756852011876721CoxHHughesJDanielsJCommunity-based treatment of drug-resistant tuberculosis in Khayelitsha, South AfricaInt J Tuberc Lung Dis1820144414482467070022ScribaTJTamerisMMansoorNModified vaccinia Ankara-expressing Ag85A, a novel tuberculosis vaccine, is safe in adolescents and children, and induces polyfunctional CD4+ T cellsEur J Immunol4020102792902001718823HanekomWAHughesJMavinkurveMNovel application of a whole blood intracellular cytokine detection assay to quantitate specific T-cell frequency in field studiesJ Immunol Methods29120041851951534531624GartnerTBaetenMOtienoSRevetsHDe BaetselierPHuygenKMucosal prime-boost vaccination for tuberculosis based on TLR triggering OprI lipoprotein from Pseudomonas aeruginosa fused to mycolyl-transferase Ag85AImmunol Lett111200726351757053525RangakaMXGideonHPWilkinsonKAInterferon release does not add discriminatory value to smear-negative HIV-tuberculosis algorithmsEur Respir J3920121631712171948726SattiIMeyerJHarrisSASafety and immunogenicity of a candidate tuberculosis vaccine MVA85A delivered by aerosol in BCG-vaccinated healthy adults: a phase 1, double-blind, randomised controlled trialLancet Infect Dis1420149399462515122527RangakaMXWilkinsonRJBoulleAIsoniazid plus antiretroviral therapy to prevent tuberculosis: a randomised double-blind, placebo-controlled trialLancet384201468269024835842Supplementary MaterialSupplementary appendixAcknowledgmentsThe study was funded by the European & Developing Countries Clinical Trials Partnership (IP.07.32080.002), Aeras, Bill & Melinda Gates Foundation, the Wellcome Trust (095780, 084323, and 088316), and the Oxford-Emergent Tuberculosis Consortium. Quintiles (Bloemfontein, South Africa) were used for the statistical analysis, and Aeras paid for this service. The appendix includes a complete list of acknowledgments. We dedicate this study to the memory of Robyn Louw.ContributorsBPN, FT, SD, HE, RG, VJ, IN, TO, AT, MRa, BSL, SM, and RJW were responsible for implementation of the study and supervision at the study sites. MC, TND, KH, MRo, IS, and KAW did the immunological analysis. MO, RJW, SM, and HM raised the funding and wrote the protocol. All authors contributed to data analysis and contributed to the writing of the report.Declaration of interestsHM was previously a shareholder in the Oxford-Emergent Tuberculosis Consortium (OETC), a joint venture established for the development of MVA85A (OETC no longer exists). KH has a patent (US 5736524 A) related to the development of a DNA vaccine against Mycobacterium tuberculosis. RJW received grants from the European & Developing Countries Clinical Trials Partnership, the Wellcome Trust, the UK Medical Research Council, and the European Union during the conduct of the study, and personal fees from GlaxoSmithKline unrelated to this work. All other authors declare no competing interests.Figure 1Trial profileFigure 2Vaccine immunogenicity (both study sites combined)(A) Antigen 85A (Ag85A) interferon γ enzyme-linked immunospot analysis responses. Data are presented as spot-forming cells (SFC) per million peripheral blood mononuclear cells (PBMCs). p values were calculated with Wilcoxon matched-pair signed-rank tests. Box and whisker plots show median, IQR, and minimum and maximum values. (B) Whole blood intracellular cytokine staining assay of total cytokines. Data are presented as frequency of CD4 and CD8 T cells producing cytokines. Box and whisker plots show median, IQR, and minimum and maximum values. IFNγ=interferon γ. TNFα=tumour necrosis factor α. IL=interleukin. V1=vaccination 1. V2=vaccination 2.Figure 3Polyfunctional CD4 T cellsPlots show frequency of CD4 T cells producing combinations of the studied cytokines. Bars are median values and dots represent individual volunteers. IFNγ=interferon γ. TNFα=tumour necrosis factor α. IL=interleukin. V1=vaccination 1. V2=vaccination 2.Figure 4Cumulative incidence of diagnosis of tuberculosis endpoint 1 by treatment groupEndpoint 1 was defined as a positive finding from culture or GeneXpert MTB/RIF assay.Table 1Demographic and baseline characteristics (safety analysis population)Placebo (n=325)MVA85A (n=324)Median age, years (range)39·0 (22–41)38·0 (21–49)Women255 (78%)265 (82%)Ethnic originBlack304 (94%)302 (93%)Mixed21 (6%)22 (7%)QFT test resultPositive150 (46%)135 (42%)Negative173 (53%)188 (58%)Indeterminate2 (1%)1 (<1%)TST result>5 mm128 (39%)124 (38%)≤5 mm191 (59%)190 (59%)Missing data6 (2%)10 (3%)Latent tuberculosis infection178 (55%)164 (51%)5–6 months IPT before enrolment144 (44%)133 (41%)Receiving antiretroviral therapy256 (79%)257 (79%)CD4 count (cells per mm3)Participants not receiving antiretroviral therapy564 (169·8)571 (187·5)Participants receiving antiretroviral therapy599 (199·6)598 (220·7)HIV viral load (copies per mL)Participants not receiving antiretroviral therapy41\u2008371 (92\u2008456·9)62\u2008168 (166\u2008912·1)Participants receiving antiretroviral therapy29 (27·1)34 (63·7)Data are n (%) or mean (SD), unless otherwise stated. QFT=QuantiFERON-TB Gold In-Tube. TST=tuberculin skin test. IPT=isoniazid preventive therapy.Table 2Overview of adverse events (safety analysis population)OverallParticipants not receiving antiretroviral therapyParticipants receiving antiretroviral therapyPlacebo (n=325)MVA85A (n=324)Difference (MVA85A minus placebo) (95% CI)Placebo (n=69)MVA85A (n=67)Difference (MVA85A minus placebo) (95% CI)Placebo (n=256)MVA85A (n=257)Difference (MVA85A minus placebo) (95% CI)Any adverse event312 (96·0%; 93·3–97·7)321 (99·1%; 97·3–99·7)3·1 (0·7 to 5·4)67 (97·1%; 90·0–99·2)66 (98·5%; 92·0–99·7)1·4 (−3·5 to 6·3)245 (95·7%; 92·5–97·6)255 (99·2%; 97·2–99·8)3·5 (0·8 to 6·2)Solicited adverse event235 (72·3%; 67·2–76·9)288 (88·9%; 85·0–91·9)16·6 (10·6 to 22·5)50 (72·5%; 61·0–81·6)63 (94·0%; 85·6–97·7)21·6 (9·6 to 33·5)185 (72·3%; 66·5–77·4)225 (87·5%; 83·0–91·0)15·3 (8·5 to 22·1)Serious adverse event17 (5·2%; 3·9–8·2)17 (5·2%; 3·3–8·2)0·02 (−3·4 to 3·4)2 (2·9%; 0·8–10·0)9 (13·4%; 7·2–23·6)10·5 (1·5 to 19·6)15 (5·9%; 3·6–9·4)8 (3·1%; 1·6–6·0)−2·7 (−6·3 to 0·8)Related adverse event307 (94·5%; 91·4–96·5)318 (98·1%; 96·0–99·2)3·7 (0·8 to 6·6)66 (95·7%; 88·0–98·5)66 (98·5%; 92·0–99·7)2·9 (−2·8 to 8·5)241 (94·1%; 90·6–96·4)252 (98·1%; 95·5–99·1)3·9 (0·6 to 7·2)Severe adverse event84 (25·8%; 21·4–30·9)100 (30·9%; 26·1-36·1)5·0 (−1·9 to 11·9)15 (21·7%; 13·6–32·8)22 (32·8%; 22·8–44·8)11·1 (−3·8 to 26)69 (27·0%; 21·7–32·9)78 (30·4%; 25·1–36·2)3·4 (−4·4 to 11·2)Data are n (%; 95% CI), unless otherwise stated. Serious adverse events were coded with Medical Dictionary for Regulatory Activities version 14.0. Patients with multiple events in each category are counted only once in each category.Table 3Total intracellular cytokine response, presented as frequency of CD4 T cells and CD8 T cells producing specific cytokinesMVA85A (n=28)MVA85A timepoint comparisons (p values)Placebo (n=29)Day 0 (vaccination 1)Day 7 (vaccination 1)Day 0 (vaccination 2)Day 7 (vaccination 2)Day 0 (vaccination 1) vs day 7 (vaccination 1)Day 0 (vaccination 1) vs day 0 (vaccination 2)Day 0 (vaccination 1) vs day 7 (vaccination 2)Day 0 (vaccination 2) vs day 7 (vaccination 2)Day 0 (vaccination 1)Day 7 (vaccination 1)Day 0 (vaccination 2)Day 7 (vaccination 2)CD4 IFNγ0·01 (0–0·07)0·1 (0–1·12)0·03 (0–0·28)0·11 (0·02–0·82)<0·00010·0015<0·0001<0·00010·02 (0–0·12)0·01 (0–0·08)0 (0–0·08)0·01 (0–0·18)CD4 TNFα0·02 (0–0·12)0·11 (0–0·53)0·05 (0–0·57)0·11 (0–0·46)<0·00010·0403<0·0001<0·00010·02 (0–0·15)0·02 (0-0·14)0·02 (0–0·11)0·02 (0–0·23)CD4 IL-20·021 (0–0·11)0·07 (0–0·68)0·04 (0–0·27)0·1 (0·03–0·44)<0·00010·0421<0·0001<0·00010·02 (0–0·08)0·017 (0–0·08)0·02 (0–0·09)0·018 (0–0·06)CD4 IL-170·09 (0·01–0·28)0·12 (0·03–0·27)0·09 (0–0·37)0·1 (0·03–0·23)0·09460·54250·40470·28430·07 (0–0·27)0·06 (0·02–0·27)0·08 (0·01–0·26)0·078 (0–0·25)CD8 IFNγ0 (0–0·21)0·02 (0–0·94)0 (0–0·58)0·01 (0–0·3)0·01010·54990·22640·28970 (0–0·35)0 (0–0·19)0 (0–0·33)0 (0–0·24)CD8 TNFα0 (0–0·28)0 (0–0·24)0 (0–0·48)0 (0–0·05)0·45130·76150·73370·39530 (0–0·09)0 (0–0·38)0 (0–0·2)0 (0–0·13)Data are median (minimum to maximum) of total cytokines at each of the study timepoints, unless otherwise stated. Population is the immunology substudy (the first 70 participants), of which complete data were available for 57 participants. Statistical comparison of total cytokine responses in MVA85A study group used Wilcoxon matched-pairs signed-rank test. IL=interleukin. IFNγ=interferon γ. TNFα=tumour necrosis factor α.Table 4Primary and secondary efficacy results (per-protocol population)OverallParticipants not receiving antiretroviral therapyParticipants receiving antiretroviral therapyPlaceboMVA85AVaccine efficacy (95% CI)PlaceboMVA85AVaccine efficacy (95% CI)PlaceboMVA85AVaccine efficacy (95% CI)Disease endpoint 1 (primary efficacy endpoint)9/325 (2·8%)6/320 (1·9%)32·8%(−111·5 to 80·3)1/69 (1·4%)2/65 (3·1%)−114·1%(−12\u2008528·3 to 88·9)8/256 (3·1%)4/255 (1·6%)50·3%(−85·4 to 89·1)Disease endpoint 39/325 (2·8%)8/320 (2·5%)10·5%(−161·3 to 70·0)1/69 (1·4%)3/65 (4·6%)−224·7%(−16\u2008947·7 to 73·9)8/256 (3·1%)5/255 (2·0%)38·2%(−114·1 to 84·1)QFT positive conversion40/173 (23·1%)38/186 (20·4%)11·7%(−41·3 to 44·9)11/36 (30·6%)6/38 (15·8%)44·2%(−64·8 to 83·0)29/137 (21·2%)32/148 (21·6%)−0·1%(−71·5 to 41·4)Data are n/N (%), unless otherwise stated. Disease endpoint 1 was defined as culture or GeneXpert MTB/RIF positivity; disease endpoint 2 included endpoint 1 and a composite clinical endpoint; and disease endpoint 3 was commencement on anti-tubercular chemotherapy. No additional participants met endpoint 2 who did not already meet endpoint 1. QFT=QuantiFERON-TB Gold In-Tube.", 'title': 'Safety, immunogenicity, and efficacy of the candidate tuberculosis vaccine MVA85A in healthy adults infected with HIV-1: a randomised, placebo-controlled, phase 2 trial.', 'date': '2015-03-03'}, '23391465': {'article_id': '23391465', 'content': "LancetLancetLancet (London, England)0140-67361474-547XElsevier233914655424647S0140-6736(13)60177-410.1016/S0140-6736(13)60177-4ArticlesSafety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trialTamerisMichele DDrMBChBmichele.tameris@uct.ac.zaa**HatherillMarkFCPa*LandryBernard SMPHbScribaThomas JPhDaSnowdenMargaret AnnMPHbLockhartStephenDMcdSheaJacqueline EPhDcMcClainJ BruceMDbHusseyGregory DProfFFCHafHanekomWillem AProfFCPaMahomedHassanMMedag†McShaneHelenProfFRCPhelen.mcshane@ndm.ox.ac.uke†**the MVA85A 020 Trial Study TeamaSouth African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and School of Child and Adolescent Health, University of Cape Town, Cape Town, South AfricabAeras, Rockville, MD, USAcOxford-Emergent Tuberculosis Consortium, Wokingham, Berkshire, UKdEmergent Product Development UK, Wokingham, Berkshire, UKeJenner Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UKfVaccines for Africa, Institute of Infectious Disease and Molecular Medicine and Department of Medical Microbiology, University of Cape Town, Cape Town, South AfricagDepartment of Health, Western Cape and Division of Community Health, Stellenbosch University, Stellenbosch, South Africa*Correspondence to: Dr Michele D Tameris, South African Tuberculosis Vaccine Initiative (SATVI), Brewelskloof Hospital, Haarlem Street, Worcester 6850, South Africa michele.tameris@uct.ac.za**Prof Helen McShane, University of Oxford, Jenner Institute, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK helen.mcshane@ndm.ox.ac.uk*Contributed equally†Senior authors422013422013381987110211028© 2013 Published by Elsevier Ltd.2013Elsevier LtdSummaryBackgroundBCG vaccination provides incomplete protection against tuberculosis in infants. A new vaccine, modified Vaccinia Ankara virus expressing antigen 85A (MVA85A), was designed to enhance the protective efficacy of BCG. We aimed to assess safety, immunogenicity, and efficacy of MVA85A against tuberculosis and Mycobacterium tuberculosis infection in infants.MethodsIn our double-blind, randomised, placebo-controlled phase 2b trial, we enrolled healthy infants (aged 4–6 months) without HIV infection who had previously received BCG vaccination. We randomly allocated infants (1:1), according to an independently generated sequence with block sizes of four, to receive one intradermal dose of MVA85A or an equal volume of Candida skin test antigen as placebo at a clinical facility in a rural region near Cape Town, South Africa. We actively followed up infants every 3 months for up to 37 months. The primary study outcome was safety (incidence of adverse and serious adverse events) in all vaccinated participants, but we also assessed efficacy in a protocol-defined group of participants who received at least one dose of allocated vaccine. The primary efficacy endpoint was incident tuberculosis incorporating microbiological, radiological, and clinical criteria, and the secondary efficacy endpoint was M tuberculosis infection according to QuantiFERON TB Gold In-tube conversion (Cellestis, Australia). This trial was registered with the South African National Clinical Trials Register (DOH-27-0109-2654) and with ClinicalTrials.gov on July 31, 2009, number NCT00953927FindingsBetween July 15, 2009, and May 4, 2011, we enrolled 2797 infants (1399 allocated MVA85A and 1398 allocated placebo). Median follow-up in the per-protocol population was 24·6 months (IQR 19·2–28·1), and did not differ between groups. More infants who received MVA85A than controls had at least one local adverse event (1251 [89%] of 1399 MVA85A recipients and 628 [45%] of 1396 controls who received the allocated intervention) but the numbers of infants with systemic adverse events (1120 [80%] and 1059 [76%]) or serious adverse events (257 [18%] and 258 (18%) did not differ between groups. None of the 648 serious adverse events in these 515 infants was related to MVA85A. 32 (2%) of 1399 MVA85A recipients met the primary efficacy endpoint (tuberculosis incidence of 1·15 per 100 person-years [95% CI 0·79 to 1·62]; with conversion in 178 [13%] of 1398 infants [95% CI 11·0 to 14·6]) as did 39 (3%) of 1395 controls (1·39 per 100 person-years [1·00 to 1·91]; with conversion in 171 [12%] of 1394 infants [10·6 to 14·1]). Efficacy against tuberculosis was 17·3% (95% CI −31·9 to 48·2) and against M tuberculosis infection was −3·8% (–28·1 to 15·9).InterpretationMVA85A was well tolerated and induced modest cell-mediated immune responses. Reasons for the absence of MVA85A efficacy against tuberculosis or M tuberculosis infection in infants need exploration.FundingAeras, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium (OETC).IntroductionTuberculosis is a major global health problem, with an estimated 8·7 million cases and 1·4 million deaths in 2011.1 The Stop TB Partnership developed the Global Plan to Stop TB: 2006–2015, with a goal of tuberculosis elimination by 2050.2 One of the long-term strategies essential for control of the epidemic is effective vaccination. The existing BCG vaccine protects against disseminated tuberculosis in young children,3, 4 but protection against pulmonary tuberculosis is very variable.4, 5, 6 Efficacy against infection with Mycobacterium tuberculosis has only been reported in observational studies in low-burden settings.7 In endemic countries such as South Africa, the incidence of tuberculosis in infants and young children is very high despite high BCG coverage.8, 9 An improved infant tuberculosis vaccination regimen is urgently needed.12 candidate vaccines are being tested in clinical trials.10 MVA85A is a recombinant strain of modified Vaccinia Ankara virus expressing the immunodominant M tuberculosis protein, antigen 85A.11 MVA85A has been developed as a heterologous boost for BCG.11 Boosting BCG with MVA85A improved BCG-induced protection against mycobacterial challenge in animals.12, 13, 14, 15 MVA85A was well tolerated in clinical trials in infants.11, 16, 17 Furthermore, a BCG prime-MVA85A boost immunisation regimen in infants induced antigen-specific Th1 and Th17 cells,16 which are regarded as important in protection against tuberculosis.18, 19We aimed to further assess safety of MVA85A in HIV-negative infants who were previously vaccinated with BCG. As secondary endpoints, we also aimed to assess efficacy of MVA85A against tuberculosis and M tuberculosis infection beyond that of BCG alone, assess immunogenicity of MVA85A, and identify correlates of protection. To our knowledge, our investigation was the first infant efficacy trial of a new tuberculosis vaccine since BCG was last assessed in infants as part of the Chingleput-Madras trial that started in 1968.20MethodsStudy design and participantsWe undertook a parallel-group, randomised, placebo-controlled, double-blind phase 2b trial at the South African Tuberculosis Vaccine Initiative (SATVI) site in a rural region near Cape Town, South Africa. The region has a population of about 290\u2008000 people and an annual birth cohort of about 7000 babies. The overall incidence of tuberculosis in South Africa in 2011 was estimated to be almost 1% (993 per 100\u2008000 individuals).1 The incidence of tuberculosis in children younger than 2 years was about 3% at our trial site.21Parents of recently born infants were approached at local immunisation clinics or at home about study participation. We enrolled healthy infants, aged 4–6 months and who had received BCG (Danish 1331, Statens Serum Institut, Denmark) within 7 days of birth. Infants had to have received all age-appropriate routine immunisations, and two doses of pneumococcal conjugate vaccine at least 28 days before study vaccination (amended to 14 days during enrolment). All infants had to be HIV ELISA negative, QuantiFERON-TB Gold In-tube test (QFT; Cellestis, Australia) negative, and have had no substantial exposure to a patient with known tuberculosis. The appendix contains the study protocol.The trial was approved by the University of Cape Town Faculty of Health Sciences Human Research Ethics Committee, Oxford University Tropical Research Ethics Committee, and the Medicines Control Council of South Africa. Parents or legal guardians provided written, informed consent.Randomisation and maskingWe randomly allocated infants in a 1:1 ratio, with a block size of four, by use of an interactive voice/online response system to receive one intradermal dose of MVA85A (1×108 plaque-forming units in 0·06 mL) or an equal volume of Candida skin test antigen (Candin, AllerMed, USA) as placebo. Doses were prepared and labelled in masked syringes by an unmasked study pharmacist. An independent statistician prepared the randomisation schedule. The parents or legal guardians of study participants, study staff administering vaccinations or undertaking follow-up clinic assessments, and laboratory staff were masked to intervention group assignment.ProceduresThe study design included specific cohorts for specialised analyses, but all participants were followed up for assessment of efficacy and incidence of serious adverse events. Peripheral blood for routine haematological and biochemical tests was taken at screening and on day 7 and day 28 after vaccination in an initial safety cohort of at least 330 infants (study group 1). We assessed immunogenicity in three subsequent cohorts of up to 60 participants with an enzyme-linked immunosorbent spot analysis (study group 2), an intracellular cytokine staining (ICS) assay for peripheral blood mononuclear cell (PBMCs) counts (study group 3), and a whole blood ICS assay (study group 4). We enrolled remaining infants into a fifth cohort (study group 5). PBMCs obtained from all infants before and after vaccination were cryopreserved for future correlates analyses. We did QFT testing at screening, day 336, at the end of study visit, and for infants admitted to a dedicated study ward for investigation for tuberculosis.21We obtained data for incidence of solicited and unsolicited local (injection site) and systemic adverse events reported by parents or guardians on diary cards for 7 days after vaccination and by direct questioning by study staff for 28 days after vaccination. We also obtained data for serious adverse events throughout follow-up by active surveillance. Adverse events were assessed by the trial investigators and serious adverse events were assessed by the trial investigators and a local medical monitor, acting on behalf of the sponsor, to determine relation to vaccination. The trial investigators and local medical monitor were masked to intervention group throughout the trial. The safety monitoring committee (SMC) did not determine the association or severity of the adverse events. When the last infant in the safety cohort completed day 84, the SMC reviewed unmasked safety data to determine if a pattern of adverse events related to MVA85A or other safety concerns existed so as to advise on further enrolments. The SMC also conducted a second unmasked analysis-by-group safety and risk review after the 1000th infant completed their visit at study day 84.We actively followed up infants every 3 months to identify any signs, symptoms, or exposure that merited further investigation. Participants who had a persistent cough, failure to thrive, weight loss crossing a major centile band, QFT or tuberculin skin test conversion, household tuberculosis contact, or any other condition causing investigator concern were admitted to the study ward. Standardised investigations involved assessments with chest radiography, tuberculin skin test, QFT, HIV-ELISA, two consecutive early morning gastric lavage samples, and two induced sputa. Gastric lavage and sputum samples underwent auramine smear microscopy, GeneXpert MTB/RIF (Cepheid, USA; routinely from January, 2011, onwards), and MGIT (Becton Dickinson, Sparks, USA) liquid culture and sensitivity testing. Positive samples were speciated by PCR. We developed a hierarchy of three disease endpoint definitions. Endpoint 1 (panel 1) and endpoint 2 (appendix p 49) were based on the presence of specific clinical, radiological, and microbiological findings.22 Endpoint 2 (which included all infants who met endpoint 1 criteria) had marginally less stringent criteria to define tuberculosis infection and household exposure. Endpoint 3 included all participants placed on treatment for tuberculosis by a health professional. This approach allowed objective case classification without the need for an adjudication committee.The endpoint of infection with M tuberculosis was defined as conversion to a positive QFT test at any time during follow-up. We assessed rates of QFT conversion 1 year after vaccination and at end of study in those participants not previously started on anti-tuberculous treatment.We measured immunological sensitisation to M tuberculosis antigens, suggesting M tuberculosis infection, by QFT during screening, 1 year after vaccination, and at the close-out visit. We obtained blood samples from study groups 2–4 for immunogenicity analyses 7 days before vaccination and 7 days or 28 days after vaccination. We assessed immunogenicity with an ex-vivo interferon γ enzyme-linked immunosorbent spot assay, together with PBMC and whole blood ICS assays done as previously described.23 Further details of the methods are available in the appendix.Statistical analysesThe primary study outcome was safety in all vaccinated participants (safety population), including all solicited, unsolicited, and serious adverse events. We compared the proportion of participants with at least one such adverse event in the placebo and MVA85A groups with Fisher's exact test, and we calculated two-sided exact 95% CIs for proportions of individual events within treatment groups. We did immunogenicity analyses for all vaccinated participants enrolled in study groups 2–4. Statistical analyses were prespecified in a statistical analysis plan, signed off prior to study database lock and unmasking of data (appendix).The primary efficacy outcome was incidence of endpoint 1 and the secondary efficacy outcome was infection with M tuberculosis. Endpoints 2 and 3 were exploratory efficacy outcomes. All efficacy analyses were based on the per-protocol population, consisting of all randomly allocated participants who received at least one dose of study vaccine as randomised, and who had no major protocol deviations.The primary statistical method for analysis of endpoint 1 was vaccine efficacy, defined as 1 minus the estimated hazard ratio based on a Cox regression analysis of time to first diagnosis of endpoint 1. The Cox model contained one indicator variable for treatment group. To investigate the potential effect of variable follow-up times, we also did this analysis with a predefined cutoff of 2 years after vaccination. Analysis of endpoint 1 also included time (months) to initial tuberculosis diagnosis from day of vaccination in each treatment group with the Kaplan-Meier estimate of the survival function by treatment group, and the exact binomial method to estimate vaccine efficacy and its corresponding 95% CI (Clopper-Pearson with mid-p adjustment) conditional on the total number of events. We included participants with more than one diagnosis (eg, a diagnosis of tuberculosis endpoint 2 that was subsequently diagnosed as endpoint 1) in analyses separately for each diagnostic level. For the analysis of secondary and exploratory efficacy endpoints, no adjustment for multiplicity was done. We regarded a two-sided p value of less than 0·05 as significant. Summaries were presented for all cases reported during the study, and also, all cases with a diagnosis during the first 2 years of individual follow-up.For efficacy analyses, we based the sample size calculation on the primary efficacy endpoint of tuberculosis (endpoint 1). We assumed a cumulative tuberculosis incidence of 3% after a median of 18 months' follow-up in the placebo group,21 with an estimated 7·5% loss to follow-up.24 Thus, 1392 participants per intervention group would provide a 90% chance of detection of a 60% reduction between the intervention and control groups based on a two-sided log-rank test at a significance level of 0·05. We implemented a 6 month extension to the planned follow-up to achieve the target case accrual.For safety analyses, the sample size of 1392 participants receiving MVA85A would provide a greater than 75% chance of observing an adverse event that had an approximately one in 1000 actual rate of occurrence.The trial was registered with the South African National Clinical Trials Register on Nov, 4, 2008 (DOH-27-0109-2654), and with ClinicalTrials.gov on July 31, 2009, number NCT00953927.Role of the funding sourceAeras was the trial sponsor. Aeras and the Oxford-Emergent Tuberculosis Consortium (OETC) contributed to study design, data interpretation, and writing of the manuscript. MDT, MH, BSL, TJS, MAS, SL, HM, and HMcS had complete access to the data. HMcS had final responsibility for the decision to submit for publication.ResultsBetween July 15, 2009, and May 4, 2011, we obtained consent for 4754 infants. We enrolled 2797 infants who had completed screening when the enrolment target of 2784 was met (figure 1). Reasons for screening failure have been reported elsewhere.22 363 infants were entered into study group 1 (initial safety cohort; 182 in MVA85A group and 181 in the placebo group); 54 into group 2 (27 and 27), 54 into group 3 (27 and 27), and 39 into group 4 (19 and 20; immunogenicity groups); and 2287 in group 5 (1144 and 1143; correlates of protection). Follow-up was completed in October, 2012. The per-protocol population was 2794, excluding three participants from the intention-to-treat population (figure 1). The intention-to-treat analysis is not reported.Demographic and baseline clinical characteristics of the study participants were much the same between groups (table 1). In the per-protocol population, median follow-up for 1399 recipients of MVA85A was 24·6 months (range 0·2–37·3; IQR 19·2–27·8) and for 1395 controls was 24·6 months (0·3–37·3; 19·2–30·1). The number of participants discontinuing the study did not differ between the two treatment groups (figure 1). 126 infants (5%) were lost to follow-up, 11 died (<1%), and 62 (2%) had consent withdrawn.At least one local adverse event was reported in 628 (45%) of 1396 controls who received the allocated intervention and 1251 (89%) of 1399 recipients of MVA85A. At least one systemic adverse event was reported in 1059 (76%) controls and 1120 (80%) of recipients of MVA85A. At least one serious adverse event was reported in 258 (18%) controls and 257 (18%) recipients of MVA85A (appendix). No serious adverse events related to vaccine were reported in the MVA85A group, but one serious adverse event regarded as related to placebo occurred in the placebo group (short admission to hospital for fever 4 days after vaccination). 417 (64%) of 648 serious adverse events were acute lower-respiratory-tract infections or gastroenteritis (appendix). Seven (1%) infants died in the vaccine group (two from kwashiorkor, two from non-tuberculous meningitis, one from gastroenteritis, one from asphyxia due to drowning, and one from sudden death) and four (<1%) infants died in the placebo group (two from gastroenteritis, one from encephalitis, and one from a lower-respiratory-tract infection). During follow-up, 510 (37%) of 1395 recipients of placebo and 507 (36%) of 1399 recipients of MVA85A were admitted to the study ward for investigation.MVA85A induced an Ag85-specific T-cell response as measured by ex-vivo interferon γ enzyme-linked immunosorbent spot (median 136 spot-forming cells per million PBMCs, IQR 87–362; figure 2). Whole blood ICS showed that these cells were CD4-positive T cells predominantly expressing interferon γ, TNFα, and interleukin 2 (figure 2). We also detected CD4-positive interleukin 17-positive T cells (figure 2), some of which co-expressed Th1 cytokines (data not shown). These responses were not detected in recipients of placebo. No CD8-positive T-cell responses were detectable and no responses were detected with ICS completed on cryopreserved PBMCs (data not shown).Table 2 shows vaccine efficacy and numbers of infants who met endpoints 1, 2, or 3 by intervention group. For analysis with follow-up data truncated at 2 years after vaccination, vaccine efficacy was 23·9% (95% CI −27·9 to 54·7) for endpoint 1, −0·7% (–52·3 to 33·4) for endpoint 2, and −3·6% (–29·0 to 16·8) for endpoint 3. A post-hoc review of case distribution in the first year showed 16 recipients of placebo met endpoint 1 as did ten MVA85A recipients. Figure 3 shows the Kaplan-Meier survival analysis for endpoint 1.39 (3%) of 1395 infants assessed in the placebo group had incident tuberculosis (1·39 per 100 person-years [95% CI 1·00 to 1·91]) as did 32 (2%) of 1399 infants in the MVA85A group (1·15 per 100 person-years [0·79 to 1·62]). 171 (12% [95% CI 10·6 to 14·1]) infants assessed in the placebo group and 178 (13% [95% CI 11·0 to 14·6]) infants in the MVA85A group became infected with M tuberculosis as defined by QFT conversion during the course of the study. Vaccine efficacy against infection was −3·8% (95% CI −28·1 to 15·9). Efficacy was much the same when the comparison was restricted to QFT conversion at day 336 and end of study visit (data not shown).DiscussionWe report completion of a phase 2b safety and efficacy trial for infants with a new tuberculosis vaccine strategy (panel 2). In this trial, MVA85A was well tolerated and immunogenic in healthy infants who had previously been vaccinated with BCG, with a safety and immunogenicity profile consistent with that reported in other studies of infants.16, 17 However, we noted no significant efficacy against tuberculosis or M tuberculosis infection.This absence of efficacy was not consistent with findings from studies in animals, which suggested potential for efficacy,12, 13, 14, 15 and evidence of immunogenicity in previous clinical trials16, 17, 23 that measured immune responses regarded as important for protection.18, 19 Our results suggest that the CD4-positive T cells induced by MVA85A—at least at the modest frequencies noted in this trial—do not correlate with protection against tuberculosis or M tuberculosis infection. Frequencies of antigen-specific Th1 cells observed in infants with MVA85A were up to a tenth of the frequencies noted in adults.16, 25Our efficacy trial was undertaken in infants. However, this group is not responsible for most transmission of M tuberculosis. Thus, MVA85A could potentially protect adolescents or adults against pulmonary tuberculosis, in view of the fact that immunologically immature infants do not respond as well to this vaccine as adults do. MVA85A could also potentially have high efficacy in people of all ages against severe forms of tuberculosis, including pulmonary tuberculosis, without preventing infection or mild forms of disease. A high efficacy against severe disease could be masked in a trial that predominantly detects mild forms of tuberculosis. The sample size of a trial powered to detect only severe or disseminated disease would be prohibitively large. The safety and immunogenicity of MVA85A alone in infants exposed to HIV is currently being assessed.26 BCG-specific Th1 and Th17 responses were recently shown not to correlate with risk of tuberculosis in infants after BCG vaccination.27 Whether a substantially greater magnitude of response, a response that is qualitatively different, or a completely new immunological response would be necessary for protection is unclear. In our study, frequencies of BCG-primed Ag85A-specific T cells detected before MVA85A vaccination were very low or undetectable (figure 2). Conversely, adults and adolescents have significantly higher Ag85A-specific responses before vaccination,16 which might be an important factor in the stronger responses induced by MVA85A in older individuals. MVA85A was designed to boost BCG-primed responses, and the low frequencies of BCG-induced cells in infants might restrict the immunogenicity, and potentially the efficacy, of MVA85A in this age group. Ongoing assessment of study samples for potential correlates of risk might also yield important insights into why MVA85A did not confer protection in this trial and could add to the design and assessment of the next generation of tuberculosis vaccine candidates. Identification of immune correlates of protection would greatly aid vaccine design and assessment. However such correlates can only be identified in trials in which efficacy was shown. Identification and optimisation of animal models that accurately predict efficacy in human beings is also needed. Other efficacy trials of new HIV and malaria vaccines have reported early but waning efficacy.28, 29 In this trial, a post-hoc analysis of distribution of case accrual in the first year suggested a possible early effect on disease that merits further study of route of administration, regimen, and dosing strategies with MVA85A and other vaccines.Despite concerns about potential immunopathology induced by new tuberculosis vaccines,30 we noted no evidence for this effect. The high incidence of respiratory and gastrointestinal serious adverse events recorded in this trial reflects the known burden of childhood morbidity in this community.24 High numbers of unrelated serious adverse events should be expected in clinical trials in infant populations in developing countries. The high frequency of mild, self-limiting local reactions in MVA85A recipients is consistent with previous studies.16, 17 These local reactions were only partially controlled for by Candin, a placebo selected for its local reactogenicity profile. The overall safety profile supports modified Vaccinia Ankara virus as a suitable vector for infant vaccination strategies.The high incidence of disease noted in our study was comparable to the high rates noted in previous trials.21, 23 We noted no confirmed cases of disseminated tuberculosis (two cases of tuberculous meningitis met the definition for endpoint 2) and no deaths from tuberculosis, supporting our previous observation that disseminated and severe tuberculosis are uncommon in a setting of modern trials with active surveillance, effective isoniazid prophylaxis, and effective anti-tuberculous treatment.21 The high overall rate of M tuberculosis infection noted in this trial (349 [13%] of 2792) suggests a high level of exposure and transmission in this community. This infection burden suggests that M tuberculosis infection might be a suitable endpoint for future trials of new tuberculosis vaccines that aim to prevent infection and subsequent disease. Because BCG is regarded as less effective for prevention of infection than prevention of disease, our finding that MVA85A did not prevent infection is unsurprising and should be interpreted separately from the findings about efficacy against disease. We recognise that QFT has not been validated as a diagnostic test for M tuberculosis infection in infants and young children; however, a previous study31 done by our group showed good correlation between QFT and the tuberculin skin test.Our study showed that a large efficacy trial of a new tuberculosis vaccine in a high-burden setting is feasible with a stringent and objective case definition that incorporated the primary elements proposed in a recent consensus statement.32 We have also shown that standardised investigation for tuberculosis with multiple respiratory sampling, microbiological confirmation of disease, and masked expert panel review of digital radiograph images is feasible in a developing country setting where tuberculosis vaccine efficacy trials are likely to be done. We recognise that there is no gold standard definition of childhood tuberculosis,33 but we believe that the hierarchal endpoint definition used in this trial is robust and might be suitable for future tuberculosis vaccine trials.Cohort retention was very high in this trial, and no evidence was noted that the rate of loss to follow-up had a differential effect on case accrual. Similarly, exclusion of three enrolled infants in the per-protocol analysis did not affect the results.In conclusion, MVA85A was well tolerated, modestly immunogenic but unable to confer significant protection against tuberculosis or M tuberculosis infection. The information gained from the successful execution of this study will aid the planning of future trials and vaccination strategies. Substantial global efforts to develop an improved vaccine against tuberculosis must continue.References1WHOGlobal tuberculosis report 2012http://apps.who.int/iris/bitstream/10665/75938/1/9789241564502_eng.pdf(accessed Jan 2, 2013).2Stop TB PartnershipThe global plan to stop TB 2011–2015http://www.stoptb.org/global/plan/(accessed Jan 2, 2013).3TrunzBFinePDyeCEffect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectivenessLancet367200611731180166165604RodriguesLDiwanVWheelerJProtective effect of BCG against tuberculous meningitis and miliary tuberculosis: a meta-analysisInt J Epidemiol2219931154115881442995FinePVariation in protection by BCG: implications of and for heterologous immunityLancet34619951339134574757766ColditzGABerkeyCSMostellerFThe efficacy of bacillus Calmette-Guerin vaccination of newborns and infants in the prevention of tuberculosis: meta-analyses of the published literaturePediatrics961995293575967187Basu RoyRSotgiuGAltet-GomezNIdentifying predictors of interferon-gamma release assay results in pediatric latent tuberculosis: a protective role of bacillus Calmette-Guerin?: a pTB-NET collaborative studyAm J Respir Crit Care Med1862012378384227008628MahomedHKibelMHawkridgeTThe impact of a change in bacille Calmette-Guerin vaccine policy on tuberculosis incidence in children in Cape Town, South AfricaPediatr Infect Dis J25200611671172171331649MoyoSVerverSMahomedHAge-related tuberculosis incidence and severity in children under 5 years of age in Cape Town, South AfricaInt J Tuberc Lung Dis1420101491542007440410BrennanMJTholeJTuberculosis vaccines: a strategic blueprint for the next decadeTuberculosis (Edinb)92suppl 12012S6132244116011McShaneHPathanASanderCRecombinant modified vaccinia virus Ankara expressing antigen 85A boosts BCG-primed and naturally acquired antimycobacterial immunity in humansNat Med102004124012441550283912VordermeierHVillarreal-RamosBCocklePViral booster vaccines improve Mycobacterium bovis BCG-induced protection against bovine tuberculosisInfect Immun772009336433731948747613VerreckFVervenneRKondovaIMVA85A boosting of BCG and an attenuated, phoP deficient M tuberculosis vaccine both show protective efficacy against tuberculosis in rhesus macaquesPloS One42009e52641936733914GoonetillekeNMcShaneHHannanCAndersonRBrookesRHillAEnhanced immunogenicity and protective efficacy against Mycobacterium tuberculosis of bacille Calmette-Guerin vaccine using mucosal administration and boosting with a recombinant modified vaccinia virus AnkaraJ Immunol1712003160216091287425515WilliamsAGoonetillekeNPMcShaneHBoosting with poxviruses enhances Mycobacterium bovis BCG efficacy against tuberculosis in guinea pigsInfect Immun732005381438161590842016ScribaTJTamerisMMansoorNDose-finding study of the novel tuberculosis vaccine, MVA85A, in healthy BCG-vaccinated infantsJ Infect Dis2032011183218432160654217OtaMOdutolaAOwiafePImmunogenicity of the tuberculosis vaccine MVA85A is reduced by coadministration with EPI vaccines in a randomized controlled trial in Gambian infantsSci Transl Med3201188ra5618KaufmannSHFact and fiction in tuberculosis vaccine research: 10 years laterLancet Infect Dis1120116336402179846319HanekomWDockrellHOttenhoffTImmunological outcomes of new tuberculosis vaccine trials: WHO panel recommendationsPLoS Med52008e1451859755120BailyGVTuberculosis prevention trial, MadrasIndian J Med Res72suppl1980174700508621HawkridgeAHatherillMLittleFEfficacy of percutaneous versus intradermal BCG in the prevention of tuberculosis in South African infants: randomised trialBMJ33720081275128222Tameris M, McShane H, McClain J, et al. Lessons learnt from the first efficacy trial of a new infant tuberculosis vaccine since BCG. Tuberculosis (Edin) (in press).23ScribaTJTamerisMMansoorNModified vaccinia Ankara-expressing Ag85A, a novel tuberculosis vaccine, is safe in adolescents and children, and induces polyfunctional CD4+ T cellsEur J Immunol4020102792902001718823MoyoSVerverSHawkridgeATuberculosis case finding for vaccine trials in young children in high-incidence settings: a randomised trialInt J Tuberc Lung Dis1620121851912223691825MeyerJHarrisSSattiIComparing the safety and immunogenicity of a candidate TB vaccine MVA85A administered by intramuscular and intradermal deliveryVaccine312013102610332326634226HatherillMSafety and immunogenicity of MVA85A prime and bacille Calmette-Guérin boost vaccination (MVA(TB)029)http://www.clinicaltrials.gov/ct2/show/NCT1650389(accessed Jan 29, 2013).27KaginaBAbelBScribaTSpecific T cell frequency and cytokine expression profile do not correlate with protection against tuberculosis after bacillus Calmette-Guerin vaccination of newbornsAm J Resp Crit Care Med1822010107310792055862728Rerks-NgarmSPitisuttithumPNitayaphanSVaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in ThailandN Engl J Med3612009220922201984355729RtsSCTPAgnandjiSLellBA phase 3 trial of RTS,S/AS01 malaria vaccine in African infantsN Engl J Med3672012228422952313690930TaylorJTurnerOBasarabaRBelisleJHuygenKOrmeIPulmonary necrosis resulting from DNA vaccination against tuberculosisInfect Immun712003219221981265484131MoyoSIsaacsFGelderbloemSTuberculin skin test and QuantiFERON® assay in young children investigated for tuberculosis in South AfricaInt J Tuberc Lung Dis152011117611812194384132GrahamSAhmedTAmanullahFEvaluation of tuberculosis diagnostics in children: 1. Proposed clinical case definitions for classification of intrathoracic tuberculosis disease. Consensus from an expert panelJ Infect Dis205Suppl 22012S199S2082244802333HatherillMVerverSMahomedHConsensus statement on diagnostic end points for infant tuberculosis vaccine trialsClin Infect Dis54201249350122144538Supplementary MaterialSupplementary appendixAcknowledgmentsWe thank study participants and their families, the community of Cape Winelands East district, and South African Tuberculosis Vaccine Initiative (SATVI) personnel (Tony Hawkridge and Zainab Waggie [medical monitors]; Savvas Andronikou, Tracy Kilborn, and Nicky Wieselthaler [radiograph reviewers]; Andre Burger, Lizette Phillips, Danie Theron, Luise Lunnon [Cape Winelands Department of Health], staff of Cape Winelands East public health clinics and hospitals, Andrew Whitelaw and staff of National Health Laboratory Service, Groote Schuur Hospital, Cape Town; Jasur Ishmukhamedov, Sharon Sutton, Amy Lwin, Michael Raine, Christine Fattore, Wasima Rida, and E Martin Stals [Aeras]; and Andreas Diacon [Chair], James Balsley, Prakash Jeena, Neil Cameron, Alison Elliot, and Gil Price [safety monitoring committee]).ContributorsAll authors, on behalf of the MVA85A 020 Trial Study Team, contributed to study design, data analysis and interpretation, and writing and approval of the manuscript. MDT, MH, TJS, and HM contributed to the implementation of the study and supervision at the study site. MDT, GDH, and HM were the principal investigators. MAS designed and led the statistical analysis.The MVA85A 020 Trial Study TeamLinda Van Der Merwe, E Jane Hughes, Hennie Geldenhuys, Angelique K K Luabeya, Susan Rossouw, Erica Smit, Yolande Browne, Frances Ratangee, Cynthia Ontong, Marwou De Kock, Humphrey Mulenga, Ashley Veldsman, Stephanie Abrahim, Lilly Denation, Veronica Baartman, Amaryl Van Schalkwyk, Mariana Jacks, Colleen Krohn, Fazlin Kafaar, Marcia Steyn, Lebohang Makhete, Fatima Isaacs, Julia Noble, and Welile Sikhondze from the South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and School of Child and Adolescent Health, University of Cape Town, Cape Town, South Africa. Thomas Evans and Jerald Sadoff from Aeras, Rockville, MD, USA. Adrian V S Hill, Alison M Lawrie, Nathaniel J Brittain, and Samantha Vermaak from the Jenner Institute, Nuffield Department of Clinical Medicine, University of Oxford, UK.Conflicts of interestSL and JES are employees of Emergent BioSolutions and own shares and stock options in the company. HMcS is a shareholder in the Oxford-Emergent Tuberculosis Consortium (a joint venture between Emergent BioSolutions and the University of Oxford). All other authors declare that they have no conflicts of interest.Figure 1Trial profile*One infant developed gastroenteritis that precluded inclusion and one infant became ineligible after a randomisation error. QFT=QuantiFERON-TB Gold In-tube.Figure 2Vaccine immunogenicity(A) Frequencies of Ag85A-specific T cells measured by interferon-γ enzyme-linked immunosorbent spot assay in infants in study group 2 (27 infants in the MVA85A group and 27 infants in the placebo group) before administration of placebo or MVA85A (day 0) and 7 days after vaccination. (B) Frequencies of cytokine-expressing Ag85A-specific Th1 (CD4-positive T cells expressing IFN-γ, TNFα, or interleukin 2) and (C) frequencies of Ag85A-specific Th17 (CD4-positive T cells expressing interleukin 17) cells, measured by whole blood intracellular cytokine staining 28 days after administration of placebo or MVA85A to infants in study group four (17 infants in the MVA85A group and 19 infants in the placebo group). SFC=spot-forming cells. PBMC=peripheral blood mononuclear cell.Figure 3Cumulative incidence of diagnosis of tuberculosis endpoint 1Table 1Demographics and baseline characteristics of the per-protocol populationPlacebo (n=1395)MVA85A (n=1399)Overall (n=2794)Age, days145·7 (13·5)146·6 (14·3)146·2 (13·9)Sex, male714 (51%)708 (51%)1422 (51%)Ethnic groupBlack267 (19%)287 (21%)554 (20%)Mixed race1126 (81%)1107 (79%)2233 (80%)Asian1 (<1%)3 (<1%)4 (<1%)White1 (<1%)2 (<1%)3 (<1%)WeightInfants assessed1389 (>99%)1394 (>99%)2783 (>99%)Mean, kg6·47 (0·98)6·45 (0·99)6·46 (0·98)Full-term birth (≥38 weeks)983 (70%)1031 (74%)2014 (72%)Data are mean (SD) or n (%).Table 2Primary and secondary efficacy endpointsPlacebo (n=1395)MVA85A (n=1399)Vaccine efficacyEndpoint 1 (primary efficacy endpoint)39 (3%)32 (2%)17·3% (–31·9 to 48·2)Endpoint 2 (exploratory efficacy endpoint)52 (4%)55 (4%)–6·9% (–56·1 to 26·9)Endpoint 3 (exploratory efficacy endpoint)177 (13%)196 (14%)–12·1% (–37·4 to 8·5)Data are n (%) or % (95% CI). Participants with more than one diagnosis were analysed in each level of diagnosis attained. Vaccine efficacy and corresponding 95% CI was estimated with the Cox regression model (1 – estimated hazard ratio).Panel 1Definition of endpoint 1Any of the following criteria:•Isolation of Mycobacterium tuberculosis from any site•Identification of M tuberculosis by an approved molecular diagnostic technique from any site•Histopathology diagnostic for tuberculosis disease (eg, caseating granulomas)•Choroidal tubercle diagnosed by an ophthalmologist•Miliary pattern on chest radiograph in an HIV-negative infant•Clinical diagnosis of tuberculous meningitis (cerebrospinal fluid protein concentrations >0·6 g/L and pleocytosis of >50 cells per μL with >50% mononuclear cells) with features of basal meningeal enhancement and hydrocephalus on head CT•Vertebral spondylosis•One smear or histology specimen positive for auramine-positive bacilli from a normally sterile body site•One of each of the following:•Evidence of mycobacterial infection defined as two acid-fast positive smears (each from a separate collection) that were morphologically consistent with mycobacteria from either sputum or gastric aspirate that were not found to be non-tuberculous mycobacteria bacteria on culture; QuantiFERON-TB Gold In-tube test conversion from negative to positive; or tuberculin skin test ≥15 mmand•Radiographic findings compatible with tuberculosis defined as ≥1 of the following factors identified independently by at least two of three paediatric radiologists serving on a masked review panel: calcified Ghon focus, pulmonary cavity, hilar or mediastinal adenopathy, pleural effusion, or airspace opacificationand•Clinical manifestations compatible with tuberculosis defined as cough without improvement for >2 weeks; weight loss of >10% of bodyweight for >2 months; or failure to thrive, defined as crossing >1 complete major centile band (<97th–90th, <90th–75th, <75th–50th, <50th–25th, <25th–10th, and <10th–3rd weight-for-age centiles) downward for >2 monthsPanel 2Research in contextSystematic reviewTo our knowledge, our trial is the first efficacy study of a novel BCG booster tuberculosis vaccine in infants. A systematic review is not applicable.InterpretationThe safety of MVA85A reported in our large cohort is an important finding for tuberculosis vaccine development. However the absence of efficacy noted, despite studies in animals suggesting potential for efficacy and evidence of immunogenicity in previous clinical trials, was unexpected and suggests that the present parameters for selection of tuberculosis vaccine candidates might be inadequate. The relatively weak immunogenicity we noted in this study makes it difficult to conclude whether a higher magnitude response (ie, one that is qualitatively different or a completely new immunological mechanism) will be required for a protective vaccine. Lessons learnt from this trial, including trial design, execution, and vaccine selection, will be of enormous importance to the broader specialty of vaccine development.", 'title': 'In vivo detection of non-cavitated caries lesions on occlusal surfaces by visual inspection and quantitative light-induced fluorescence.', 'date': '2007-05-22'}, '29028973': {'article_id': '29028973', 'content': 'Clin Infect DisClin. Infect. DiscidClinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America1058-48381537-6591Oxford University PressUS29028973584909010.1093/cid/cix834cix834Articles and CommentariesSafety and Immunogenicity of Newborn MVA85A Vaccination and Selective, Delayed Bacille Calmette-Guerin for Infants of Human Immunodeficiency Virus-Infected Mothers: A Phase 2 Randomized, Controlled TrialNemesElisa1HesselingAnneke C2TamerisMichele1MauffKatya1DowningKatrina1MulengaHumphrey1RosePenelope2van der ZalmMarieke2MbabaSharon2Van AsDanelle1HanekomWillem A1WalzlGerhard3ScribaThomas J1McShaneHelen4HatherillMark1MVA029 Study Team\nAbrahamsCharmaineAbrahamsDeborahAfricaHadnBaartmanVeronicaBavumaBeautyBilekNicoleBotesNatasjaBrownYolandeCloeteYolundiDamonsMargarethDe VosRonelDlakavuPortiaDu PreezKarenErasmusMzwandileFrancisClaudiaGeldenhuysHendrikGeldenhuysMandyGoedemanKatrienaGolliathSandraMoutonAngelique HendricksHopleyChristiaanJansenRuwijdaJonesCarolynneKeyserAlanaKaginaBenjaminKhombaGloriaKola–CassiemFazlinKrugerSandraLeukesDaphneLouwLoyisoLuabeyaAngeliqueMaartTheresaMakhetheLebohangMbabweSimbarasheMtshambaEuniceMvinjelwaBoniswaNkantsuLungisaNobleJuliaNqwenisoSizweOppermanFajwaPetersenChristelPlaatjiePatiswaRossouwSusanSolomomsRoxanneSteynMarciaSwanepoelLiticiaToefyAsmavan DeventerHeidivan RooyenElmavan SterDaphneVazanaBongiweVeldsmanAshleyXoyanaNoncedo1South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease & Molecular Medicine and Division of Immunology, Department of Science & Technology/National Research Foundation, University of Cape Town2Desmond Tutu Tuberculosis Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences3DST/NRF Centre of Excellence for Biomedical Tuberculosis Research/Medical Research Council Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa4Jenner Institute, Oxford University, United KingdomE. N. and A. C. H. contributed equally to this manuscript.The members of the MVA029 Study Team are listed in the Appendix.Correspondence: M. Hatherill, South African Tuberculosis Vaccine Initiative, Room S2.01, Wernher and Beit Building, University of Cape Town Faculty of Health Sciences, Anzio Road, Observatory 7925, Cape Town, South Africa. (mark.hatherill@uct.ac.za).15220182610201726102017664554563056201723102017© The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America.2017This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.Newborn MVA85A prime vaccination was safe and induced an early immune response that did not interfere with immunogenicity of subsequent bacille Calmette-Guérin vaccination. New tuberculosis vaccine candidates should be tested using this strategy, which appears safe regardless of infant human immunodeficiency virus exposure.AbstractBackgroundVaccination of human immunodeficiency virus (HIV)-infected infants with bacille Calmette-Guérin (BCG) is contraindicated. HIV-exposed newborns need a new tuberculosis vaccination strategy that protects against tuberculosis early in life and avoids the potential risk of BCG disease until after HIV infection has been excluded.MethodsThis double-blind, randomized, controlled trial compared newborn MVA85A prime vaccination (1 × 108 PFU) vs Candin® control, followed by selective, deferred BCG vaccination at age 8 weeks for HIV-uninfected infants and 12 months follow-up for safety and immunogenicity.ResultsA total of 248 HIV-exposed infants were enrolled. More frequent mild–moderate reactogenicity events were seen after newborn MVA85A vaccination. However, no significant difference was observed in the rate of severe or serious adverse events, HIV acquisition (n = 1 per arm), or incident tuberculosis disease (n = 5 MVA85A; n = 3 control) compared to the control arm. MVA85A vaccination induced modest but significantly higher Ag85A-specific interferon gamma (IFNγ)+ CD4+ T cells compared to control at weeks 4 and 8 (P < .0001). BCG did not further boost this response in MVA85A vaccinees. The BCG-induced Ag85A-specific IFNγ+ CD4+ T-cell response at weeks 16 and 52 was of similar magnitude in the control arm compared to the MVA85A arm at all time points. Proliferative capacity, functional profiles, and memory phenotype of BCG-specific CD4 responses were similar across study arms.ConclusionsMVA85A prime vaccination of HIV-exposed newborns was safe and induced an early modest antigen-specific immune response that did not interfere with, or enhance, immunogenicity of subsequent BCG vaccination. New protein-subunit and viral-vectored tuberculosis vaccine candidates should be tested in HIV-exposed newborns.Clinical Trials RegistrationNCT01650389.HIV-exposed infantsMVA85ABCGvaccinationtuberculosisBacille Calmette-Guérin (BCG) vaccination of infants remains a key tool to protect young children against tuberculosis [1]. Given young children’s high risk of progression from Mycobacterium tuberculosis infection to disease and disseminated forms of tuberculosis, which is associated with severe morbidity and mortality, tuberculosis prevention strategies are of great importance in this population [2, 3]. Infant BCG vaccination offers partial protection against pulmonary, miliary, and meningitic tuberculosis in children [4, 5].In settings with high tuberculosis burden, all children born to human immunodeficiency virus (HIV)-infected mothers are at increased risk of tuberculosis, including those who remain HIV uninfected [6–8]. A safe and effective tuberculosis vaccine for infants with perinatal HIV exposure is needed urgently, since BCG vaccination of infants known to be HIV infected is contraindicated due to the risk of local, regional, and disseminated BCG disease as well as BCG immune reconstitution inflammatory syndrome following antiretroviral therapy (ART) initiation [9–13]. However, delay in BCG vaccination to allow exclusion of perinatal HIV acquisition would put infants at risk of acquiring tuberculosis in the first weeks of life, in the period before BCG could be administered without safety concerns. These competing risks and benefits have resulted in a pragmatic approach to continued BCG vaccination of HIV-exposed newborns whose HIV infection status is not yet known in settings where rates of childhood tuberculosis and maternal HIV infection are high [13, 14]. For example, approximately one fifth of South African women of reproductive age were HIV infected in 2017 [15]. Despite recent reductions in perinatal HIV transmission [16], the HIV infection rate at age 18 months is considerably higher than at 8 weeks due to high-risk mixed feeding practices [17]. There were an estimated 320 000 South African children living with HIV in 2016 [18]; 50% of deaths among children aged <5 years were associated with HIV infection [19]. Although early HIV polymerase chain reaction (PCR) testing is being introduced, this advance does not solve the BCG safety dilemma because routine BCG is usually given at birth. Also, since HIV-exposed infants in sub-Saharan Africa are often exclusively breast fed, HIV infection may be acquired subsequent to negative PCR testing at age 2 weeks.Given the high risk of both tuberculosis and BCG-associated adverse events (AEs) in HIV-infected infants, we hypothesized that delaying routine newborn BCG vaccination until HIV infection had been excluded, but preceded by a novel tuberculosis vaccine given at birth, would be safe and more immunogenic than delayed BCG vaccination alone for HIV-exposed infants [20]. We previously showed that delayed BCG vaccination of HIV-unexposed South African infants induces a long-lasting polyfunctional T-cell response, with higher frequencies and better quality of BCG-specific CD4 T cells at age 1 year compared to newborn BCG vaccination [21]. Conflicting studies have shown no significant immunological benefit of delayed BCG [22–24]. However, in utero exposure to maternal HIV and M. tuberculosis infection does not appear to alter long-term immune responses of HIV-uninfected infants to BCG vaccination when given at age 6 weeks [25, 26].New tuberculosis vaccine candidates in clinical development include recombinant and live-attenuated mycobacterial vaccines and viral-vectored or protein-subunit vaccines [27]. A nonreplicating vaccine with a track record of safety in infants and HIV-infected persons would be required to test this novel strategy. Although MVA85A did not confer additional protection when given as a boost vaccine after BCG prime in HIV-uninfected infants [28], MVA85A is an ideal candidate vaccine to test this experimental strategy since MVA85A was safe in this high-risk population [29–33].Here, we report on the safety and immunogenicity of MVA85A vaccination in newborns of HIV-infected mothers, followed by selective deferred BCG vaccination at 8 weeks for HIV-uninfected infants, in a double-blind, randomized, controlled trial.METHODSThe trial was conducted at 2 sites near Cape Town, South Africa. Mothers provided written antenatal and postnatal consent for infant participation. The protocol was approved by the ethics committees of the universities of Cape Town (013/2012), Stellenbosch (M12/03/020), and Oxford (02-12). Eligible infants (see Supplementary Materials) were randomized 1:1 to receive either MVA85A vaccine (1 × 108 PFU) or Candin® control within 96 hours of birth in blinded fashion (Figure 1A). BCG was administered (1–4 × 105 cfu) at age 8 weeks only to infants documented to be HIV-uninfected at age 6 weeks by negative HIV DNA PCR (Roche Diagnostic COBAS AmpliPrep COBAS Taqman HIV-1 Qual test version 2.0)[Figure 1A]. HIV DNA PCR testing prior to age 6 weeks was not routine at the time. All infants were followed for safety endpoints at weeks 1, 4, 6, and 8 after MVA85A/control vaccination and thereafter at weeks 9, 12, and 16 (corresponding to weeks 1, 4, and 8 following delayed BCG vaccination at 8 age weeks) and at week 52. All infants underwent safety monitoring for solicited and unsolicited local, regional, and systemic AEs. For immunogenicity analyses, blood was collected at weeks 4, 8, 16, and 52 (Figure 1A).Figure 1.Study design (A) and CONSORT diagram (B). Abbreviations: BCG, bacille Calmette-Guérin; CONSORT, Consolidated Standards of Reporting Trials; HIV, human immunodeficiency virus; PCR, polymerase chain reaction; TB, tuberculosis.QuantiFERON-TB Gold (QFT, Qiagen) was performed on mothers at enrollment of newborns and on infants at age 1 year. Infants who reported a new household tuberculosis contact or developed symptoms or signs of tuberculosis were investigated for tuberculosis as previously described [28]. HIV-uninfected infants with a household tuberculosis contact or positive QFT or tuberculin skin test were referred for isoniazid preventive therapy after exclusion of active tuberculosis. All infants diagnosed with tuberculosis started tuberculosis treatment for disease as per national guidelines.Whole Blood Functional AssaysVenous blood was collected in sodium heparin–containing tubes for short- (12 hours) and long-term (7 days) functional assays to measure antigen-specific T-cell responses and proliferative capacity, respectively. Whole blood was left unstimulated (negative control) or stimulated with Ag85A peptide pool, BCG, and phytohemagglutinin (positive control). Assays were conducted as previously described [34, 35] (see Supplementary Materials). Samples were stained with optimized panels of monoclonal antibodies (Supplementary Materials, Table S1) and analyzed using flow cytometry (Supplementary Materials, Figures S1 and S2).Statistical AnalysesIn the intention-to-treat (ITT) population for safety analysis, the number of AEs was compared between study arms for the periods prior to and following BCG vaccination and for the entire observation period. In each period, counts and percentages of AEs were determined per arm, per category of interest. Tests of proportions per category were used to compare the number of AEs between arms for each type of AE and categories. The Bonferroni correction was applied to account for multiple testing.Linear mixed-effect models were used to assess the impact of study arm and time and their interaction on the (logged) frequencies of cytokine-producing or cytokine-proliferating T cells. In cases where the distributional assumptions of the model were not met, nonparametric tests were used to assess differences between arms at each time point and changes over time between arms (Wilcoxon rank sum test) and changes over time within arms (Wilcoxon signed rank test).The ITT population for safety analysis included all infants who received either MVA85A or control. The modified ITT (mITT) population for immunology analysis included all infants who received either MVA85A or control and BCG vaccine and who were not HIV infected, including data from all available sampling time points.RESULTSParticipantsAfter screening 261 infants, 248 were randomized and included in the ITT safety analysis; 213 infants were analyzed per protocol (Figure 1B). MVA85A and BCG immunogenicity was assessed in 65 infants in the mITT population who received MVA85A (n = 32) or control (n = 33) at birth and BCG at age 8 weeks (n = 65). The median age of infants’ mothers was 28 years; 80% of mothers were receiving long-term ART with median CD4 cell count 424 cells/mm3; and 43% of mothers tested QFT positive. Median gestational age of infants was 40 weeks; 48% were male; median birth weight was 3.2 kg; and 61% were breastfed as the initial feeding choice. Baseline demographics by study arm are shown in Table 1.Table 1.Baseline DemographicsCharacteristicMVA85A (n = 123)Candin® Control (n = 125)Median birth weight, g (IQR)3220 (2970–3420)3170 (2880–3410)Median gestational age, weeks (IQR)39 (39–40)40 (39–40)Gender female, n (%)63 (51)64 (51)Breastfed, n (%)70 (57)75 (60)Median maternal age, years (IQR)29 (26–32)28 (25–33)Mother receiving antiretroviral therapy, n (%)98 (80)101 (81)Median maternal CD4 count, cells/mm3 (IQR)442 (306–607)400 (262–554.5)Maternal QuantiFERON-tuberculosis Gold + n (%)51 (42)55 (44)Abbreviation: IQR, interquartile range.SafetyAll AEs are shown in Table 2. At least 1 AE was experienced by 243 infants including 239 infants with injection site AEs. The majority of infants experienced mild or moderate AEs. Twenty-five infants experienced at least 1 severe AE, with no difference in rate between the MVA85A (n = 11) and control (n = 14) arms. No life-threatening AEs were observed. Fifty-eight infants had at least 1 serious AE (SAE; n = 26 MVA85A; n = 32 control), including 4 deaths (n = 3 MVA85A; n = 1 control), none of which were classified as related to the investigational product. SAE diagnoses reflected the pattern of respiratory and gastroenteritic illnesses typically observed in the study communities.Table 2.All Adverse Events in the Intention-to-Treat Population Throughout Follow-up VariableTotal, n (%)MVA85A, n (%)Candin® Control, n (%)\nP ValueParticipants with ≥1 adverse event243 (98)122 (99.2)121 (96.8)Category\u2003Injection site239 (96.4)121 (98.4)118 (94.4).094\u2003Lymphadenopathy13 (5.2)4 (3.3)9 (7.2).163\u2003Systemic210 (84.7)106 (86.2)104 (83.2).515\u2003Laboratory27 (10.9)14 (11.4)13 (10.4).804Body system\u2003Cardiovascular3 (1.2)1 (0.8)2 (1.6)\u2003Digestive74 (29.8)35 (28.5)39 (31.2)\u2003Endocrine15 (6)6 (4.9)9 (7.2)\u2003Hematologic/lymphatic21 (8.5)10 (8.1)11 (8.8)\u2003Metabolic/nutritional80 (32.3)42 (34.1)38 (30.4)\u2003Musculoskeletal1 (0.4)1 (0.8)0 (0)\u2003Neurological69 (27.8)34 (27.6)35 (28)\u2003Respiratory87 (35.1)42 (34.1)45 (36)\u2003Skin241 (97.2)121 (98.4)120 (96).259\u2003Urogenital5 (2)2 (1.6)3 (2.4)Severity\u2003Mild243 (98)122 (99.2)121 (96.8).181\u2003Moderate116 (46.8)62 (50.4)54 (43.2).255\u2003Severe25 (10.1)11 (8.9)14 (11.2).555\u2003Life-threatening0 (0) 0 (0) 0 (0)Vaccine relationship (MVA85A/control)\u2003Not related236 (95.2)116 (94.3)120 (96)\u2003Unlikely98 (39.5)50 (40.7)48 (38.4)\u2003Possible66 (26.6)41 (33.3)25 (20)\u2003Probable9 (3.6)7 (5.7)2 (1.6)\u2003Definite138 (55.6)105 (85.4)33 (26.4)Vaccine relationship (bacille Calmette-Guérin)\u2003Not related229 (92.3)122 (99.2)107 (85.6)\u2003Unlikely55 (22.2)28 (22.8)27 (21.6)\u2003Possible31 (12.5)14 (11.4)17 (13.6)\u2003Probable4 (1.6)2 (1.6)2 (1.6)\u2003Definite228 (91.9)110 (89.4)118 (94.4)Outcome\u2003Death4 (1.6)3 (2.4)1 (0.8)\u2003Ongoing219 (88.3)106 (86.2)113 (90.4)\u2003Recovered with sequelae24 (9.7)14 (11.4)10 (8)\u2003Recovered without sequelae238 (96)121 (99.4)117 (93.6)\u2003Unknown2 (0.8)1 (0.8)1 (0.8)Seriousness\u2003Serious58 (23.4)26 (21.1)32 (25.6)\u2003Not serious243 (98)122 (99.2)121 (96.8)Numerator is participants with at least 1 adverse event; denominator is participants in study/arm.In the 8-week period after newborn MVA85A/control injection and before BCG vaccination, infants in the MVA85A arm were more likely to experience an AE (n = 120) than those in the control arm (n = 84; Table 3). Injection site reactions in this period were more frequent in MVA85A recipients than in controls (n = 119 MVA85A vs n = 32 control; P < .0001); there were more AEs among MVA85A recipients that were mild in severity (n = 116 MVA85A vs n = 75 control; P < .0001). There was no difference in the rate of AEs, including injection site AEs, after BCG vaccination between study arms (Supplementary Materials, Table S2).Table 3.Adverse Events in the Intention-to-Treat Population Occurring in the Period After MVA85A/Candin® Control Injection and Before bacille Calmette-Guérin Vaccination VariableTotal, n (%)MVA85A, n (%)Candin® Control, |n (%)\nP ValueParticipants with ≥1 adverse event204 (82.3)120 (97.6)84 (67.2)Category\u2003Injection site151 (60.9)119 (96.7)32 (25.6)<.0001\u2003Lymphadenopathy11 (4.4)4 (3.3)7 (5.6).369\u2003Systemic148 (59.7)76 (61.8)72 (57.6).501\u2003Laboratory10 (4)7 (5.7)3 (2.4).188Body system\u2003Cardiovascular1 (0.4)0 (0)1 (0.8)\u2003Digestive37 (14.9)16 (13)21 (16.8)\u2003Endocrine3 (1.2)2 (1.6)1 (0.8)\u2003Hematologic/lymphatic14 (5.6)7 (5.7)7 (5.6)\u2003Metabolic/nutritional33 (13.3)18 (14.6)15 (12)\u2003Musculoskeletal0 (0)0 (0)0 (0)\u2003Neurological57 (23)28 (22.8)29 (23.2)\u2003Respiratory28 (11.3)14 (11.4)14 (11.2)\u2003Skin174 (70.2)119 (96.7)55 (44)<.0001\u2003Urogenital2 (0.8)1 (0.8)1 (0.8)Severity\u2003Mild191 (77)116 (94.3)75 (60)<.0001\u2003Moderate67 (27)43 (35)24 (19.2).005\u2003Severe10 (4)4 (3.3)6 (4.8).536\u2003Life-threatening0 (0)0 (0)0 (0)Relationship (MVA85A/control)\u2003Not related75 (30.2)37 (30.1)38 (30.4)\u2003Unlikely73 (29.4)37 (30.1)36 (28.8)\u2003Possible64 (25.8)40 (32.5)24 (19.2)\u2003Probable9 (3.6)7 (5.7)2 (1.6)\u2003Definite135 (54.4)105 (85.4)30 (24)Outcome\u2003Recovered without sequelae199 (80.2)81 (65.9)118 (94.4)\u2003Recovered with sequelae12 (4.8)6 (4.9)6 (4.8)\u2003Ongoing11 (4.4)8 (6.5)3 (2.4)\u2003Death1 (0.4)1 (0.8)0 (0)\u2003Unknown0 (0)0 (0)0 (0)Seriousness\u2003Serious24 (9.7)10 (8.1)14 (11.2)\u2003Not serious201 (81)120 (97.6)81 (64.8)Numerator is participants with at least 1 adverse event; denominator is participants in study/arm.HIV and M. tuberculosis Acquisition, Diagnosis of Tuberculosis DiseaseOne infant (<1%; control arm) was diagnosed as HIV PCR positive at age 6 weeks and, per protocol, did not receive BCG vaccination at week 8. One (breastfed) infant (<1%; MVA85A arm) was HIV PCR negative at age 6 weeks and received BCG vaccine but subsequently tested HIV PCR positive at age 1 year.Five infants tested QFT positive at age 1 year (n = 1 MVA85A arm; n = 4 control arm). Eight infants were found to have tuberculosis within the 1-year follow-up period (n = 5 MVA85A; n = 3 control), of whom 1 was M. tuberculosis culture positive and 7 were diagnosed on clinical/radiographic grounds and tuberculosis contact history. Two of the tuberculosis cases were QFT positive.Ag85A and BCG-Specific T-Cell ResponsesTo evaluate the immunogenicity of MVA85A and BCG, we measured frequencies of cytokine-producing T cells (expressing combinations of interferon gamma [IFNγ], tumor necrosis factor alpha [TNFɑ], interleukin [IL] 2, IL17, and/or IL22) and their differentiation (based on coexpression of CD45RA and CCR7) after 12-hour stimulation of whole blood with Ag85A or BCG, respectively.MVA85A induced higher frequencies of Ag85A-specific IFNγ+ CD4+ T cells 4 and 8 weeks post-vaccination compared to control (Figure 2A). BCG-induced Ag85A-specific CD4+ T cells in placebo recipients were of similar magnitude to those induced by MVA85A. BCG vaccination did not boost Ag85A-specific CD4+ T cells induced by MVA85A (Figure 2B).Figure 2.Ag85A-specific CD4 cytokine responses. Fresh whole blood was stimulated with Ag85A peptides for 12 hours prior to intracellular cytokine staining and flow cytometry analysis. A, Cross-sectional comparison of frequencies of Ag85A-specific CD4+ T cells expressing interferon gamma (IFNγ) in participants who were vaccinated with MVA85A (red) or control (black) at birth. Bacille Calmette-Guérin was administered to all participants at age 8 weeks. B, Longitudinal changes of Ag85A-specific CD4+ T cells expressing IFNγ are indicated by arrows (red for MVA85A arm and black for control arm). Medians and 95% confidence intervals (for the medians) are shown. C, Frequencies of Ag85A-specific CD4+ T cells expressing different combinations of IFNγ, tumor necrosis factor alpha, and interleukin 2 were compared between MVA85A arm (solid boxes) and control arm (clear boxes) at weeks 4 (blue), 8 (purple), 16 (green), and 52 (orange). Box and whiskers denote median, interquartile range, and minimum/maximum. Unadjusted P values were calculated by mixed effects models in A and B and by Mann-Whitney test in C. Abbreviations: BCG, bacille Calmette-Guérin; IFNγ, interferon gamma; IL, interleukin; TNFα, tumor necrosis factor alpha.MVA85A induced mainly IFNγ-expressing CD4+ T cells, many of which coexpressed IL2 and TNFɑ (Figure 2C). There was no detectable IL17 or IL22 production by Ag85A-specific CD4+ T cells before BCG vaccination (data not shown).BCG vaccination induced markedly increased and durable CD4+ T-cell responses in the MVA85A prime and control groups (Figure 3A). The cytokine coexpression profiles of BCG-specific CD4+ T cells were different during the effector (week 16) and memory (week 52) phases of the response and were not affected by MVA85A prime (Figure 3B). At week 52 most BCG-specific CD4+ T cells were monofunctional (Figure 3B, blue slice), and the predominant subset of these cells expressed IL22 alone (Figure 3B, purple arc).Figure 3.Bacille Calmette-Guérin (BCG)-specific CD4 cytokine responses. Fresh whole blood was stimulated with BCG for 12 hours prior to intracellular cytokine staining and flow cytometry analysis. A, Longitudinal changes of BCG-specific CD4+ T cells expressing any combination of interferon gamma (IFNγ), tumor necrosis factor alpha (TNFα), interleukin (IL) 2, IL17, and/or IL22 are indicated by arrows (red for MVA85A arm and black for control arm). Medians and 95% confidence intervals (CIs; for the medians) are shown. Unadjusted P values were calculated by mixed effects models. B, Cytokine coexpression patterns of BCG-specific CD4 responses at week 16 (left) and week 52 (right) in the MVA85A (top) and control (bottom) arms by permutation test. Pies represent total BCG-specific CD4+ T cells expressing any cytokine; slices show the relative proportion of cells coexpressing 1 (blue), 2 (green), 3 (yellow), or 4 (orange) cytokines, identified by the external arcs: IFNγ (red), IL2 (black), IL17 (orange), IL22 (purple), and TNFα (dark green). C, Differentiation profiles were defined based on expression patterns of CD45RA and CCR7 as follows: naive-like (TNL, CD45RA+ CCR7+), central memory (TCM, CD45RA- CCR7+), effector (TE, CD45RA- CCR7-), and terminal effector (TTE, CD45RA+ CCR7-). Representative flow cytometry plot of BCG-specific cytokine+ CD4+ T cells (pink) overlaid on total CD4+ T cells (black). D, Longitudinal changes of BCG-specific cytokine+ CD4+ T cells expressing TNL (maroon), TCM (blue), TE (orange), or TTE (green) phenotype in MVA85A (left) or control (right) recipients. Medians and 95% CIs (for the medians) are shown. The number of participants meeting cutoff criteria for this analysis (see methods) is shown for each visit. Frequencies of all subsets significantly increased (P < .025) upon BCG vaccination (week 8 vs week 16) and decreased (P < .025) between week 16 and 52, with the exception of TCM in the MVA85A arm. Unadjusted P values were calculated by Wilcoxon matched-pairs test; week 4 and 8 were not compared due to low numbers of paired samples (less than 10). No significant differences were observed when comparing frequencies of each subset at each visit between study arms. Abbreviations: BCG, bacille Calmette-Guérin; IFNγ, interferon gamma; IL, interleukin; TNFα, tumor necrosis factor alpha.We also measured memory phenotype of cytokine-expressing, BCG-specific CD4+ T cells (Figure 3C). Frequencies of naive-like (TNL), central memory (TCM), effector (TE), and terminal effector (TTE) BCG-specific CD4+ T cells were not different between study arms at any visit, although BCG administration induced all subsets significantly (week 8 vs 16; P < .025 for all subsets in both study arms). Central memory T cells were maintained at similar levels between week 16 and week 52 only in the MVA85A arm, while all other subsets decreased (P < .025).Ag85A- and BCG-specific CD8+ T cells were detected at low levels, predominantly expressed IFNγ or TNFα, and were not different between the study groups (Supplementary Materials, Figure S3A, S3B and data not shown).T-Cell Proliferative Responses to Ag85A and BCGT-cell proliferation is a sensitive measurement of vaccine immunogenicity. BCG-specific proliferative responses are typically not persistently affected by HIV exposure [26] or delayed BCG administration [23]. Long-term recall and effector potential of MVA85A and BCG-induced T-cell responses were assessed by measuring proliferative capacity (expression of cell cycle–associated marker Ki67) of antigen-specific T cells and their cytotoxic potential (upregulation of cytotoxic mediators granzyme A, granzyme B, granzyme K, granulysin, and perforin) upon 7-day stimulation of whole blood with Ag85A or BCG, respectively.MVA85A and BCG induced similar low CD4 proliferative responses to Ag85, which was lost by age 1 year (Figure 4A). BCG administration did not further boost proliferative responses primed by MVA85A.Figure 4.CD4+ T cell proliferation in response to Ag85A and bacille Calmette-Guérin (BCG). Fresh whole blood was stimulated with Ag85A peptides or BCG for 7 days prior to intracellular staining of Ki67 and cytotoxic markers and flow cytometric analysis. Frequencies of Ag85A-specific (A) and BCG-specific (B) CD4+ T cells expressing the proliferation marker Ki67 were analyzed longitudinally in MVA85A (red lines and arrows) and control (black lines and arrows) arms. Medians and 95% confidence intervals (for the medians) are shown. Unadjusted P values were calculated by mixed effects models. C, Cytotoxic mediator coexpression patterns of BCG-specific CD4 responses were compared across study weeks in MVA85A arm (top) and control arm (bottom) by permutation test. No significant differences between study arms were observed at any visit. Pies represent total BCG-specific CD4+ T cells expressing Ki67, and slices represent the relative proportion of cells coexpressing cytotoxic markers identified by the external arcs: granzyme A (blue), granzyme B (red), granulysin (green), granzyme K (orange), and perforin (purple). Black slices denote the proportion of proliferating cells that do not express any cytotoxic marker. The number of participants meeting cutoff criteria for this analysis (see methods) is shown within each pie. Abbreviations: BCG, bacille Calmette-Guérin.BCG vaccination induced a strong CD4 proliferative response to BCG, which did not differ by study arm and was not sustained above prevaccination levels by age 1 year (Figure 4B).During the effector phase of BCG-induced responses (week 16), the majority of proliferating CD4+ T cells upregulated expression of cytotoxic mediators (Figure 4C), mostly granzyme A (blue arc), granzyme B (red arc), and granulysin (green arc). Proportions of proliferating CD4+ T cells expressing cytotoxic mediators had decreased by week 52 but still comprised approximately one third of BCG-specific CD4+ T cells (Figure 4C). No differences in the cytotoxic potential were observed between study arms at any time point (Figure 4C).DISCUSSIONNewborn administration of a viral-vectored prime vaccine (MVA85A), followed by BCG vaccine boost at age 8 weeks, had an acceptable safety and reactogenicity profile; induced modest, antigen-specific responses before BCG administration; and did not interfere with or enhance subsequent BCG immunogenicity. These findings demonstrate proof of principle that a novel tuberculosis vaccination strategy based on a newborn priming vaccine other than BCG, including candidates that are potentially more immunogenic than MVA85A, can be administered safely to HIV-exposed newborns. Such a strategy would avoid the risks associated with administration of live BCG vaccine to infants with undiagnosed perinatal HIV infection. We infer from these findings that a new efficacious subunit or viral-vectored tuberculosis vaccine might also be given safely to newborns to provide protection against tuberculosis disease in the early weeks of life.It is notable that the rate of HIV acquisition (<1%) was low compared to historical perinatal HIV transmission rates in South Africa (2.7% in 2012 [17]). This is due in part to systemic improvements in the perinatal HIV prevention (prevention of mother-to-child transmission [PMTCT]) and because maternal ART or perinatal prophylaxis was a requirement for infant enrollment. Therefore, this alternative tuberculosis vaccination strategy would be expected to have even greater impact on BCG vaccine safety in countries where PMTCT programs are weaker and perinatal HIV transmission rates are higher.It is also striking that the rate of QFT conversion in HIV-exposed infants at age 1 year (2.5%) was lower than that reported for HIV-unexposed infants in these communities (6%–7%) [28, 36]. While the overall incidence of tuberculosis (3.3%) was similar to what has been described in previous reports [28], clinical diagnoses are likely to have resulted in overestimation of the true disease rate. It is likely that the exclusion criterion for household tuberculosis contact reduced the risk for tuberculosis transmission and disease in study infants, as evidenced by the maternal QFT positive rate (43%), which is considerably lower than that observed in HIV-uninfected young adults in the same community [36].We and others have shown that deferring BCG administration from birth to age 6–18 weeks does not impair long-term BCG immunogenicity [21–24]. Here, we evaluated the effects of administering a newborn prime tuberculosis vaccine on the immunogenicity of deferred BCG vaccination. MVA85A was weakly immunogenic, inducing mainly IFNγ+ Ag85A-specific cells before BCG administration. In BCG-vaccinated infants, higher abundance of cells releasing IFNγ upon BCG stimulation was associated with lower risk of progression to tuberculosis disease [37]. Whether the low IFNγ+ T-cell responses induced by MVA85A could be sufficient to protect against tuberculosis before BCG administration is unknown. Our findings differ from those in previous observations in HIV-exposed and HIV-unexposed infants [38, 39] in which MVA.HIVA was poorly immunogenic, due possibly to differences in study design, lower dose of MVA.HIVA, age at administration, and the assay used to measure immunogenicity. Nevertheless, these trials showed no interference by MVA administration with immunogenicity of routine childhood vaccines, further supporting the clinical development of this strategy.Remarkably, BCG did not further boost MVA85A-primed Ag85A-specific T-cell responses. These findings differ from observations made using the converse vaccination strategy, in which MVA85A significantly enhanced Ag85A-specific CD4 T-cell responses primed by BCG [28]. These observations suggest that either MVA85A is more immunogenic when used as a boost vaccine after BCG priming or, alternatively, that BCG cannot further boost Ag85A-specific T-cell responses that have been maximally primed by MVA85A. Regardless, BCG vaccination induced similar magnitudes of Ag85A-specific T-cell responses in the control and MVA85A groups. We deduce that for a given antigen, MVA is as good a vector as BCG, but that the immune response to Ag85A in this newborn population is weak. Importantly, MVA85A prime did not interfere with BCG immunogenicity with respect to the magnitude, functional quality, memory phenotype, and proliferative capacity of antigen-specific CD4+ T cells.T-cell proliferation was measured to assess relevant immune functions other than cytokine production, such as long-term recall responses and cytotoxic potential, with a more sensitive assay. Unlike cytokine production, T-cell proliferative responses to Ag85A and BCG were not sustained at age 1 year. Similarly, we previously reported that IFNγ release measured upon a 7-day whole blood stimulation with BCG was mostly undetectable by age 1 year, irrespective of age at BCG administration (birth vs 14 weeks) and HIV exposure [40]. While the underlying reasons for the loss of proliferative potential remain to be determined, it is clear that measuring T-cell functions other than IFNγ production is important to assess immunogenicity of novel vaccination strategies.Interpretation of our findings is limited by the lack of HIV-unexposed and BCG-naive control groups, both of which would not be ethically permissible in a highly tuberculosis-endemic setting. Further, the study sample size was selected to assess safety and immunogenicity and was not powered to test efficacy against M. tuberculosis infection or tuberculosis disease. Finally, although MVA85A has an excellent safety track record that is ideal for an experimental medicine study, further studies are needed to test this principle for potentially more efficacious tuberculosis vaccine candidates.In conclusion, the acceptable safety and reactogenicity profile, modest immunogenicity, and lack of interference with immunogenicity of BCG support further testing of alternative newborn prime vaccines, including other vector-based and protein-adjuvant candidates with additional antigens to enhance immunogenicity. This novel strategy should be pursued in order to provide protective immunity against M. tuberculosis in the first months of life, while being safe for all HIV-exposed infants.Supplementary DataSupplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.Supplementary MaterialSupplementary Figure 1Click here for additional data file.Supplementary Figure 2Click here for additional data file.Supplementary Figure 3Click here for additional data file.Supplementary Table 1Click here for additional data file.Supplementary Table 2Click here for additional data file.Supplementary InformationClick here for additional data file.Notes\nAcknowledgments. We thank study participants, their families, and the communities of Cape Winelands East district and Khayelitsha; personnel at the South African Tuberculosis Vaccine Initiative and the Desmond Tutu TB Center; and the study Safety Monitor (Zaynab Waggie) and Data Safety Monitoring Committee (Prakash Jeena, Brian Eley, Lewellys Barker, and Margaret Snowden).\nFinancial support. This work was supported by the UK Medical Research Council, Department for International Development, and Wellcome Trust Joint Global Health Trials programme (grant G1100570/1) and by AERAS. H. Mc. S. is a Wellcome senior clinical research fellow.\nPotential conflicts of interest. The authors declare no conflict of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.References1.\nZwerlingA, BehrMA, VermaA, BrewerTF, MenziesD, PaiM\nThe BCG world atlas: a database of global BCG vaccination policies and practices. PLoS Med2011; 8:e1001012.214453252.\nMaraisBJ, GieRP, SchaafHS\nThe clinical epidemiology of childhood pulmonary tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis2004; 8:278–85.151394653.\nMaraisBJ, GieRP, SchaafHS\nThe natural history of childhood intra-thoracic tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis2004; 8:392–402.151417294.\nColditzGA, BerkeyCS, MostellerF\nThe efficacy of bacillus Calmette-Guérin vaccination of newborns and infants in the prevention of tuberculosis: meta-analyses of the published literature. Pediatrics1995; 96:29–35.75967185.\nMangtaniP, AbubakarI, AritiC\nProtection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trials. Clin Infect Dis2014; 58:470–80.243369116.\nMartinsonNA, MoultrieH, van NiekerkR\nHAART and risk of tuberculosis in HIV-infected South African children: a multi-site retrospective cohort. Int J Tuberc Lung Dis2009; 13:862–7.195555367.\nCottonMF, SchaafHS, LotteringG, WeberHL, CoetzeeJ, NachmanS; PACTG 1041 Team\nTuberculosis exposure in HIV-exposed infants in a high-prevalence setting. Int J Tuberc Lung Dis2008; 12:225–7.182302598.\nMadhiSA, NachmanS, ViolariA; P1041 Study Team\nPrimary isoniazid prophylaxis against tuberculosis in HIV-exposed children. N Engl J Med2011; 365:21–31.217328349.\nSmithK, KuhnL, CoovadiaA\nImmune reconstitution inflammatory syndrome among HIV-infected South African infants initiating antiretroviral therapy. AIDS2009; 23:1097–107.1941758110.\nNuttallJJ, DaviesMA, HusseyGD, EleyBS\nBacillus Calmette-Guérin (BCG) vaccine-induced complications in children treated with highly active antiretroviral therapy. Int J Infect Dis2008; 12:e99–105.1879933911.\nHesselingAC, CottonMF, Fordham von ReynC, GrahamSM, GieRP, HusseyGD\nConsensus statement on the revised World Health Organization recommendations for BCG vaccination in HIV-infected infants. Int J Tuberc Lung Dis2008; 12:1376–9.1901744512.\nHesselingAC, JohnsonLF, JaspanH\nDisseminated bacille Calmette-Guérin disease in HIV-infected South African infants. Bull World Health Organ2009; 87:505–11.1964936413.\nGlobal Advisory Committee on Vaccine Safety, 29–30 November 2006. Wkly Epidemiol Rec2007; 82: 18–24.1723626214.\nAzzopardiP, BennettCM, GrahamSM, DukeT\nBacille Calmette-Guérin vaccine-related disease in HIV-infected children: a systematic review. Int J Tuberc Lung Dis2009; 13:1331–44.1986100315.\nKanabusA.\nInformation about Tuberculosis: TB Statistics-Global, Regional and High Burden. Global Health Education (GHE), 2017\nwww.tbfacts.org. Accessed 14 October 2017.16.\nBhardwajS, BarronP, PillayY\nElimination of mother-to-child transmission of HIV in South Africa: rapid scale-up using quality improvement. S Afr Med J2014; 104:239–43.2489350017.\nJoint review of HIV, TB and PMTCT programmes in South Africa. Department of Health, Republic of South Africa, 2014.18.\nSouth Africa. HIV and AIDS estimates, 2016\nwww.unaids.org. Accessed 14 October 2017.19.\nBarronP, PillayY, DohertyT\nEliminating mother-to-child HIV transmission in South Africa. Bull World Health Organ2013; 91:70–4.2339735320.\nHatherillM, MahomedH, HanekomW\nNovel vaccine prime and selective BCG boost: a new tuberculosis vaccine strategy for infants of HIV-infected mothers. Vaccine2010; 28:4550–2.2047079721.\nKaginaBM, AbelB, BowmakerM\nDelaying BCG vaccination from birth to 10 weeks of age may result in an enhanced memory CD4 T cell response. Vaccine2009; 27:5488–95.1961649422.\nBurlS, AdetifaUJ, CoxM\nDelaying bacillus Calmette-Guérin vaccination from birth to 4½ months of age reduces postvaccination Th1 and IL-17 responses but leads to comparable mycobacterial responses at 9 months of age. J Immunol2010; 185:2620–8.2064416023.\nTchakouteCT, HesselingAC, KidzeruEB\nDelaying BCG vaccination until 8 weeks of age results in robust BCG-specific T-cell responses in HIV-exposed infants. J Infect Dis2015; 211:338–46.2510802724.\nLutwamaF, KaginaBM, WajjaA\nDistinct T-cell responses when BCG vaccination is delayed from birth to 6 weeks of age in Ugandan infants. J Infect Dis2014; 209:887–97.2417911125.\nMansoorN, ScribaTJ, de KockM\nHIV-1 infection in infants severely impairs the immune response induced by Bacille Calmette-Guérin vaccine. J Infect Dis2009; 199:982–90.1923628026.\nJonesCE, HesselingAC, Tena-CokiNG\nThe impact of HIV exposure and maternal Mycobacterium tuberculosis infection on infant immune responses to bacille Calmette-Guérin vaccination. AIDS2015; 29:155–65.2553575227.\nRowlandR, McShaneH\nTuberculosis vaccines in clinical trials. Expert Rev Vaccines2011; 10:645–58.2160498528.\nTamerisMD, HatherillM, LandryBS; MVA85A 020 Trial Study Team\nSafety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial. Lancet2013; 381:1021–8.2339146529.\nScribaTJ, TamerisM, MansoorN\nDose-finding study of the novel tuberculosis vaccine, MVA85A, in healthy BCG-vaccinated infants. J Infect Dis2011; 203:1832–43.2160654230.\nMinassianAM, RowlandR, BeveridgeNE\nA phase I study evaluating the safety and immunogenicity of MVA85A, a candidate TB vaccine, in HIV-infected adults. BMJ Open2011; 1:e000223.31.\nScribaTJ, TamerisM, SmitE\nA phase IIa trial of the new tuberculosis vaccine, MVA85A, in HIV- and/or Mycobacterium tuberculosis-infected adults. Am J Respir Crit Care Med2012; 185:769–78.2228183132.\nNdiayeBP, ThienemannF, OtaM; MVA85A 030 Trial Investigators\nSafety, immunogenicity, and efficacy of the candidate tuberculosis vaccine MVA85A in healthy adults infected with HIV-1: a randomised, placebo-controlled, phase 2 trial. Lancet Respir Med2015; 3:190–200.2572608833.\nDieyeTN, NdiayeBP, DiengAB\nTwo doses of candidate TB vaccine MVA85A in antiretroviral therapy (ART) naïve subjects gives comparable immunogenicity to one dose in ART+ subjects. PLoS One2013; 8:e67177.2384061834.\nKaginaBM, MansoorN, KpameganEP\nQualification of a whole blood intracellular cytokine staining assay to measure mycobacteria-specific CD4 and CD8 T cell immunity by flow cytometry. J Immunol Methods2015; 417:22–33.2552392335.\nSoaresA, GovenderL, HughesJ\nNovel application of Ki67 to quantify antigen-specific in vitro lymphoproliferation. J Immunol Methods2010; 362:43–50.2080006636.\nMahomedH, HughesEJ, HawkridgeT\nComparison of mantoux skin test with three generations of a whole blood IFN-gamma assay for tuberculosis infection. Int J Tuberc Lung Dis2006; 10:310–6.1656271237.\nFletcherHA, SnowdenMA, LandryB\nT-cell activation is an immune correlate of risk in BCG vaccinated infants. Nat Commun2016; 7:11290.2706870838.\nNjugunaIN, AmblerG, ReillyM\nPedVacc 002: a phase I/II randomized clinical trial of MVA.HIVA vaccine administered to infants born to human immunodeficiency virus type 1-positive mothers in Nairobi. Vaccine2014; 32:5801–8.2517348439.\nAfolabiMO, NdureJ, DrammehA\nA phase I randomized clinical trial of candidate human immunodeficiency virus type 1 vaccine MVA.HIVA administered to Gambian infants. PLoS One2013; 8:e78289.2420518540.\nHesselingAC, JaspanHB, BlackGF, NeneN, WalzlG\nImmunogenicity of BCG in HIV-exposed and non-exposed infants following routine birth or delayed vaccination. Int J Tuberc Lung Dis2015; 19:454–62.25860002Appendix\nMVA029 Study Team. Charmaine Abrahams, Deborah Abrahams, Hadn Africa, Veronica Baartman, Beauty Bavuma, Nicole Bilek, Natasja Botes, Yolande Brown, Yolundi Cloete, Margareth Damons, Ronel De Vos, Portia Dlakavu, Karen Du Preez, Mzwandile Erasmus, Claudia Francis, Hendrik Geldenhuys, Mandy Geldenhuys, Katriena Goedeman, Sandra Golliath, Angelique Hendricks Mouton, Christiaan Hopley, Ruwijda Jansen, Carolynne Jones, Alana Keyser, Benjamin Kagina, Gloria Khomba, Fazlin Kola–Cassiem, Sandra Kruger, Daphne Leukes, Loyiso Louw, Angelique Luabeya, Theresa Maart, Lebohang Makhethe, Simbarashe Mbabwe, Eunice Mtshamba, Boniswa Mvinjelwa, Lungisa Nkantsu, Julia Noble, Sizwe Nqweniso, Fajwa Opperman, Christel Petersen, Patiswa Plaatjie, Susan Rossouw, Roxanne Solomoms, Marcia Steyn, Liticia Swanepoel, Asma Toefy, Heidi van Deventer, Elma van Rooyen, Daphne van Ster, Bongiwe Vazana, Ashley Veldsman, Noncedo Xoyana.', 'title': 'Safety and Immunogenicity of Newborn MVA85A Vaccination and Selective, Delayed Bacille Calmette-Guerin for Infants of Human Immunodeficiency Virus-Infected Mothers: A Phase 2 Randomized, Controlled Trial.', 'date': '2017-10-14'}}
| 0.333333
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Public Health, Epidemiology & Health Systems
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69
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Is the risk of life‐threatening serious adverse effects higher, lower, or the same when comparing MVA85A added to BCG to BCG alone?
|
no difference
|
high
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yes
|
['25726088', '23391465', '29028973']
| 31,038,197
| 2,019
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{'25726088': {'article_id': '25726088', 'content': "Lancet Respir MedLancet Respir MedThe Lancet. Respiratory Medicine2213-26002213-2619Elsevier257260884648060S2213-2600(15)00037-510.1016/S2213-2600(15)00037-5ArticlesSafety, immunogenicity, and efficacy of the candidate tuberculosis vaccine MVA85A in healthy adults infected with HIV-1: a randomised, placebo-controlled, phase 2 trialNdiayeBirahim PierreMDa*ThienemannFriedrichMDbd*OtaMartinFWACPeLandryBernard SMPHfCamaraMakhtarPhDaDièyeSiryMDaDieyeTandakha NdiayePhDaEsmailHanifMRCPbjGoliathReneBScbHuygenKrisPhDgJanuaryVanessabNdiayeIbrahimaMDaOniToluMDbcRaineMichaelBScfRomanoMartaPhDgSattiImanPhDiSuttonSharonBSfThiamAminataMDhWilkinsonKatalin APhDbdkMboupSouleymaneProfPhDaWilkinsonRobert JProfFRCPbdjk†McShaneHelenProfFRCPhelen.mcshane@ndm.ox.ac.uki*†for the MVA85A 030 trial investigators‡aLaboratoire de Bactériologie–Virologie, Centre Hospitalier Universitaire Le Dantec, Dakar, SenegalbClinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South AfricacDivision of Public Health Medicine, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South AfricadDepartment of Medicine, University of Cape Town, Cape Town, South AfricaeMedical Research Council Unit, Fajara, The GambiafAeras, Rockville, MD, USAgImmunology Service, Scientific Institute of Public Health (WIV-ISP), Brussels, BelgiumhCentre de Traitement Ambulatoire, Centre Hospitalier Universitaire de Fann, Dakar, SenegaliJenner Institute, University of Oxford, Oxford, UKjDepartment of Medicine, Imperial College London, London, UKkMRC National Institute for Medical Research, London, UK*Correspondence to: Prof Helen McShane, Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK helen.mcshane@ndm.ox.ac.uk*Joint first authors†Joint last authors‡Listed in appendix1320153201533190200© 2015 Ndiaye et al. Open Access article distributed under the terms of CC BY2015This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).SummaryBackgroundHIV-1 infection is associated with increased risk of tuberculosis and a safe and effective vaccine would assist control measures. We assessed the safety, immunogenicity, and efficacy of a candidate tuberculosis vaccine, modified vaccinia virus Ankara expressing antigen 85A (MVA85A), in adults infected with HIV-1.MethodsWe did a randomised, double-blind, placebo-controlled, phase 2 trial of MVA85A in adults infected with HIV-1, at two clinical sites, in Cape Town, South Africa and Dakar, Senegal. Eligible participants were aged 18–50 years, had no evidence of active tuberculosis, and had baseline CD4 counts greater than 350 cells per μL if they had never received antiretroviral therapy or greater than 300 cells per μL (and with undetectable viral load before randomisation) if they were receiving antiretroviral therapy; participants with latent tuberculosis infection were eligible if they had completed at least 5 months of isoniazid preventive therapy, unless they had completed treatment for tuberculosis disease within 3 years before randomisation. Participants were randomly assigned (1:1) in blocks of four by randomly generated sequence to receive two intradermal injections of either MVA85A or placebo. Randomisation was stratified by antiretroviral therapy status and study site. Participants, nurses, investigators, and laboratory staff were masked to group allocation. The second (booster) injection of MVA85A or placebo was given 6–12 months after the first vaccination. The primary study outcome was safety in all vaccinated participants (the safety analysis population). Safety was assessed throughout the trial as defined in the protocol. Secondary outcomes were immunogenicity and vaccine efficacy against Mycobacterium tuberculosis infection and disease, assessed in the per-protocol population. Immunogenicity was assessed in a subset of participants at day 7 and day 28 after the first and second vaccination, and M tuberculosis infection and disease were assessed at the end of the study. The trial is registered with ClinicalTrials.gov, number NCT01151189.FindingsBetween Aug 4, 2011, and April 24, 2013, 650 participants were enrolled and randomly assigned; 649 were included in the safety analysis (324 in the MVA85A group and 325 in the placebo group) and 645 in the per-protocol analysis (320 and 325). 513 (71%) participants had CD4 counts greater than 300 cells per μL and were receiving antiretroviral therapy; 136 (21%) had CD4 counts above 350 cells per μL and had never received antiretroviral therapy. 277 (43%) had received isoniazid prophylaxis before enrolment. Solicited adverse events were more frequent in participants who received MVA85A (288 [89%]) than in those given placebo (235 [72%]). 34 serious adverse events were reported, 17 (5%) in each group. MVA85A induced a significant increase in antigen 85A-specific T-cell response, which peaked 7 days after both vaccinations and was primarily monofunctional. The number of participants with negative QuantiFERON-TB Gold In-Tube findings at baseline who converted to positive by the end of the study was 38 (20%) of 186 in the MVA85A group and 40 (23%) of 173 in the placebo group, for a vaccine efficacy of 11·7% (95% CI −41·3 to 44·9). In the per-protocol population, six (2%) cases of tuberculosis disease occurred in the MVA85A group and nine (3%) occurred in the placebo group, for a vaccine efficacy of 32·8% (95% CI −111·5 to 80·3).InterpretationMVA85A was well tolerated and immunogenic in adults infected with HIV-1. However, we detected no efficacy against M tuberculosis infection or disease, although the study was underpowered to detect an effect against disease. Potential reasons for the absence of detectable efficacy in this trial include insufficient induction of a vaccine-induced immune response or the wrong type of vaccine-induced immune response, or both.FundingEuropean & Developing Countries Clinical Trials Partnership (IP.2007.32080.002), Aeras, Bill & Melinda Gates Foundation, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium.Research in contextEvidence before this studyOne previous study assessed the efficacy of several doses of the saprophyte Mycobacterium vaccae against tuberculosis disease in adults infected with HIV-1, and showed a decreased risk of protocol-defined pulmonary tuberculosis. A previous study with the MVA85A, the candidate vaccine under assessment here, has showed that boosting with MVA85A did not enhance protective efficacy in BCG-vaccinated infants. Adults infected with HIV-1 are an important target population for a new tuberculosis vaccine, and in earlier studies, vaccine-induced immunogenicity in adults infected with HIV-1 was higher than in infants.Added value of this studyThis is the first time that a candidate tuberculosis vaccine has been assessed for efficacy against Mycobacterium tuberculosis infection in people infected with HIV-1. The results show that vaccinating adults infected with HIV-1 with MVA85A is safe, but does not confer protection against infection with M tuberculosis.Implications of all the available evidenceThe safety of MVA85A in this large study population of adults with HIV infection is an important finding for tuberculosis vaccine development. The vector is safe to give to people without HIV testing; these safety data provide some generic reassurance that new candidate tuberculosis vaccines are safe in this higher risk population. Additionally, this study has shown that high-quality, multicentre tuberculosis vaccine trials in vulnerable populations are possible. The absence of efficacy despite immunogenicity in this and previous clinical trials of MVA85A suggests that the current parameters for selection of tuberculosis vaccine candidates are inadequate. Standardised preclinical animal models that better represent human infection and disease, and a greater understanding of immune mechanisms of protection in human tuberculosis are both urgently needed. Alternative approaches to vaccine development, including the delivery of candidate vaccines direct to the respiratory mucosa, merit assessment. Other lessons learnt from this trial include the characterisation of the epidemiology of M tuberculosis infection and disease associated with HIV-1 infection in a setting of antiretroviral therapy and isoniazid chemoprophylaxis.IntroductionTuberculosis is a substantial global cause of mortality and morbidity, with 9 million new cases of active tuberculosis and 1·5 million deaths occurring in 2013.1 One third of the world's population is infected with Mycobacterium tuberculosis.1 HIV-1 co-infection is one of the most important risk factors for both infection with M tuberculosis and active tuberculosis disease,2 with an estimated 1·1 million of all new tuberculosis cases in 2013 occurring in people co-infected with HIV-1.1 The WHO African region accounts for 80% of HIV-1-associated tuberculosis.1 Additionally, the growing incidence of drug-resistant tuberculosis is associated with poor treatment outcome and increased mortality.3 The global Stop TB Partnership aims to eliminate tuberculosis as a public health problem by 2050. An agreed major component to advance this aim would be an effective vaccine.4 BCG is the only licensed tuberculosis vaccine—it provides protection against severe childhood tuberculosis,5, 6 but the protection conferred against pulmonary tuberculosis in adults and adolescents is highly variable.7, 8At least 16 candidate tuberculosis vaccines have advanced to clinical testing.9 The modified vaccinia virus Ankara expressing the major M tuberculosis antigen 85A (MVA85A) is a clinically advanced candidate vaccine.10, 11, 12 MVA85A is well tolerated and immunogenic in adults infected and not infected with HIV-1, and in infants not exposed to HIV-1.10, 11, 12, 13, 14 MVA85A adds to BCG-induced protection against mycobacterial challenge in some preclinical animal models.15, 16, 17, 18, 19 However, boosting BCG with MVA85A in South African infants not infected with HIV-1 did not confer additional protection against tuberculosis disease or M tuberculosis infection.10Administration of several doses of the saprophyte Mycobacterium vaccae to adults infected with HIV-1 was associated with a decreased risk of protocol-defined pulmonary tuberculosis,20 suggesting that vaccination might be effective in people infected with HIV-1. Here we report the results of a multisite, randomised, placebo-controlled, phase 2 trial to assess the safety, immunogenicity, and efficacy of MVA85A in healthy adults infected with HIV-1.MethodsStudy design and participantsWe did a proof-of-concept, randomised, double-blind, placebo-controlled, phase 2 trial of MVA85A at two clinical sites, in Cape Town, South Africa and Dakar, Senegal. In Cape Town, participants were recruited in the community and from primary care clinics in Khayelitsha by use of radio and newspaper advertisements, flyers, pamphlets, and information campaigns at the clinics. Khayelitsha is a densely populated, low-income, peri-urban township. In 2010, antenatal HIV-1 prevalence was 33% and the tuberculosis case notification rate was at least 1500 per 100\u2008000 population per year.21 In Dakar, participants were recruited from public service HIV clinics at the Centre de Traitement Ambulatoire and the Centre de Recherche Clinique et de Formation, Centre Hospitalier Universitaire de Fann. Senegal had an estimated HIV-1 prevalence in adults of less than 1% in 2012, and a reported tuberculosis incidence rate of 0·14% in 2013.1 The annual rate of M tuberculosis infection has not previously been estimated at either site. Eligibility criteria included participants aged 18–50 years with no evidence of active tuberculosis, and baseline CD4 counts greater than 350 cells per μL if they were not receiving antiretroviral therapy, or greater than 300 cells per μL (and with undetectable viral load before randomisation) if they were receiving antiretroviral therapy. Participants with latent tuberculosis infection were eligible for enrolment if they had completed at least 5 months of isoniazid preventive therapy, unless they had completed treatment for tuberculosis disease within 3 years before randomisation. The complete inclusion criteria are listed in the study protocol (appendix).The trial adhered to International Conference on Harmonisation Good Clinical Practice guidelines, and was approved by the University of Cape Town's Faculty of Health Sciences Human Research Ethics Committee and the Medicines Control Council of South Africa; the Senegalese National Ethics Committee for Research in Health; and the Oxford University Tropical Research Ethics Committee. All participants provided written informed consent before any study procedure.Randomisation and maskingParticipants were randomly assigned (1:1) in blocks of four by a randomly generated sequence of participant identification numbers via an interactive voice response system to receive two intradermal injections of either 1\u2008×\u2008108 pfu MVA85A or placebo (Candida skin test antigen [Candin], Allermed Laboratories, San Diego, CA, USA). Randomisation was stratified by antiretroviral therapy status and study site. A statistician uninvolved with study analyses prepared the interactive voice response system randomisation schedule. Doses of vaccines were prepared and labelled in masked syringes by a pharmacist unmasked to group allocation. Participants, nurses (who were involved in assessment and follow-up), investigators, and laboratory staff were masked to group allocation. The second (booster) injection of MVA85A or placebo was given 6–12 months after the first vaccination and participants were actively followed up every 3 months until the last participant enrolled had completed 6 months of follow-up after the booster vaccination.ProceduresWe collected data for the incidence of solicited and unsolicited adverse events, including both local injection-site reactions and systemic reactions. Participants reported solicited adverse events on diary cards for 7 days after each vaccination and in response to direct questioning by trained study staff on days 7 and 28 after each injection. Phlebotomy for routine haematological and biochemical analysis was done at screening, before booster vaccination, and on days 7 and 28 after each vaccination. Peripheral CD4 cell count and HIV-1 viral load were also measured at these timepoints and every 3 months until 6 months after booster vaccination. Serious adverse events were monitored by active surveillance throughout and until the end of the trial. The site investigators and local medical monitors determined the severity and seriousness of adverse events and the relation of these to the vaccine. An independent data monitoring committee assessed masked group safety data after 200 participants had been enrolled and unmasked after 600 participants had been enrolled.In a prespecified subset of 70 participants (35 from each group), immunology samples were obtained before each vaccination and on days 7 and 28 after each vaccination. All immunology tests were done masked to group allocation. We assessed vaccine immunogenicity with three assays. First, ex vivo interferon γ enzyme-linked immunospot (ELISPOT) analysis was done on fresh peripheral blood mononuclear cells.22 Cells were stimulated overnight with a single pool of 66 peptides of the antigen 85A (Ag85A), ESAT-6, and CFP-10. Second, Ag85A-specific intracellular cytokine staining assay was done on whole blood.23 Stimulated fixed whole blood samples were stained for CD3-positive, CD4-positive, CD8-positive, CD14-positive, and CD19-positive cells, interferon γ, tumour necrosis factor α, interleukin 17, and interleukin 2. Third, Ag85A-specific antibody response was measured on plasma. Ag85A-specific immunoglobulin G (IgG) antibodies were measured by ELISA on eight serial two-fold dilutions of plasma (1:25–1:3200), by use of affinity purified recombinant, histidine-tagged Ag85A24 (microwell plates coated with 50 ng per well of recombinant Ag85A in borate buffer, overnight at 4°C). Alkaline phosphatase-labelled goat anti-human IgG (Sigma, St Louis, MO, USA) was used as secondary antibody at a dilution of 1:1000 and optical density was read at 405 nm after development with phosphatase substrate (Sigma). Results were expressed in arbitrary units per mL (AU/mL), as compared with values of an internal tuberculosis serum standard of 2500 AU/mL.Participants were screened to exclude active tuberculosis by symptom screen and chest radiography at both sites before enrolment. In Cape Town, participants also underwent sputum collection for tuberculosis smear microscopy, GeneXpert MTB/RIF (Cepheid, Sunnyvale, CA, USA), and mycobacterial liquid culture (MGIT; Becton Dickinson, Sparks, MD, USA) because of previously documented high frequencies of asymptomatic disease at this site.25 Latent M tuberculosis infection was defined as either a positive QuantiFERON-TB Gold In-Tube (QFT) test or a tuberculin purified protein derivative skin test (tuberculin skin test) reaction greater than 5 mm.Participants were monitored throughout the trial for possible tuberculosis. Tuberculosis investigations were done in participants who had been in contact with a known case of active tuberculosis, in those who presented with at least one of cough for more than 1 week, fever for more than 1 week, drenching night sweats, unintentional weight loss of more than 3 kg, pleuritic chest pains, haemoptysis, or shortness of breath; and in those who converted to a positive QFT or tuberculin skin test (≤5 mm to >5 mm). Investigations included clinical examination, chest radiography, and collection of at least two sputum samples on which tuberculosis smear microscopy, GeneXpert MTB/RIF, and mycobacterial liquid culture were done. Chest radiographs were reviewed by two physicians, with a third reading to achieve consensus in the event of disagreement. QFT and tuberculin skin tests were repeated at the final study visit.OutcomesTuberculosis disease endpoint 1 was defined as culture or GeneXpert MTB/RIF positivity; endpoint 2 included endpoint 1 and a composite clinical endpoint (which included a single acid-fast bacilli smear from a sterile body site; two smears from pulmonary and gastric sampling, and compatible clinical symptoms and radiological signs); and endpoint 3 was participant commencement on anti-tubercular chemotherapy (see the study protocol for more information; appendix). The M tuberculosis infection endpoint was defined as conversion from negative QFT at baseline to positive QFT at the final visit.The primary study outcome was the safety of MVA85A in all participants who received at least one dose of study vaccine or placebo (the safety analysis population) as determined by the numbers and percentages of adverse events (including solicited, unsolicited, and serious adverse events).The secondary outcome was the efficacy of MVA85A for the prevention of active tuberculosis in the per-protocol population (all randomly allocated participants who received at least one dose of study vaccine or placebo and had no major protocol deviations and no tuberculosis case definition endpoints within 28 days after study day 0 [first vaccination]), which was determined by the incidence of active tuberculosis meeting the definition of endpoint 1, calculated as the number of new cases of active tuberculosis with a date of diagnosis from 28 days after the first vaccination until the end of the study follow-up (May 19, 2014). An intention-to-treat analysis was also done for disease efficacy. In the per-protocol population, we also examined the efficacy of MVA85A by antiretroviral therapy status at the time of randomisation and by baseline isoniazid preventive therapy status.Other secondary outcomes were to assess CD4-positive lymphocyte counts and HIV-1 viral load before and after administration of MVA85A compared with placebo; to assess the immunogenicity of MVA85A compared with placebo as measured by the ex-vivo interferon γ ELISPOT assay; to assess the immunogenicity of MVA85A compared with placebo as measured by flow cytometric intracellular cytokine staining of CD4-positive and CD8-positive T cells after stimulation with a peptide pool of mycobacterial antigens; to identify potential immunological correlates of protection from tuberculosis in participants vaccinated with MVA85A and to assess the QFT conversion rate at final study assessment in MVA85A recipients compared with controls without a diagnosis of tuberculosis during the trial.Statistical analysisAll sample size calculations assumed a loss to follow-up and death rate of 2%. The initial planned sample size for this trial was 1400 adult participants, to be followed up for 2 years after the last participant was enrolled. This sample size provided 80% power to detect a vaccine efficacy of 60% against tuberculosis disease. However, after review of the phase 2 infant efficacy data,10 the trial design was revised with safety as the primary objective and a smaller sample size and shorter follow-up of a minimum of 6 months. The revised sample size for this study was selected as adequate for a review of the safety profile. With 325 participants assigned to receive MVA85A, the revised sample would have a 90% probability of detecting at least one adverse event occurring at a rate of 0·71%. Because of the expected effect of antiretroviral therapy on tuberculosis disease, an estimated tuberculosis disease incidence ranging between 1·5% and 2% per year was used to estimate the power of the revised sample size for efficacy. Calculations were based on a one-sided log-rank test at a significance level of 0·10 and assumed completion of enrolment in 21 months, a follow-up period of about 15 months for the last patient enrolled, and a maximum of 36 months for the first patient enrolled. If the true efficacy was about 70%, 325 patients per treatment group (650 patients total) provided 81% power to show positive efficacy given an incidence rate of 2·0% in the control group per year, or 71% power given an incidence rate of 1·5% in the control group per year. At a true efficacy of about 60%, 325 patients per treatment group provided 67% power to show positive efficacy given an incidence rate of 2·0% per year, or 57% power given an incidence rate of 1·5% per year. Vaccine efficacy to prevent infection was a secondary endpoint: the recorded QFT conversion rate in the study provided 80% power to detect a vaccine efficacy of 50%.Statistical analyses were done using SAS version 9.2. All analyses were prespecified in the statistical analysis plan before locking of the database. For the safety analysis, we compared the proportion of participants with at least one adverse event in the MVA85A group versus those in the placebo using Fisher's exact test. We also calculated two-sided 95% CIs for proportions of adverse events within treatment groups and the differences between groups.The main statistical method used in the analysis of tuberculosis disease endpoints 1–3 was vaccine efficacy, estimated as 1 minus the estimated hazard ratio, based on a Cox regression analysis of time (days) to initial tuberculosis diagnosis, based on the per-protocol population. As supportive confirmatory analysis, we used the conditional binomial (Clopper-Pearson) method to estimate vaccine efficacy and its corresponding two-sided 95% CIs and p values. Time to initial diagnosis for each endpoint was compared by use of a two-sided log-rank test, stratified by study site and antiretroviral therapy status at randomisation. Analyses were summarised by antiretroviral therapy and treatment group for participants in the per-protocol population. Vaccine efficacy against M tuberculosis infection and the corresponding 95% CI, and p value were calculated with the conditional binomial method (Clopper-Pearson), identical to the tuberculosis case definition endpoint analysis.Other secondary endpoints were analysed in various ways. Median CD4 cell counts and associated two-sided 95% CIs were summarised by antiretroviral therapy status at randomisation, study site, treatment group, and timepoint. HIV-1 viral load (copies per mL) was summarised with medians (and associated 95% CIs) by antiretroviral therapy status at randomisation, study site, and treatment group, at each available timepoint. Both the CD4 cell counts and HIV-1 viral load values were log-transformed before any analysis was done. We used Wilcoxon paired analysis to compare within group before and after vaccination responses.Quintiles (Blomfontein, South Africa) did the statistical analysis, and Aeras paid for this service. The trial was registered with ClinicalTrials.gov, number NCT01151189.Role of the funding sourceAeras was the trial sponsor and contributed to study design and data analysis. The other funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. BPN, FT, BSL, RJW, and HM had full access to all the data in the study. HM had final responsibility for the decision to submit for publication.ResultsBetween Aug 4, 2011, and April 24, 2013, 1233 adults infected with HIV-1 were screened and 650 were randomly assigned; 649 were included in the safety analysis and 645 in the per-protocol analysis (figure 1). 513 (71%) participants had CD4 counts greater than 300 cells per μL and were receiving antiretroviral therapy; 136 (21%) had CD4 counts above 350 cells per μL and had never received antiretroviral therapy. The results of the intention-to-treat analysis were not different and are not reported. 311 (96%) participants in the placebo group and 298 (92%) in the MVA85A group received the booster vaccination. One participant was randomly assigned to placebo but received MVA85A; this participant was included in the safety population for MVA85A but not in the per-protocol efficacy population. One participant was randomly assigned to MVA85A but withdrew consent before vaccination and was not vaccinated. This participant was excluded from both the safety and per-protocol populations. Baseline demographic characteristics were similar in the two study groups and across the two study sites (table 1; appendix). 625 participants completed the study; 14 participants were lost to follow-up (nine placebo, five MVA85A), five withdrew consent (two placebo, three MVA85A), and six died (four placebo, two MVA85A).In the per-protocol population, median follow-up was 655 days for the 320 recipients of MVA85A and 654 days for the 325 placebo participants. Other than the four participants shown in figure 1, all participants were included in the analysis.At least one adverse event was reported in 312 (96%) of placebo recipients and 321 (99%) of MVA85A recipients (table 2). Solicited adverse events were more common in participants who received MVA85A than placebo (table 2). Most of these events were local injection-site reactions; other solicited adverse events included mild influenza-like symptoms and regional lymphadenopathy. We noted no significant difference between study groups in the frequency of serious adverse events. 34 serious adverse events occurred during the study, 17 in the placebo group and 17 in the MVA85A group (table 2; appendix). All but one of these events were judged to be unrelated to vaccination; a case of probable tuberculous meningitis that occurred 6 days after vaccination was judged to be possibly related to vaccination. The data monitoring committee reviewed this case, did not request unmasking, and recommended continuing with the study. The participant was treated for tuberculous meningitis and made a full recovery. At study completion, this participant was identified as having received MVA85A. 13 serious adverse events in the infections and infestations category occurred during the study (the only category with more than five serious adverse events in either group), eight in the placebo group and five in the MVA85A group; this difference was not significant (Fisher's exact test, p=0·58).The frequency of severe adverse events did not differ significantly between study groups (table 2). We noted no significant changes in CD4 cell count or HIV-1 viral load throughout the course of the trial in either study group (data not shown). Routine haematological and biochemical test results did not differ between study groups (data not shown).ELISPOT responses to Ag85A were significantly higher in participants from Dakar than in those from Cape Town at baseline (p=0·0016), but at no other timepoint. This difference was not seen with the less sensitive whole blood intracellular cytokine staining assay. MVA85A induced an Ag85A-specific T-cell response that peaked 7 days after the first and booster vaccinations (median spots per million: day 0 [first vaccination], 9·0 [IQR 2·3–51·0]; day 7 [first vaccination], 337·0 [139·3–993·8]; day 0 [booster vaccination], 103·5 [14·8–223·8]; day 7 [booster vaccination], 426·0 [150·0–745·0]; figure 2). Responses at each timepoint after vaccination did not differ by study site or by antiretroviral therapy status. Medians in the placebo group did not exceed 20 spots per million at any timepoint.Whole blood intracellular cytokine staining showed the most commonly measured cytokine from CD4 T cells was interferon γ, in agreement with the ELISPOT data. Tumour necrosis factor α and low concentrations of interleukins 2 and 17 were also detected (table 3, figure 2). Overall, numbers of antigen-specific CD8 T cells were very low and were only positive for interferon γ and tumour necrosis factor α. Multiparameter flow-cytometric analysis showed that mainly monofunctional Ag85A-specific CD4 T cells were present before and after vaccination (figure 3). Ag85A-specific antibody responses were less than twice the baseline value after vaccination in all but three participants.In the per-protocol population, the overall number of tuberculosis cases and incidence during study follow-up of tuberculosis cases (endpoint 1) was six (2%) in the MVA85A group and nine (3%) in the placebo group, for a vaccine efficacy of 32·8% (95% CI −111·5 to 80·3; table 4). Figure 4 shows the Kaplan-Meier time-to-disease analysis for endpoint 1. Stratification by antiretroviral therapy status showed no significant difference between treatment groups. Eight of the 15 endpoint 1 cases were QFT positive at enrolment. No additional participants met endpoint 2 who did not already meet endpoint 1. Vaccine efficacy for endpoint 3 was 10·5% (−161·3 to 70.0). Disease incidence did not differ by site. Median time to diagnosis of endpoint 1 was 249 days in the MVA85A group and 236 days in the placebo group. 159 (50%) of 320 MVA85A recipients and 148 (46%) of 325 placebo recipients were investigated for tuberculosis during the study. The study was insufficiently powered to assess the efficacy of MVA85A for the prevention of tuberculosis disease in the subset of participants receiving antiretroviral therapy or isoniazid prophylaxis. The absence of efficacy also made it impossible to identify potential immunological correlates of protection from tuberculosis in participants vaccinated with MVA85A.The number of QFT-negative participants who converted to QFT positive by the end of the study was 38 (20%) in the MVA85A group and 40 (23%) in the placebo group, for a vaccine efficacy of 11·7% (95% CI −41·3 to 44·9). QFT conversion did not differ by antiretroviral therapy status (data not shown), but it did differ by site. In Cape Town, 41 (31%) of 132 participants converted, whereas in Dakar, 37 (16%) of 227 converted (χ2 10·89, p=0·001). Frequency of QFT reversion (participants who were positive at baseline and negative at end of study) was similar in the two treatment groups (17 [14%] of 124 for MVA85A and 27 [19%] of 139 for placebo; p=0·22), and did not differ by antiretroviral therapy status (data not shown). Tuberculin skin test conversion was not a prespecified endpoint and is not reported here, but will be the subject of further analysis.DiscussionThis phase 2 trial in 650 adult participants infected with HIV-1 showed that MVA85A was well tolerated and immunogenic, with safety and immunogenicity profiles similar to those reported elsewhere for other populations in which this candidate vaccine has been assessed.10, 11, 12, 13, 14 However, we did not identify any significant efficacy against tuberculosis disease or M tuberculosis infection.Both first and booster vaccination with MVA85A induced a significant increase in Ag85A-specific T cells. Responses did not differ by antiretroviral therapy status. A probable explanation for this finding is the high baseline median CD4 count (571 cells per mm3; table 1, appendix) in participants who had not received antiretroviral therapy. Unlike the previously reported infant efficacy trial of MVA85A,10 baseline ELISPOT responses were detected in this trial and were significantly higher in participants from Dakar than in those from Cape Town. This result might be due to greater exposure to environmental mycobacteria; and the finding is unlikely to be due to a technical issue because it was only recorded at this timepoint, and there was a robust quality control programme in place for these assays. Furthermore, the median response 7 days after vaccination in this trial exceeded that seen in the infant trial (337 vs 136 spots per million).10 Additionally, the functional phenotype of the dominant T-cell population in this trial was monofunctional by contrast with the infant trial, in which the dominant phenotype was polyfunctional.10 In both trials, the recorded response was insufficient to be associated with protection. It is not clear whether a quantitatively greater or a qualitatively different immune response is needed for protection. Alternative approaches, including the delivery of candidate vaccines direct to the respiratory mucosa, might be more potent routes of immunisation. For example, we have previously reported that delivery of MVA85A by aerosol to HIV-negative, BCG-vaccinated adults in the UK is well tolerated and induces potent mucosal and systemic immunity.26 Further assessment is needed before this route can be examined in countries with a high burden of tuberculosis. This approach, together with other strategies to improve the immunogenicity of MVA85A, are currently under investigation.The recorded annual incidence of tuberculosis (endpoint 1) was substantial (1·43% across treatment groups) and did not differ between sites. However, this incidence was lower than previously reported in Cape Town.27 The numbers of participants receiving antiretroviral therapy was greater than originally envisaged, because of the increased availability of this therapy during the study period and the change in national and international guidelines on the provision of antiretroviral therapy. These factors, combined with the redesign of this study upon availability of the infant trial results,10 led to a reduction in statistical power to detect a difference in tuberculosis disease incidence between treatment groups, leading to wide CIs for our estimates of vaccine efficacy.In this trial, the incidence of infection determined by QFT conversion was much higher than the incidence of tuberculosis disease, so CIs around the estimates of efficacy against infection are narrower. The overall recorded annual QFT conversion rate of about 12% meant that we had about 80% power to detect a vaccine efficacy of 50% against M tuberculosis infection. In view of the cost and complexity of human efficacy studies, there is now increased focus on infection as an endpoint rather than disease in proof-of-concept studies before progression to prevention-of-disease efficacy trials.9 However, this approach presupposes that the immune mechanisms needed to prevent infection and disease are similar. Our poor understanding of the biology underlying dynamic QFT conversion and reversion further complicates this shift in emphasis. The rate of QFT reversion was almost as high as the rate of conversion: whether this finding represents a true biological effect or technical variability in the assay cannot be determined from these data.In this study, we have shown that high-quality, multicentre tuberculosis vaccine trials are possible in Africa, and have succeeded in the characterisation of the epidemiology of tuberculosis associated with HIV-1 in two African cities. Nevertheless, the disappointing finding with respect to vaccine efficacy for MVA85A suggests the need for standardised preclinical animal models that better represent human disease and an improved understanding of immune mechanisms of protection in human tuberculosis. Such advances would greatly enhance the ability to efficiently translate clinical research capacity into the development and deployment of an effective vaccine.References1WHOGlobal tuberculosis report2014World Health OrganizationGeneva2WalkerNFMeintjesGWilkinsonRJHIV-1 and the immune response to TBFuture Virol820135780236536643FalzonDWeyerKRaviglioneMCDrug-resistant tuberculosis: latest advancesLancet Respir Med12013e910243218184BrennanMJTholeJTuberculosis vaccines: a strategic blueprint for the next decadeTuberculosis92suppl 12012S613224411605RodriguesLCDiwanVKWheelerJGProtective effect of BCG against tuberculous meningitis and miliary tuberculosis: a meta-analysisInt J Epidemiol2219931154115881442996TrunzBBFinePDyeCEffect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectivenessLancet367200611731180166165607MangtaniPAbubakarIAritiCProtection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trialsClin Infect Dis582014470480243369118ColditzGABrewerTFBerkeyCSEfficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literatureJAMA271199469870283090349HawnTRDayTAScribaTJTuberculosis vaccines and prevention of infectionMicrobiol Mol Biol Rev7820146506712542893810TamerisMDHatherillMLandryBSSafety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trialLancet3812013102110282339146511McShaneHPathanAASanderCRRecombinant modified vaccinia virus Ankara expressing antigen 85A boosts BCG-primed and naturally acquired antimycobacterial immunity in humansNat Med102004124012441550283912HawkridgeTScribaTJGelderbloemSSafety and immunogenicity of a new tuberculosis vaccine, MVA85A, in healthy adults in South AfricaJ Infect Dis19820085445521858219513SanderCRPathanAABeveridgeNESafety and immunogenicity of a new tuberculosis vaccine, MVA85A, in Mycobacterium tuberculosis-infected individualsAm J Respir Crit Care Med17920097247331915119114MinassianAMRowlandRBeveridgeNEA phase I study evaluating the safety and immunogenicity of MVA85A, a candidate TB vaccine, in HIV-infected adultsBMJ Open12011e00022315WilliamsAGoonetillekeNPMcShaneHBoosting with poxviruses enhances Mycobacterium bovis BCG efficacy against tuberculosis in guinea pigsInfect Immun732005381438161590842016VordermeierHMVillarreal-RamosBCocklePJViral booster vaccines improve Mycobacterium bovis BCG-induced protection against bovine tuberculosisInfect Immun772009336433731948747617VerreckFAVervenneRAKondovaIMVA.85A boosting of BCG and an attenuated, phoP deficient M. tuberculosis vaccine both show protective efficacy against tuberculosis in rhesus macaquesPLoS One42009e52641936733918GoonetillekeNPMcShaneHHannanCMAndersonRJBrookesRHHillAVEnhanced immunogenicity and protective efficacy against Mycobacterium tuberculosis of bacille Calmette–Guérin vaccine using mucosal administration and boosting with a recombinant modified vaccinia virus AnkaraJ Immunol1712003160216091287425519McShaneHWilliamsAA review of preclinical animal models utilised for TB vaccine evaluation in the context of recent human efficacy dataTuberculosis9420141051102436998620von ReynCFMteiLArbeitRDPrevention of tuberculosis in Bacille Calmette-Guérin-primed, HIV-infected adults boosted with an inactivated whole-cell mycobacterial vaccineAIDS2420106756852011876721CoxHHughesJDanielsJCommunity-based treatment of drug-resistant tuberculosis in Khayelitsha, South AfricaInt J Tuberc Lung Dis1820144414482467070022ScribaTJTamerisMMansoorNModified vaccinia Ankara-expressing Ag85A, a novel tuberculosis vaccine, is safe in adolescents and children, and induces polyfunctional CD4+ T cellsEur J Immunol4020102792902001718823HanekomWAHughesJMavinkurveMNovel application of a whole blood intracellular cytokine detection assay to quantitate specific T-cell frequency in field studiesJ Immunol Methods29120041851951534531624GartnerTBaetenMOtienoSRevetsHDe BaetselierPHuygenKMucosal prime-boost vaccination for tuberculosis based on TLR triggering OprI lipoprotein from Pseudomonas aeruginosa fused to mycolyl-transferase Ag85AImmunol Lett111200726351757053525RangakaMXGideonHPWilkinsonKAInterferon release does not add discriminatory value to smear-negative HIV-tuberculosis algorithmsEur Respir J3920121631712171948726SattiIMeyerJHarrisSASafety and immunogenicity of a candidate tuberculosis vaccine MVA85A delivered by aerosol in BCG-vaccinated healthy adults: a phase 1, double-blind, randomised controlled trialLancet Infect Dis1420149399462515122527RangakaMXWilkinsonRJBoulleAIsoniazid plus antiretroviral therapy to prevent tuberculosis: a randomised double-blind, placebo-controlled trialLancet384201468269024835842Supplementary MaterialSupplementary appendixAcknowledgmentsThe study was funded by the European & Developing Countries Clinical Trials Partnership (IP.07.32080.002), Aeras, Bill & Melinda Gates Foundation, the Wellcome Trust (095780, 084323, and 088316), and the Oxford-Emergent Tuberculosis Consortium. Quintiles (Bloemfontein, South Africa) were used for the statistical analysis, and Aeras paid for this service. The appendix includes a complete list of acknowledgments. We dedicate this study to the memory of Robyn Louw.ContributorsBPN, FT, SD, HE, RG, VJ, IN, TO, AT, MRa, BSL, SM, and RJW were responsible for implementation of the study and supervision at the study sites. MC, TND, KH, MRo, IS, and KAW did the immunological analysis. MO, RJW, SM, and HM raised the funding and wrote the protocol. All authors contributed to data analysis and contributed to the writing of the report.Declaration of interestsHM was previously a shareholder in the Oxford-Emergent Tuberculosis Consortium (OETC), a joint venture established for the development of MVA85A (OETC no longer exists). KH has a patent (US 5736524 A) related to the development of a DNA vaccine against Mycobacterium tuberculosis. RJW received grants from the European & Developing Countries Clinical Trials Partnership, the Wellcome Trust, the UK Medical Research Council, and the European Union during the conduct of the study, and personal fees from GlaxoSmithKline unrelated to this work. All other authors declare no competing interests.Figure 1Trial profileFigure 2Vaccine immunogenicity (both study sites combined)(A) Antigen 85A (Ag85A) interferon γ enzyme-linked immunospot analysis responses. Data are presented as spot-forming cells (SFC) per million peripheral blood mononuclear cells (PBMCs). p values were calculated with Wilcoxon matched-pair signed-rank tests. Box and whisker plots show median, IQR, and minimum and maximum values. (B) Whole blood intracellular cytokine staining assay of total cytokines. Data are presented as frequency of CD4 and CD8 T cells producing cytokines. Box and whisker plots show median, IQR, and minimum and maximum values. IFNγ=interferon γ. TNFα=tumour necrosis factor α. IL=interleukin. V1=vaccination 1. V2=vaccination 2.Figure 3Polyfunctional CD4 T cellsPlots show frequency of CD4 T cells producing combinations of the studied cytokines. Bars are median values and dots represent individual volunteers. IFNγ=interferon γ. TNFα=tumour necrosis factor α. IL=interleukin. V1=vaccination 1. V2=vaccination 2.Figure 4Cumulative incidence of diagnosis of tuberculosis endpoint 1 by treatment groupEndpoint 1 was defined as a positive finding from culture or GeneXpert MTB/RIF assay.Table 1Demographic and baseline characteristics (safety analysis population)Placebo (n=325)MVA85A (n=324)Median age, years (range)39·0 (22–41)38·0 (21–49)Women255 (78%)265 (82%)Ethnic originBlack304 (94%)302 (93%)Mixed21 (6%)22 (7%)QFT test resultPositive150 (46%)135 (42%)Negative173 (53%)188 (58%)Indeterminate2 (1%)1 (<1%)TST result>5 mm128 (39%)124 (38%)≤5 mm191 (59%)190 (59%)Missing data6 (2%)10 (3%)Latent tuberculosis infection178 (55%)164 (51%)5–6 months IPT before enrolment144 (44%)133 (41%)Receiving antiretroviral therapy256 (79%)257 (79%)CD4 count (cells per mm3)Participants not receiving antiretroviral therapy564 (169·8)571 (187·5)Participants receiving antiretroviral therapy599 (199·6)598 (220·7)HIV viral load (copies per mL)Participants not receiving antiretroviral therapy41\u2008371 (92\u2008456·9)62\u2008168 (166\u2008912·1)Participants receiving antiretroviral therapy29 (27·1)34 (63·7)Data are n (%) or mean (SD), unless otherwise stated. QFT=QuantiFERON-TB Gold In-Tube. TST=tuberculin skin test. IPT=isoniazid preventive therapy.Table 2Overview of adverse events (safety analysis population)OverallParticipants not receiving antiretroviral therapyParticipants receiving antiretroviral therapyPlacebo (n=325)MVA85A (n=324)Difference (MVA85A minus placebo) (95% CI)Placebo (n=69)MVA85A (n=67)Difference (MVA85A minus placebo) (95% CI)Placebo (n=256)MVA85A (n=257)Difference (MVA85A minus placebo) (95% CI)Any adverse event312 (96·0%; 93·3–97·7)321 (99·1%; 97·3–99·7)3·1 (0·7 to 5·4)67 (97·1%; 90·0–99·2)66 (98·5%; 92·0–99·7)1·4 (−3·5 to 6·3)245 (95·7%; 92·5–97·6)255 (99·2%; 97·2–99·8)3·5 (0·8 to 6·2)Solicited adverse event235 (72·3%; 67·2–76·9)288 (88·9%; 85·0–91·9)16·6 (10·6 to 22·5)50 (72·5%; 61·0–81·6)63 (94·0%; 85·6–97·7)21·6 (9·6 to 33·5)185 (72·3%; 66·5–77·4)225 (87·5%; 83·0–91·0)15·3 (8·5 to 22·1)Serious adverse event17 (5·2%; 3·9–8·2)17 (5·2%; 3·3–8·2)0·02 (−3·4 to 3·4)2 (2·9%; 0·8–10·0)9 (13·4%; 7·2–23·6)10·5 (1·5 to 19·6)15 (5·9%; 3·6–9·4)8 (3·1%; 1·6–6·0)−2·7 (−6·3 to 0·8)Related adverse event307 (94·5%; 91·4–96·5)318 (98·1%; 96·0–99·2)3·7 (0·8 to 6·6)66 (95·7%; 88·0–98·5)66 (98·5%; 92·0–99·7)2·9 (−2·8 to 8·5)241 (94·1%; 90·6–96·4)252 (98·1%; 95·5–99·1)3·9 (0·6 to 7·2)Severe adverse event84 (25·8%; 21·4–30·9)100 (30·9%; 26·1-36·1)5·0 (−1·9 to 11·9)15 (21·7%; 13·6–32·8)22 (32·8%; 22·8–44·8)11·1 (−3·8 to 26)69 (27·0%; 21·7–32·9)78 (30·4%; 25·1–36·2)3·4 (−4·4 to 11·2)Data are n (%; 95% CI), unless otherwise stated. Serious adverse events were coded with Medical Dictionary for Regulatory Activities version 14.0. Patients with multiple events in each category are counted only once in each category.Table 3Total intracellular cytokine response, presented as frequency of CD4 T cells and CD8 T cells producing specific cytokinesMVA85A (n=28)MVA85A timepoint comparisons (p values)Placebo (n=29)Day 0 (vaccination 1)Day 7 (vaccination 1)Day 0 (vaccination 2)Day 7 (vaccination 2)Day 0 (vaccination 1) vs day 7 (vaccination 1)Day 0 (vaccination 1) vs day 0 (vaccination 2)Day 0 (vaccination 1) vs day 7 (vaccination 2)Day 0 (vaccination 2) vs day 7 (vaccination 2)Day 0 (vaccination 1)Day 7 (vaccination 1)Day 0 (vaccination 2)Day 7 (vaccination 2)CD4 IFNγ0·01 (0–0·07)0·1 (0–1·12)0·03 (0–0·28)0·11 (0·02–0·82)<0·00010·0015<0·0001<0·00010·02 (0–0·12)0·01 (0–0·08)0 (0–0·08)0·01 (0–0·18)CD4 TNFα0·02 (0–0·12)0·11 (0–0·53)0·05 (0–0·57)0·11 (0–0·46)<0·00010·0403<0·0001<0·00010·02 (0–0·15)0·02 (0-0·14)0·02 (0–0·11)0·02 (0–0·23)CD4 IL-20·021 (0–0·11)0·07 (0–0·68)0·04 (0–0·27)0·1 (0·03–0·44)<0·00010·0421<0·0001<0·00010·02 (0–0·08)0·017 (0–0·08)0·02 (0–0·09)0·018 (0–0·06)CD4 IL-170·09 (0·01–0·28)0·12 (0·03–0·27)0·09 (0–0·37)0·1 (0·03–0·23)0·09460·54250·40470·28430·07 (0–0·27)0·06 (0·02–0·27)0·08 (0·01–0·26)0·078 (0–0·25)CD8 IFNγ0 (0–0·21)0·02 (0–0·94)0 (0–0·58)0·01 (0–0·3)0·01010·54990·22640·28970 (0–0·35)0 (0–0·19)0 (0–0·33)0 (0–0·24)CD8 TNFα0 (0–0·28)0 (0–0·24)0 (0–0·48)0 (0–0·05)0·45130·76150·73370·39530 (0–0·09)0 (0–0·38)0 (0–0·2)0 (0–0·13)Data are median (minimum to maximum) of total cytokines at each of the study timepoints, unless otherwise stated. Population is the immunology substudy (the first 70 participants), of which complete data were available for 57 participants. Statistical comparison of total cytokine responses in MVA85A study group used Wilcoxon matched-pairs signed-rank test. IL=interleukin. IFNγ=interferon γ. TNFα=tumour necrosis factor α.Table 4Primary and secondary efficacy results (per-protocol population)OverallParticipants not receiving antiretroviral therapyParticipants receiving antiretroviral therapyPlaceboMVA85AVaccine efficacy (95% CI)PlaceboMVA85AVaccine efficacy (95% CI)PlaceboMVA85AVaccine efficacy (95% CI)Disease endpoint 1 (primary efficacy endpoint)9/325 (2·8%)6/320 (1·9%)32·8%(−111·5 to 80·3)1/69 (1·4%)2/65 (3·1%)−114·1%(−12\u2008528·3 to 88·9)8/256 (3·1%)4/255 (1·6%)50·3%(−85·4 to 89·1)Disease endpoint 39/325 (2·8%)8/320 (2·5%)10·5%(−161·3 to 70·0)1/69 (1·4%)3/65 (4·6%)−224·7%(−16\u2008947·7 to 73·9)8/256 (3·1%)5/255 (2·0%)38·2%(−114·1 to 84·1)QFT positive conversion40/173 (23·1%)38/186 (20·4%)11·7%(−41·3 to 44·9)11/36 (30·6%)6/38 (15·8%)44·2%(−64·8 to 83·0)29/137 (21·2%)32/148 (21·6%)−0·1%(−71·5 to 41·4)Data are n/N (%), unless otherwise stated. Disease endpoint 1 was defined as culture or GeneXpert MTB/RIF positivity; disease endpoint 2 included endpoint 1 and a composite clinical endpoint; and disease endpoint 3 was commencement on anti-tubercular chemotherapy. No additional participants met endpoint 2 who did not already meet endpoint 1. QFT=QuantiFERON-TB Gold In-Tube.", 'title': 'Safety, immunogenicity, and efficacy of the candidate tuberculosis vaccine MVA85A in healthy adults infected with HIV-1: a randomised, placebo-controlled, phase 2 trial.', 'date': '2015-03-03'}, '23391465': {'article_id': '23391465', 'content': "LancetLancetLancet (London, England)0140-67361474-547XElsevier233914655424647S0140-6736(13)60177-410.1016/S0140-6736(13)60177-4ArticlesSafety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trialTamerisMichele DDrMBChBmichele.tameris@uct.ac.zaa**HatherillMarkFCPa*LandryBernard SMPHbScribaThomas JPhDaSnowdenMargaret AnnMPHbLockhartStephenDMcdSheaJacqueline EPhDcMcClainJ BruceMDbHusseyGregory DProfFFCHafHanekomWillem AProfFCPaMahomedHassanMMedag†McShaneHelenProfFRCPhelen.mcshane@ndm.ox.ac.uke†**the MVA85A 020 Trial Study TeamaSouth African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and School of Child and Adolescent Health, University of Cape Town, Cape Town, South AfricabAeras, Rockville, MD, USAcOxford-Emergent Tuberculosis Consortium, Wokingham, Berkshire, UKdEmergent Product Development UK, Wokingham, Berkshire, UKeJenner Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UKfVaccines for Africa, Institute of Infectious Disease and Molecular Medicine and Department of Medical Microbiology, University of Cape Town, Cape Town, South AfricagDepartment of Health, Western Cape and Division of Community Health, Stellenbosch University, Stellenbosch, South Africa*Correspondence to: Dr Michele D Tameris, South African Tuberculosis Vaccine Initiative (SATVI), Brewelskloof Hospital, Haarlem Street, Worcester 6850, South Africa michele.tameris@uct.ac.za**Prof Helen McShane, University of Oxford, Jenner Institute, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK helen.mcshane@ndm.ox.ac.uk*Contributed equally†Senior authors422013422013381987110211028© 2013 Published by Elsevier Ltd.2013Elsevier LtdSummaryBackgroundBCG vaccination provides incomplete protection against tuberculosis in infants. A new vaccine, modified Vaccinia Ankara virus expressing antigen 85A (MVA85A), was designed to enhance the protective efficacy of BCG. We aimed to assess safety, immunogenicity, and efficacy of MVA85A against tuberculosis and Mycobacterium tuberculosis infection in infants.MethodsIn our double-blind, randomised, placebo-controlled phase 2b trial, we enrolled healthy infants (aged 4–6 months) without HIV infection who had previously received BCG vaccination. We randomly allocated infants (1:1), according to an independently generated sequence with block sizes of four, to receive one intradermal dose of MVA85A or an equal volume of Candida skin test antigen as placebo at a clinical facility in a rural region near Cape Town, South Africa. We actively followed up infants every 3 months for up to 37 months. The primary study outcome was safety (incidence of adverse and serious adverse events) in all vaccinated participants, but we also assessed efficacy in a protocol-defined group of participants who received at least one dose of allocated vaccine. The primary efficacy endpoint was incident tuberculosis incorporating microbiological, radiological, and clinical criteria, and the secondary efficacy endpoint was M tuberculosis infection according to QuantiFERON TB Gold In-tube conversion (Cellestis, Australia). This trial was registered with the South African National Clinical Trials Register (DOH-27-0109-2654) and with ClinicalTrials.gov on July 31, 2009, number NCT00953927FindingsBetween July 15, 2009, and May 4, 2011, we enrolled 2797 infants (1399 allocated MVA85A and 1398 allocated placebo). Median follow-up in the per-protocol population was 24·6 months (IQR 19·2–28·1), and did not differ between groups. More infants who received MVA85A than controls had at least one local adverse event (1251 [89%] of 1399 MVA85A recipients and 628 [45%] of 1396 controls who received the allocated intervention) but the numbers of infants with systemic adverse events (1120 [80%] and 1059 [76%]) or serious adverse events (257 [18%] and 258 (18%) did not differ between groups. None of the 648 serious adverse events in these 515 infants was related to MVA85A. 32 (2%) of 1399 MVA85A recipients met the primary efficacy endpoint (tuberculosis incidence of 1·15 per 100 person-years [95% CI 0·79 to 1·62]; with conversion in 178 [13%] of 1398 infants [95% CI 11·0 to 14·6]) as did 39 (3%) of 1395 controls (1·39 per 100 person-years [1·00 to 1·91]; with conversion in 171 [12%] of 1394 infants [10·6 to 14·1]). Efficacy against tuberculosis was 17·3% (95% CI −31·9 to 48·2) and against M tuberculosis infection was −3·8% (–28·1 to 15·9).InterpretationMVA85A was well tolerated and induced modest cell-mediated immune responses. Reasons for the absence of MVA85A efficacy against tuberculosis or M tuberculosis infection in infants need exploration.FundingAeras, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium (OETC).IntroductionTuberculosis is a major global health problem, with an estimated 8·7 million cases and 1·4 million deaths in 2011.1 The Stop TB Partnership developed the Global Plan to Stop TB: 2006–2015, with a goal of tuberculosis elimination by 2050.2 One of the long-term strategies essential for control of the epidemic is effective vaccination. The existing BCG vaccine protects against disseminated tuberculosis in young children,3, 4 but protection against pulmonary tuberculosis is very variable.4, 5, 6 Efficacy against infection with Mycobacterium tuberculosis has only been reported in observational studies in low-burden settings.7 In endemic countries such as South Africa, the incidence of tuberculosis in infants and young children is very high despite high BCG coverage.8, 9 An improved infant tuberculosis vaccination regimen is urgently needed.12 candidate vaccines are being tested in clinical trials.10 MVA85A is a recombinant strain of modified Vaccinia Ankara virus expressing the immunodominant M tuberculosis protein, antigen 85A.11 MVA85A has been developed as a heterologous boost for BCG.11 Boosting BCG with MVA85A improved BCG-induced protection against mycobacterial challenge in animals.12, 13, 14, 15 MVA85A was well tolerated in clinical trials in infants.11, 16, 17 Furthermore, a BCG prime-MVA85A boost immunisation regimen in infants induced antigen-specific Th1 and Th17 cells,16 which are regarded as important in protection against tuberculosis.18, 19We aimed to further assess safety of MVA85A in HIV-negative infants who were previously vaccinated with BCG. As secondary endpoints, we also aimed to assess efficacy of MVA85A against tuberculosis and M tuberculosis infection beyond that of BCG alone, assess immunogenicity of MVA85A, and identify correlates of protection. To our knowledge, our investigation was the first infant efficacy trial of a new tuberculosis vaccine since BCG was last assessed in infants as part of the Chingleput-Madras trial that started in 1968.20MethodsStudy design and participantsWe undertook a parallel-group, randomised, placebo-controlled, double-blind phase 2b trial at the South African Tuberculosis Vaccine Initiative (SATVI) site in a rural region near Cape Town, South Africa. The region has a population of about 290\u2008000 people and an annual birth cohort of about 7000 babies. The overall incidence of tuberculosis in South Africa in 2011 was estimated to be almost 1% (993 per 100\u2008000 individuals).1 The incidence of tuberculosis in children younger than 2 years was about 3% at our trial site.21Parents of recently born infants were approached at local immunisation clinics or at home about study participation. We enrolled healthy infants, aged 4–6 months and who had received BCG (Danish 1331, Statens Serum Institut, Denmark) within 7 days of birth. Infants had to have received all age-appropriate routine immunisations, and two doses of pneumococcal conjugate vaccine at least 28 days before study vaccination (amended to 14 days during enrolment). All infants had to be HIV ELISA negative, QuantiFERON-TB Gold In-tube test (QFT; Cellestis, Australia) negative, and have had no substantial exposure to a patient with known tuberculosis. The appendix contains the study protocol.The trial was approved by the University of Cape Town Faculty of Health Sciences Human Research Ethics Committee, Oxford University Tropical Research Ethics Committee, and the Medicines Control Council of South Africa. Parents or legal guardians provided written, informed consent.Randomisation and maskingWe randomly allocated infants in a 1:1 ratio, with a block size of four, by use of an interactive voice/online response system to receive one intradermal dose of MVA85A (1×108 plaque-forming units in 0·06 mL) or an equal volume of Candida skin test antigen (Candin, AllerMed, USA) as placebo. Doses were prepared and labelled in masked syringes by an unmasked study pharmacist. An independent statistician prepared the randomisation schedule. The parents or legal guardians of study participants, study staff administering vaccinations or undertaking follow-up clinic assessments, and laboratory staff were masked to intervention group assignment.ProceduresThe study design included specific cohorts for specialised analyses, but all participants were followed up for assessment of efficacy and incidence of serious adverse events. Peripheral blood for routine haematological and biochemical tests was taken at screening and on day 7 and day 28 after vaccination in an initial safety cohort of at least 330 infants (study group 1). We assessed immunogenicity in three subsequent cohorts of up to 60 participants with an enzyme-linked immunosorbent spot analysis (study group 2), an intracellular cytokine staining (ICS) assay for peripheral blood mononuclear cell (PBMCs) counts (study group 3), and a whole blood ICS assay (study group 4). We enrolled remaining infants into a fifth cohort (study group 5). PBMCs obtained from all infants before and after vaccination were cryopreserved for future correlates analyses. We did QFT testing at screening, day 336, at the end of study visit, and for infants admitted to a dedicated study ward for investigation for tuberculosis.21We obtained data for incidence of solicited and unsolicited local (injection site) and systemic adverse events reported by parents or guardians on diary cards for 7 days after vaccination and by direct questioning by study staff for 28 days after vaccination. We also obtained data for serious adverse events throughout follow-up by active surveillance. Adverse events were assessed by the trial investigators and serious adverse events were assessed by the trial investigators and a local medical monitor, acting on behalf of the sponsor, to determine relation to vaccination. The trial investigators and local medical monitor were masked to intervention group throughout the trial. The safety monitoring committee (SMC) did not determine the association or severity of the adverse events. When the last infant in the safety cohort completed day 84, the SMC reviewed unmasked safety data to determine if a pattern of adverse events related to MVA85A or other safety concerns existed so as to advise on further enrolments. The SMC also conducted a second unmasked analysis-by-group safety and risk review after the 1000th infant completed their visit at study day 84.We actively followed up infants every 3 months to identify any signs, symptoms, or exposure that merited further investigation. Participants who had a persistent cough, failure to thrive, weight loss crossing a major centile band, QFT or tuberculin skin test conversion, household tuberculosis contact, or any other condition causing investigator concern were admitted to the study ward. Standardised investigations involved assessments with chest radiography, tuberculin skin test, QFT, HIV-ELISA, two consecutive early morning gastric lavage samples, and two induced sputa. Gastric lavage and sputum samples underwent auramine smear microscopy, GeneXpert MTB/RIF (Cepheid, USA; routinely from January, 2011, onwards), and MGIT (Becton Dickinson, Sparks, USA) liquid culture and sensitivity testing. Positive samples were speciated by PCR. We developed a hierarchy of three disease endpoint definitions. Endpoint 1 (panel 1) and endpoint 2 (appendix p 49) were based on the presence of specific clinical, radiological, and microbiological findings.22 Endpoint 2 (which included all infants who met endpoint 1 criteria) had marginally less stringent criteria to define tuberculosis infection and household exposure. Endpoint 3 included all participants placed on treatment for tuberculosis by a health professional. This approach allowed objective case classification without the need for an adjudication committee.The endpoint of infection with M tuberculosis was defined as conversion to a positive QFT test at any time during follow-up. We assessed rates of QFT conversion 1 year after vaccination and at end of study in those participants not previously started on anti-tuberculous treatment.We measured immunological sensitisation to M tuberculosis antigens, suggesting M tuberculosis infection, by QFT during screening, 1 year after vaccination, and at the close-out visit. We obtained blood samples from study groups 2–4 for immunogenicity analyses 7 days before vaccination and 7 days or 28 days after vaccination. We assessed immunogenicity with an ex-vivo interferon γ enzyme-linked immunosorbent spot assay, together with PBMC and whole blood ICS assays done as previously described.23 Further details of the methods are available in the appendix.Statistical analysesThe primary study outcome was safety in all vaccinated participants (safety population), including all solicited, unsolicited, and serious adverse events. We compared the proportion of participants with at least one such adverse event in the placebo and MVA85A groups with Fisher's exact test, and we calculated two-sided exact 95% CIs for proportions of individual events within treatment groups. We did immunogenicity analyses for all vaccinated participants enrolled in study groups 2–4. Statistical analyses were prespecified in a statistical analysis plan, signed off prior to study database lock and unmasking of data (appendix).The primary efficacy outcome was incidence of endpoint 1 and the secondary efficacy outcome was infection with M tuberculosis. Endpoints 2 and 3 were exploratory efficacy outcomes. All efficacy analyses were based on the per-protocol population, consisting of all randomly allocated participants who received at least one dose of study vaccine as randomised, and who had no major protocol deviations.The primary statistical method for analysis of endpoint 1 was vaccine efficacy, defined as 1 minus the estimated hazard ratio based on a Cox regression analysis of time to first diagnosis of endpoint 1. The Cox model contained one indicator variable for treatment group. To investigate the potential effect of variable follow-up times, we also did this analysis with a predefined cutoff of 2 years after vaccination. Analysis of endpoint 1 also included time (months) to initial tuberculosis diagnosis from day of vaccination in each treatment group with the Kaplan-Meier estimate of the survival function by treatment group, and the exact binomial method to estimate vaccine efficacy and its corresponding 95% CI (Clopper-Pearson with mid-p adjustment) conditional on the total number of events. We included participants with more than one diagnosis (eg, a diagnosis of tuberculosis endpoint 2 that was subsequently diagnosed as endpoint 1) in analyses separately for each diagnostic level. For the analysis of secondary and exploratory efficacy endpoints, no adjustment for multiplicity was done. We regarded a two-sided p value of less than 0·05 as significant. Summaries were presented for all cases reported during the study, and also, all cases with a diagnosis during the first 2 years of individual follow-up.For efficacy analyses, we based the sample size calculation on the primary efficacy endpoint of tuberculosis (endpoint 1). We assumed a cumulative tuberculosis incidence of 3% after a median of 18 months' follow-up in the placebo group,21 with an estimated 7·5% loss to follow-up.24 Thus, 1392 participants per intervention group would provide a 90% chance of detection of a 60% reduction between the intervention and control groups based on a two-sided log-rank test at a significance level of 0·05. We implemented a 6 month extension to the planned follow-up to achieve the target case accrual.For safety analyses, the sample size of 1392 participants receiving MVA85A would provide a greater than 75% chance of observing an adverse event that had an approximately one in 1000 actual rate of occurrence.The trial was registered with the South African National Clinical Trials Register on Nov, 4, 2008 (DOH-27-0109-2654), and with ClinicalTrials.gov on July 31, 2009, number NCT00953927.Role of the funding sourceAeras was the trial sponsor. Aeras and the Oxford-Emergent Tuberculosis Consortium (OETC) contributed to study design, data interpretation, and writing of the manuscript. MDT, MH, BSL, TJS, MAS, SL, HM, and HMcS had complete access to the data. HMcS had final responsibility for the decision to submit for publication.ResultsBetween July 15, 2009, and May 4, 2011, we obtained consent for 4754 infants. We enrolled 2797 infants who had completed screening when the enrolment target of 2784 was met (figure 1). Reasons for screening failure have been reported elsewhere.22 363 infants were entered into study group 1 (initial safety cohort; 182 in MVA85A group and 181 in the placebo group); 54 into group 2 (27 and 27), 54 into group 3 (27 and 27), and 39 into group 4 (19 and 20; immunogenicity groups); and 2287 in group 5 (1144 and 1143; correlates of protection). Follow-up was completed in October, 2012. The per-protocol population was 2794, excluding three participants from the intention-to-treat population (figure 1). The intention-to-treat analysis is not reported.Demographic and baseline clinical characteristics of the study participants were much the same between groups (table 1). In the per-protocol population, median follow-up for 1399 recipients of MVA85A was 24·6 months (range 0·2–37·3; IQR 19·2–27·8) and for 1395 controls was 24·6 months (0·3–37·3; 19·2–30·1). The number of participants discontinuing the study did not differ between the two treatment groups (figure 1). 126 infants (5%) were lost to follow-up, 11 died (<1%), and 62 (2%) had consent withdrawn.At least one local adverse event was reported in 628 (45%) of 1396 controls who received the allocated intervention and 1251 (89%) of 1399 recipients of MVA85A. At least one systemic adverse event was reported in 1059 (76%) controls and 1120 (80%) of recipients of MVA85A. At least one serious adverse event was reported in 258 (18%) controls and 257 (18%) recipients of MVA85A (appendix). No serious adverse events related to vaccine were reported in the MVA85A group, but one serious adverse event regarded as related to placebo occurred in the placebo group (short admission to hospital for fever 4 days after vaccination). 417 (64%) of 648 serious adverse events were acute lower-respiratory-tract infections or gastroenteritis (appendix). Seven (1%) infants died in the vaccine group (two from kwashiorkor, two from non-tuberculous meningitis, one from gastroenteritis, one from asphyxia due to drowning, and one from sudden death) and four (<1%) infants died in the placebo group (two from gastroenteritis, one from encephalitis, and one from a lower-respiratory-tract infection). During follow-up, 510 (37%) of 1395 recipients of placebo and 507 (36%) of 1399 recipients of MVA85A were admitted to the study ward for investigation.MVA85A induced an Ag85-specific T-cell response as measured by ex-vivo interferon γ enzyme-linked immunosorbent spot (median 136 spot-forming cells per million PBMCs, IQR 87–362; figure 2). Whole blood ICS showed that these cells were CD4-positive T cells predominantly expressing interferon γ, TNFα, and interleukin 2 (figure 2). We also detected CD4-positive interleukin 17-positive T cells (figure 2), some of which co-expressed Th1 cytokines (data not shown). These responses were not detected in recipients of placebo. No CD8-positive T-cell responses were detectable and no responses were detected with ICS completed on cryopreserved PBMCs (data not shown).Table 2 shows vaccine efficacy and numbers of infants who met endpoints 1, 2, or 3 by intervention group. For analysis with follow-up data truncated at 2 years after vaccination, vaccine efficacy was 23·9% (95% CI −27·9 to 54·7) for endpoint 1, −0·7% (–52·3 to 33·4) for endpoint 2, and −3·6% (–29·0 to 16·8) for endpoint 3. A post-hoc review of case distribution in the first year showed 16 recipients of placebo met endpoint 1 as did ten MVA85A recipients. Figure 3 shows the Kaplan-Meier survival analysis for endpoint 1.39 (3%) of 1395 infants assessed in the placebo group had incident tuberculosis (1·39 per 100 person-years [95% CI 1·00 to 1·91]) as did 32 (2%) of 1399 infants in the MVA85A group (1·15 per 100 person-years [0·79 to 1·62]). 171 (12% [95% CI 10·6 to 14·1]) infants assessed in the placebo group and 178 (13% [95% CI 11·0 to 14·6]) infants in the MVA85A group became infected with M tuberculosis as defined by QFT conversion during the course of the study. Vaccine efficacy against infection was −3·8% (95% CI −28·1 to 15·9). Efficacy was much the same when the comparison was restricted to QFT conversion at day 336 and end of study visit (data not shown).DiscussionWe report completion of a phase 2b safety and efficacy trial for infants with a new tuberculosis vaccine strategy (panel 2). In this trial, MVA85A was well tolerated and immunogenic in healthy infants who had previously been vaccinated with BCG, with a safety and immunogenicity profile consistent with that reported in other studies of infants.16, 17 However, we noted no significant efficacy against tuberculosis or M tuberculosis infection.This absence of efficacy was not consistent with findings from studies in animals, which suggested potential for efficacy,12, 13, 14, 15 and evidence of immunogenicity in previous clinical trials16, 17, 23 that measured immune responses regarded as important for protection.18, 19 Our results suggest that the CD4-positive T cells induced by MVA85A—at least at the modest frequencies noted in this trial—do not correlate with protection against tuberculosis or M tuberculosis infection. Frequencies of antigen-specific Th1 cells observed in infants with MVA85A were up to a tenth of the frequencies noted in adults.16, 25Our efficacy trial was undertaken in infants. However, this group is not responsible for most transmission of M tuberculosis. Thus, MVA85A could potentially protect adolescents or adults against pulmonary tuberculosis, in view of the fact that immunologically immature infants do not respond as well to this vaccine as adults do. MVA85A could also potentially have high efficacy in people of all ages against severe forms of tuberculosis, including pulmonary tuberculosis, without preventing infection or mild forms of disease. A high efficacy against severe disease could be masked in a trial that predominantly detects mild forms of tuberculosis. The sample size of a trial powered to detect only severe or disseminated disease would be prohibitively large. The safety and immunogenicity of MVA85A alone in infants exposed to HIV is currently being assessed.26 BCG-specific Th1 and Th17 responses were recently shown not to correlate with risk of tuberculosis in infants after BCG vaccination.27 Whether a substantially greater magnitude of response, a response that is qualitatively different, or a completely new immunological response would be necessary for protection is unclear. In our study, frequencies of BCG-primed Ag85A-specific T cells detected before MVA85A vaccination were very low or undetectable (figure 2). Conversely, adults and adolescents have significantly higher Ag85A-specific responses before vaccination,16 which might be an important factor in the stronger responses induced by MVA85A in older individuals. MVA85A was designed to boost BCG-primed responses, and the low frequencies of BCG-induced cells in infants might restrict the immunogenicity, and potentially the efficacy, of MVA85A in this age group. Ongoing assessment of study samples for potential correlates of risk might also yield important insights into why MVA85A did not confer protection in this trial and could add to the design and assessment of the next generation of tuberculosis vaccine candidates. Identification of immune correlates of protection would greatly aid vaccine design and assessment. However such correlates can only be identified in trials in which efficacy was shown. Identification and optimisation of animal models that accurately predict efficacy in human beings is also needed. Other efficacy trials of new HIV and malaria vaccines have reported early but waning efficacy.28, 29 In this trial, a post-hoc analysis of distribution of case accrual in the first year suggested a possible early effect on disease that merits further study of route of administration, regimen, and dosing strategies with MVA85A and other vaccines.Despite concerns about potential immunopathology induced by new tuberculosis vaccines,30 we noted no evidence for this effect. The high incidence of respiratory and gastrointestinal serious adverse events recorded in this trial reflects the known burden of childhood morbidity in this community.24 High numbers of unrelated serious adverse events should be expected in clinical trials in infant populations in developing countries. The high frequency of mild, self-limiting local reactions in MVA85A recipients is consistent with previous studies.16, 17 These local reactions were only partially controlled for by Candin, a placebo selected for its local reactogenicity profile. The overall safety profile supports modified Vaccinia Ankara virus as a suitable vector for infant vaccination strategies.The high incidence of disease noted in our study was comparable to the high rates noted in previous trials.21, 23 We noted no confirmed cases of disseminated tuberculosis (two cases of tuberculous meningitis met the definition for endpoint 2) and no deaths from tuberculosis, supporting our previous observation that disseminated and severe tuberculosis are uncommon in a setting of modern trials with active surveillance, effective isoniazid prophylaxis, and effective anti-tuberculous treatment.21 The high overall rate of M tuberculosis infection noted in this trial (349 [13%] of 2792) suggests a high level of exposure and transmission in this community. This infection burden suggests that M tuberculosis infection might be a suitable endpoint for future trials of new tuberculosis vaccines that aim to prevent infection and subsequent disease. Because BCG is regarded as less effective for prevention of infection than prevention of disease, our finding that MVA85A did not prevent infection is unsurprising and should be interpreted separately from the findings about efficacy against disease. We recognise that QFT has not been validated as a diagnostic test for M tuberculosis infection in infants and young children; however, a previous study31 done by our group showed good correlation between QFT and the tuberculin skin test.Our study showed that a large efficacy trial of a new tuberculosis vaccine in a high-burden setting is feasible with a stringent and objective case definition that incorporated the primary elements proposed in a recent consensus statement.32 We have also shown that standardised investigation for tuberculosis with multiple respiratory sampling, microbiological confirmation of disease, and masked expert panel review of digital radiograph images is feasible in a developing country setting where tuberculosis vaccine efficacy trials are likely to be done. We recognise that there is no gold standard definition of childhood tuberculosis,33 but we believe that the hierarchal endpoint definition used in this trial is robust and might be suitable for future tuberculosis vaccine trials.Cohort retention was very high in this trial, and no evidence was noted that the rate of loss to follow-up had a differential effect on case accrual. Similarly, exclusion of three enrolled infants in the per-protocol analysis did not affect the results.In conclusion, MVA85A was well tolerated, modestly immunogenic but unable to confer significant protection against tuberculosis or M tuberculosis infection. The information gained from the successful execution of this study will aid the planning of future trials and vaccination strategies. Substantial global efforts to develop an improved vaccine against tuberculosis must continue.References1WHOGlobal tuberculosis report 2012http://apps.who.int/iris/bitstream/10665/75938/1/9789241564502_eng.pdf(accessed Jan 2, 2013).2Stop TB PartnershipThe global plan to stop TB 2011–2015http://www.stoptb.org/global/plan/(accessed Jan 2, 2013).3TrunzBFinePDyeCEffect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectivenessLancet367200611731180166165604RodriguesLDiwanVWheelerJProtective effect of BCG against tuberculous meningitis and miliary tuberculosis: a meta-analysisInt J Epidemiol2219931154115881442995FinePVariation in protection by BCG: implications of and for heterologous immunityLancet34619951339134574757766ColditzGABerkeyCSMostellerFThe efficacy of bacillus Calmette-Guerin vaccination of newborns and infants in the prevention of tuberculosis: meta-analyses of the published literaturePediatrics961995293575967187Basu RoyRSotgiuGAltet-GomezNIdentifying predictors of interferon-gamma release assay results in pediatric latent tuberculosis: a protective role of bacillus Calmette-Guerin?: a pTB-NET collaborative studyAm J Respir Crit Care Med1862012378384227008628MahomedHKibelMHawkridgeTThe impact of a change in bacille Calmette-Guerin vaccine policy on tuberculosis incidence in children in Cape Town, South AfricaPediatr Infect Dis J25200611671172171331649MoyoSVerverSMahomedHAge-related tuberculosis incidence and severity in children under 5 years of age in Cape Town, South AfricaInt J Tuberc Lung Dis1420101491542007440410BrennanMJTholeJTuberculosis vaccines: a strategic blueprint for the next decadeTuberculosis (Edinb)92suppl 12012S6132244116011McShaneHPathanASanderCRecombinant modified vaccinia virus Ankara expressing antigen 85A boosts BCG-primed and naturally acquired antimycobacterial immunity in humansNat Med102004124012441550283912VordermeierHVillarreal-RamosBCocklePViral booster vaccines improve Mycobacterium bovis BCG-induced protection against bovine tuberculosisInfect Immun772009336433731948747613VerreckFVervenneRKondovaIMVA85A boosting of BCG and an attenuated, phoP deficient M tuberculosis vaccine both show protective efficacy against tuberculosis in rhesus macaquesPloS One42009e52641936733914GoonetillekeNMcShaneHHannanCAndersonRBrookesRHillAEnhanced immunogenicity and protective efficacy against Mycobacterium tuberculosis of bacille Calmette-Guerin vaccine using mucosal administration and boosting with a recombinant modified vaccinia virus AnkaraJ Immunol1712003160216091287425515WilliamsAGoonetillekeNPMcShaneHBoosting with poxviruses enhances Mycobacterium bovis BCG efficacy against tuberculosis in guinea pigsInfect Immun732005381438161590842016ScribaTJTamerisMMansoorNDose-finding study of the novel tuberculosis vaccine, MVA85A, in healthy BCG-vaccinated infantsJ Infect Dis2032011183218432160654217OtaMOdutolaAOwiafePImmunogenicity of the tuberculosis vaccine MVA85A is reduced by coadministration with EPI vaccines in a randomized controlled trial in Gambian infantsSci Transl Med3201188ra5618KaufmannSHFact and fiction in tuberculosis vaccine research: 10 years laterLancet Infect Dis1120116336402179846319HanekomWDockrellHOttenhoffTImmunological outcomes of new tuberculosis vaccine trials: WHO panel recommendationsPLoS Med52008e1451859755120BailyGVTuberculosis prevention trial, MadrasIndian J Med Res72suppl1980174700508621HawkridgeAHatherillMLittleFEfficacy of percutaneous versus intradermal BCG in the prevention of tuberculosis in South African infants: randomised trialBMJ33720081275128222Tameris M, McShane H, McClain J, et al. Lessons learnt from the first efficacy trial of a new infant tuberculosis vaccine since BCG. Tuberculosis (Edin) (in press).23ScribaTJTamerisMMansoorNModified vaccinia Ankara-expressing Ag85A, a novel tuberculosis vaccine, is safe in adolescents and children, and induces polyfunctional CD4+ T cellsEur J Immunol4020102792902001718823MoyoSVerverSHawkridgeATuberculosis case finding for vaccine trials in young children in high-incidence settings: a randomised trialInt J Tuberc Lung Dis1620121851912223691825MeyerJHarrisSSattiIComparing the safety and immunogenicity of a candidate TB vaccine MVA85A administered by intramuscular and intradermal deliveryVaccine312013102610332326634226HatherillMSafety and immunogenicity of MVA85A prime and bacille Calmette-Guérin boost vaccination (MVA(TB)029)http://www.clinicaltrials.gov/ct2/show/NCT1650389(accessed Jan 29, 2013).27KaginaBAbelBScribaTSpecific T cell frequency and cytokine expression profile do not correlate with protection against tuberculosis after bacillus Calmette-Guerin vaccination of newbornsAm J Resp Crit Care Med1822010107310792055862728Rerks-NgarmSPitisuttithumPNitayaphanSVaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in ThailandN Engl J Med3612009220922201984355729RtsSCTPAgnandjiSLellBA phase 3 trial of RTS,S/AS01 malaria vaccine in African infantsN Engl J Med3672012228422952313690930TaylorJTurnerOBasarabaRBelisleJHuygenKOrmeIPulmonary necrosis resulting from DNA vaccination against tuberculosisInfect Immun712003219221981265484131MoyoSIsaacsFGelderbloemSTuberculin skin test and QuantiFERON® assay in young children investigated for tuberculosis in South AfricaInt J Tuberc Lung Dis152011117611812194384132GrahamSAhmedTAmanullahFEvaluation of tuberculosis diagnostics in children: 1. Proposed clinical case definitions for classification of intrathoracic tuberculosis disease. Consensus from an expert panelJ Infect Dis205Suppl 22012S199S2082244802333HatherillMVerverSMahomedHConsensus statement on diagnostic end points for infant tuberculosis vaccine trialsClin Infect Dis54201249350122144538Supplementary MaterialSupplementary appendixAcknowledgmentsWe thank study participants and their families, the community of Cape Winelands East district, and South African Tuberculosis Vaccine Initiative (SATVI) personnel (Tony Hawkridge and Zainab Waggie [medical monitors]; Savvas Andronikou, Tracy Kilborn, and Nicky Wieselthaler [radiograph reviewers]; Andre Burger, Lizette Phillips, Danie Theron, Luise Lunnon [Cape Winelands Department of Health], staff of Cape Winelands East public health clinics and hospitals, Andrew Whitelaw and staff of National Health Laboratory Service, Groote Schuur Hospital, Cape Town; Jasur Ishmukhamedov, Sharon Sutton, Amy Lwin, Michael Raine, Christine Fattore, Wasima Rida, and E Martin Stals [Aeras]; and Andreas Diacon [Chair], James Balsley, Prakash Jeena, Neil Cameron, Alison Elliot, and Gil Price [safety monitoring committee]).ContributorsAll authors, on behalf of the MVA85A 020 Trial Study Team, contributed to study design, data analysis and interpretation, and writing and approval of the manuscript. MDT, MH, TJS, and HM contributed to the implementation of the study and supervision at the study site. MDT, GDH, and HM were the principal investigators. MAS designed and led the statistical analysis.The MVA85A 020 Trial Study TeamLinda Van Der Merwe, E Jane Hughes, Hennie Geldenhuys, Angelique K K Luabeya, Susan Rossouw, Erica Smit, Yolande Browne, Frances Ratangee, Cynthia Ontong, Marwou De Kock, Humphrey Mulenga, Ashley Veldsman, Stephanie Abrahim, Lilly Denation, Veronica Baartman, Amaryl Van Schalkwyk, Mariana Jacks, Colleen Krohn, Fazlin Kafaar, Marcia Steyn, Lebohang Makhete, Fatima Isaacs, Julia Noble, and Welile Sikhondze from the South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and School of Child and Adolescent Health, University of Cape Town, Cape Town, South Africa. Thomas Evans and Jerald Sadoff from Aeras, Rockville, MD, USA. Adrian V S Hill, Alison M Lawrie, Nathaniel J Brittain, and Samantha Vermaak from the Jenner Institute, Nuffield Department of Clinical Medicine, University of Oxford, UK.Conflicts of interestSL and JES are employees of Emergent BioSolutions and own shares and stock options in the company. HMcS is a shareholder in the Oxford-Emergent Tuberculosis Consortium (a joint venture between Emergent BioSolutions and the University of Oxford). All other authors declare that they have no conflicts of interest.Figure 1Trial profile*One infant developed gastroenteritis that precluded inclusion and one infant became ineligible after a randomisation error. QFT=QuantiFERON-TB Gold In-tube.Figure 2Vaccine immunogenicity(A) Frequencies of Ag85A-specific T cells measured by interferon-γ enzyme-linked immunosorbent spot assay in infants in study group 2 (27 infants in the MVA85A group and 27 infants in the placebo group) before administration of placebo or MVA85A (day 0) and 7 days after vaccination. (B) Frequencies of cytokine-expressing Ag85A-specific Th1 (CD4-positive T cells expressing IFN-γ, TNFα, or interleukin 2) and (C) frequencies of Ag85A-specific Th17 (CD4-positive T cells expressing interleukin 17) cells, measured by whole blood intracellular cytokine staining 28 days after administration of placebo or MVA85A to infants in study group four (17 infants in the MVA85A group and 19 infants in the placebo group). SFC=spot-forming cells. PBMC=peripheral blood mononuclear cell.Figure 3Cumulative incidence of diagnosis of tuberculosis endpoint 1Table 1Demographics and baseline characteristics of the per-protocol populationPlacebo (n=1395)MVA85A (n=1399)Overall (n=2794)Age, days145·7 (13·5)146·6 (14·3)146·2 (13·9)Sex, male714 (51%)708 (51%)1422 (51%)Ethnic groupBlack267 (19%)287 (21%)554 (20%)Mixed race1126 (81%)1107 (79%)2233 (80%)Asian1 (<1%)3 (<1%)4 (<1%)White1 (<1%)2 (<1%)3 (<1%)WeightInfants assessed1389 (>99%)1394 (>99%)2783 (>99%)Mean, kg6·47 (0·98)6·45 (0·99)6·46 (0·98)Full-term birth (≥38 weeks)983 (70%)1031 (74%)2014 (72%)Data are mean (SD) or n (%).Table 2Primary and secondary efficacy endpointsPlacebo (n=1395)MVA85A (n=1399)Vaccine efficacyEndpoint 1 (primary efficacy endpoint)39 (3%)32 (2%)17·3% (–31·9 to 48·2)Endpoint 2 (exploratory efficacy endpoint)52 (4%)55 (4%)–6·9% (–56·1 to 26·9)Endpoint 3 (exploratory efficacy endpoint)177 (13%)196 (14%)–12·1% (–37·4 to 8·5)Data are n (%) or % (95% CI). Participants with more than one diagnosis were analysed in each level of diagnosis attained. Vaccine efficacy and corresponding 95% CI was estimated with the Cox regression model (1 – estimated hazard ratio).Panel 1Definition of endpoint 1Any of the following criteria:•Isolation of Mycobacterium tuberculosis from any site•Identification of M tuberculosis by an approved molecular diagnostic technique from any site•Histopathology diagnostic for tuberculosis disease (eg, caseating granulomas)•Choroidal tubercle diagnosed by an ophthalmologist•Miliary pattern on chest radiograph in an HIV-negative infant•Clinical diagnosis of tuberculous meningitis (cerebrospinal fluid protein concentrations >0·6 g/L and pleocytosis of >50 cells per μL with >50% mononuclear cells) with features of basal meningeal enhancement and hydrocephalus on head CT•Vertebral spondylosis•One smear or histology specimen positive for auramine-positive bacilli from a normally sterile body site•One of each of the following:•Evidence of mycobacterial infection defined as two acid-fast positive smears (each from a separate collection) that were morphologically consistent with mycobacteria from either sputum or gastric aspirate that were not found to be non-tuberculous mycobacteria bacteria on culture; QuantiFERON-TB Gold In-tube test conversion from negative to positive; or tuberculin skin test ≥15 mmand•Radiographic findings compatible with tuberculosis defined as ≥1 of the following factors identified independently by at least two of three paediatric radiologists serving on a masked review panel: calcified Ghon focus, pulmonary cavity, hilar or mediastinal adenopathy, pleural effusion, or airspace opacificationand•Clinical manifestations compatible with tuberculosis defined as cough without improvement for >2 weeks; weight loss of >10% of bodyweight for >2 months; or failure to thrive, defined as crossing >1 complete major centile band (<97th–90th, <90th–75th, <75th–50th, <50th–25th, <25th–10th, and <10th–3rd weight-for-age centiles) downward for >2 monthsPanel 2Research in contextSystematic reviewTo our knowledge, our trial is the first efficacy study of a novel BCG booster tuberculosis vaccine in infants. A systematic review is not applicable.InterpretationThe safety of MVA85A reported in our large cohort is an important finding for tuberculosis vaccine development. However the absence of efficacy noted, despite studies in animals suggesting potential for efficacy and evidence of immunogenicity in previous clinical trials, was unexpected and suggests that the present parameters for selection of tuberculosis vaccine candidates might be inadequate. The relatively weak immunogenicity we noted in this study makes it difficult to conclude whether a higher magnitude response (ie, one that is qualitatively different or a completely new immunological mechanism) will be required for a protective vaccine. Lessons learnt from this trial, including trial design, execution, and vaccine selection, will be of enormous importance to the broader specialty of vaccine development.", 'title': 'In vivo detection of non-cavitated caries lesions on occlusal surfaces by visual inspection and quantitative light-induced fluorescence.', 'date': '2007-05-22'}, '29028973': {'article_id': '29028973', 'content': 'Clin Infect DisClin. Infect. DiscidClinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America1058-48381537-6591Oxford University PressUS29028973584909010.1093/cid/cix834cix834Articles and CommentariesSafety and Immunogenicity of Newborn MVA85A Vaccination and Selective, Delayed Bacille Calmette-Guerin for Infants of Human Immunodeficiency Virus-Infected Mothers: A Phase 2 Randomized, Controlled TrialNemesElisa1HesselingAnneke C2TamerisMichele1MauffKatya1DowningKatrina1MulengaHumphrey1RosePenelope2van der ZalmMarieke2MbabaSharon2Van AsDanelle1HanekomWillem A1WalzlGerhard3ScribaThomas J1McShaneHelen4HatherillMark1MVA029 Study Team\nAbrahamsCharmaineAbrahamsDeborahAfricaHadnBaartmanVeronicaBavumaBeautyBilekNicoleBotesNatasjaBrownYolandeCloeteYolundiDamonsMargarethDe VosRonelDlakavuPortiaDu PreezKarenErasmusMzwandileFrancisClaudiaGeldenhuysHendrikGeldenhuysMandyGoedemanKatrienaGolliathSandraMoutonAngelique HendricksHopleyChristiaanJansenRuwijdaJonesCarolynneKeyserAlanaKaginaBenjaminKhombaGloriaKola–CassiemFazlinKrugerSandraLeukesDaphneLouwLoyisoLuabeyaAngeliqueMaartTheresaMakhetheLebohangMbabweSimbarasheMtshambaEuniceMvinjelwaBoniswaNkantsuLungisaNobleJuliaNqwenisoSizweOppermanFajwaPetersenChristelPlaatjiePatiswaRossouwSusanSolomomsRoxanneSteynMarciaSwanepoelLiticiaToefyAsmavan DeventerHeidivan RooyenElmavan SterDaphneVazanaBongiweVeldsmanAshleyXoyanaNoncedo1South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease & Molecular Medicine and Division of Immunology, Department of Science & Technology/National Research Foundation, University of Cape Town2Desmond Tutu Tuberculosis Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences3DST/NRF Centre of Excellence for Biomedical Tuberculosis Research/Medical Research Council Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa4Jenner Institute, Oxford University, United KingdomE. N. and A. C. H. contributed equally to this manuscript.The members of the MVA029 Study Team are listed in the Appendix.Correspondence: M. Hatherill, South African Tuberculosis Vaccine Initiative, Room S2.01, Wernher and Beit Building, University of Cape Town Faculty of Health Sciences, Anzio Road, Observatory 7925, Cape Town, South Africa. (mark.hatherill@uct.ac.za).15220182610201726102017664554563056201723102017© The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America.2017This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.Newborn MVA85A prime vaccination was safe and induced an early immune response that did not interfere with immunogenicity of subsequent bacille Calmette-Guérin vaccination. New tuberculosis vaccine candidates should be tested using this strategy, which appears safe regardless of infant human immunodeficiency virus exposure.AbstractBackgroundVaccination of human immunodeficiency virus (HIV)-infected infants with bacille Calmette-Guérin (BCG) is contraindicated. HIV-exposed newborns need a new tuberculosis vaccination strategy that protects against tuberculosis early in life and avoids the potential risk of BCG disease until after HIV infection has been excluded.MethodsThis double-blind, randomized, controlled trial compared newborn MVA85A prime vaccination (1 × 108 PFU) vs Candin® control, followed by selective, deferred BCG vaccination at age 8 weeks for HIV-uninfected infants and 12 months follow-up for safety and immunogenicity.ResultsA total of 248 HIV-exposed infants were enrolled. More frequent mild–moderate reactogenicity events were seen after newborn MVA85A vaccination. However, no significant difference was observed in the rate of severe or serious adverse events, HIV acquisition (n = 1 per arm), or incident tuberculosis disease (n = 5 MVA85A; n = 3 control) compared to the control arm. MVA85A vaccination induced modest but significantly higher Ag85A-specific interferon gamma (IFNγ)+ CD4+ T cells compared to control at weeks 4 and 8 (P < .0001). BCG did not further boost this response in MVA85A vaccinees. The BCG-induced Ag85A-specific IFNγ+ CD4+ T-cell response at weeks 16 and 52 was of similar magnitude in the control arm compared to the MVA85A arm at all time points. Proliferative capacity, functional profiles, and memory phenotype of BCG-specific CD4 responses were similar across study arms.ConclusionsMVA85A prime vaccination of HIV-exposed newborns was safe and induced an early modest antigen-specific immune response that did not interfere with, or enhance, immunogenicity of subsequent BCG vaccination. New protein-subunit and viral-vectored tuberculosis vaccine candidates should be tested in HIV-exposed newborns.Clinical Trials RegistrationNCT01650389.HIV-exposed infantsMVA85ABCGvaccinationtuberculosisBacille Calmette-Guérin (BCG) vaccination of infants remains a key tool to protect young children against tuberculosis [1]. Given young children’s high risk of progression from Mycobacterium tuberculosis infection to disease and disseminated forms of tuberculosis, which is associated with severe morbidity and mortality, tuberculosis prevention strategies are of great importance in this population [2, 3]. Infant BCG vaccination offers partial protection against pulmonary, miliary, and meningitic tuberculosis in children [4, 5].In settings with high tuberculosis burden, all children born to human immunodeficiency virus (HIV)-infected mothers are at increased risk of tuberculosis, including those who remain HIV uninfected [6–8]. A safe and effective tuberculosis vaccine for infants with perinatal HIV exposure is needed urgently, since BCG vaccination of infants known to be HIV infected is contraindicated due to the risk of local, regional, and disseminated BCG disease as well as BCG immune reconstitution inflammatory syndrome following antiretroviral therapy (ART) initiation [9–13]. However, delay in BCG vaccination to allow exclusion of perinatal HIV acquisition would put infants at risk of acquiring tuberculosis in the first weeks of life, in the period before BCG could be administered without safety concerns. These competing risks and benefits have resulted in a pragmatic approach to continued BCG vaccination of HIV-exposed newborns whose HIV infection status is not yet known in settings where rates of childhood tuberculosis and maternal HIV infection are high [13, 14]. For example, approximately one fifth of South African women of reproductive age were HIV infected in 2017 [15]. Despite recent reductions in perinatal HIV transmission [16], the HIV infection rate at age 18 months is considerably higher than at 8 weeks due to high-risk mixed feeding practices [17]. There were an estimated 320 000 South African children living with HIV in 2016 [18]; 50% of deaths among children aged <5 years were associated with HIV infection [19]. Although early HIV polymerase chain reaction (PCR) testing is being introduced, this advance does not solve the BCG safety dilemma because routine BCG is usually given at birth. Also, since HIV-exposed infants in sub-Saharan Africa are often exclusively breast fed, HIV infection may be acquired subsequent to negative PCR testing at age 2 weeks.Given the high risk of both tuberculosis and BCG-associated adverse events (AEs) in HIV-infected infants, we hypothesized that delaying routine newborn BCG vaccination until HIV infection had been excluded, but preceded by a novel tuberculosis vaccine given at birth, would be safe and more immunogenic than delayed BCG vaccination alone for HIV-exposed infants [20]. We previously showed that delayed BCG vaccination of HIV-unexposed South African infants induces a long-lasting polyfunctional T-cell response, with higher frequencies and better quality of BCG-specific CD4 T cells at age 1 year compared to newborn BCG vaccination [21]. Conflicting studies have shown no significant immunological benefit of delayed BCG [22–24]. However, in utero exposure to maternal HIV and M. tuberculosis infection does not appear to alter long-term immune responses of HIV-uninfected infants to BCG vaccination when given at age 6 weeks [25, 26].New tuberculosis vaccine candidates in clinical development include recombinant and live-attenuated mycobacterial vaccines and viral-vectored or protein-subunit vaccines [27]. A nonreplicating vaccine with a track record of safety in infants and HIV-infected persons would be required to test this novel strategy. Although MVA85A did not confer additional protection when given as a boost vaccine after BCG prime in HIV-uninfected infants [28], MVA85A is an ideal candidate vaccine to test this experimental strategy since MVA85A was safe in this high-risk population [29–33].Here, we report on the safety and immunogenicity of MVA85A vaccination in newborns of HIV-infected mothers, followed by selective deferred BCG vaccination at 8 weeks for HIV-uninfected infants, in a double-blind, randomized, controlled trial.METHODSThe trial was conducted at 2 sites near Cape Town, South Africa. Mothers provided written antenatal and postnatal consent for infant participation. The protocol was approved by the ethics committees of the universities of Cape Town (013/2012), Stellenbosch (M12/03/020), and Oxford (02-12). Eligible infants (see Supplementary Materials) were randomized 1:1 to receive either MVA85A vaccine (1 × 108 PFU) or Candin® control within 96 hours of birth in blinded fashion (Figure 1A). BCG was administered (1–4 × 105 cfu) at age 8 weeks only to infants documented to be HIV-uninfected at age 6 weeks by negative HIV DNA PCR (Roche Diagnostic COBAS AmpliPrep COBAS Taqman HIV-1 Qual test version 2.0)[Figure 1A]. HIV DNA PCR testing prior to age 6 weeks was not routine at the time. All infants were followed for safety endpoints at weeks 1, 4, 6, and 8 after MVA85A/control vaccination and thereafter at weeks 9, 12, and 16 (corresponding to weeks 1, 4, and 8 following delayed BCG vaccination at 8 age weeks) and at week 52. All infants underwent safety monitoring for solicited and unsolicited local, regional, and systemic AEs. For immunogenicity analyses, blood was collected at weeks 4, 8, 16, and 52 (Figure 1A).Figure 1.Study design (A) and CONSORT diagram (B). Abbreviations: BCG, bacille Calmette-Guérin; CONSORT, Consolidated Standards of Reporting Trials; HIV, human immunodeficiency virus; PCR, polymerase chain reaction; TB, tuberculosis.QuantiFERON-TB Gold (QFT, Qiagen) was performed on mothers at enrollment of newborns and on infants at age 1 year. Infants who reported a new household tuberculosis contact or developed symptoms or signs of tuberculosis were investigated for tuberculosis as previously described [28]. HIV-uninfected infants with a household tuberculosis contact or positive QFT or tuberculin skin test were referred for isoniazid preventive therapy after exclusion of active tuberculosis. All infants diagnosed with tuberculosis started tuberculosis treatment for disease as per national guidelines.Whole Blood Functional AssaysVenous blood was collected in sodium heparin–containing tubes for short- (12 hours) and long-term (7 days) functional assays to measure antigen-specific T-cell responses and proliferative capacity, respectively. Whole blood was left unstimulated (negative control) or stimulated with Ag85A peptide pool, BCG, and phytohemagglutinin (positive control). Assays were conducted as previously described [34, 35] (see Supplementary Materials). Samples were stained with optimized panels of monoclonal antibodies (Supplementary Materials, Table S1) and analyzed using flow cytometry (Supplementary Materials, Figures S1 and S2).Statistical AnalysesIn the intention-to-treat (ITT) population for safety analysis, the number of AEs was compared between study arms for the periods prior to and following BCG vaccination and for the entire observation period. In each period, counts and percentages of AEs were determined per arm, per category of interest. Tests of proportions per category were used to compare the number of AEs between arms for each type of AE and categories. The Bonferroni correction was applied to account for multiple testing.Linear mixed-effect models were used to assess the impact of study arm and time and their interaction on the (logged) frequencies of cytokine-producing or cytokine-proliferating T cells. In cases where the distributional assumptions of the model were not met, nonparametric tests were used to assess differences between arms at each time point and changes over time between arms (Wilcoxon rank sum test) and changes over time within arms (Wilcoxon signed rank test).The ITT population for safety analysis included all infants who received either MVA85A or control. The modified ITT (mITT) population for immunology analysis included all infants who received either MVA85A or control and BCG vaccine and who were not HIV infected, including data from all available sampling time points.RESULTSParticipantsAfter screening 261 infants, 248 were randomized and included in the ITT safety analysis; 213 infants were analyzed per protocol (Figure 1B). MVA85A and BCG immunogenicity was assessed in 65 infants in the mITT population who received MVA85A (n = 32) or control (n = 33) at birth and BCG at age 8 weeks (n = 65). The median age of infants’ mothers was 28 years; 80% of mothers were receiving long-term ART with median CD4 cell count 424 cells/mm3; and 43% of mothers tested QFT positive. Median gestational age of infants was 40 weeks; 48% were male; median birth weight was 3.2 kg; and 61% were breastfed as the initial feeding choice. Baseline demographics by study arm are shown in Table 1.Table 1.Baseline DemographicsCharacteristicMVA85A (n = 123)Candin® Control (n = 125)Median birth weight, g (IQR)3220 (2970–3420)3170 (2880–3410)Median gestational age, weeks (IQR)39 (39–40)40 (39–40)Gender female, n (%)63 (51)64 (51)Breastfed, n (%)70 (57)75 (60)Median maternal age, years (IQR)29 (26–32)28 (25–33)Mother receiving antiretroviral therapy, n (%)98 (80)101 (81)Median maternal CD4 count, cells/mm3 (IQR)442 (306–607)400 (262–554.5)Maternal QuantiFERON-tuberculosis Gold + n (%)51 (42)55 (44)Abbreviation: IQR, interquartile range.SafetyAll AEs are shown in Table 2. At least 1 AE was experienced by 243 infants including 239 infants with injection site AEs. The majority of infants experienced mild or moderate AEs. Twenty-five infants experienced at least 1 severe AE, with no difference in rate between the MVA85A (n = 11) and control (n = 14) arms. No life-threatening AEs were observed. Fifty-eight infants had at least 1 serious AE (SAE; n = 26 MVA85A; n = 32 control), including 4 deaths (n = 3 MVA85A; n = 1 control), none of which were classified as related to the investigational product. SAE diagnoses reflected the pattern of respiratory and gastroenteritic illnesses typically observed in the study communities.Table 2.All Adverse Events in the Intention-to-Treat Population Throughout Follow-up VariableTotal, n (%)MVA85A, n (%)Candin® Control, n (%)\nP ValueParticipants with ≥1 adverse event243 (98)122 (99.2)121 (96.8)Category\u2003Injection site239 (96.4)121 (98.4)118 (94.4).094\u2003Lymphadenopathy13 (5.2)4 (3.3)9 (7.2).163\u2003Systemic210 (84.7)106 (86.2)104 (83.2).515\u2003Laboratory27 (10.9)14 (11.4)13 (10.4).804Body system\u2003Cardiovascular3 (1.2)1 (0.8)2 (1.6)\u2003Digestive74 (29.8)35 (28.5)39 (31.2)\u2003Endocrine15 (6)6 (4.9)9 (7.2)\u2003Hematologic/lymphatic21 (8.5)10 (8.1)11 (8.8)\u2003Metabolic/nutritional80 (32.3)42 (34.1)38 (30.4)\u2003Musculoskeletal1 (0.4)1 (0.8)0 (0)\u2003Neurological69 (27.8)34 (27.6)35 (28)\u2003Respiratory87 (35.1)42 (34.1)45 (36)\u2003Skin241 (97.2)121 (98.4)120 (96).259\u2003Urogenital5 (2)2 (1.6)3 (2.4)Severity\u2003Mild243 (98)122 (99.2)121 (96.8).181\u2003Moderate116 (46.8)62 (50.4)54 (43.2).255\u2003Severe25 (10.1)11 (8.9)14 (11.2).555\u2003Life-threatening0 (0) 0 (0) 0 (0)Vaccine relationship (MVA85A/control)\u2003Not related236 (95.2)116 (94.3)120 (96)\u2003Unlikely98 (39.5)50 (40.7)48 (38.4)\u2003Possible66 (26.6)41 (33.3)25 (20)\u2003Probable9 (3.6)7 (5.7)2 (1.6)\u2003Definite138 (55.6)105 (85.4)33 (26.4)Vaccine relationship (bacille Calmette-Guérin)\u2003Not related229 (92.3)122 (99.2)107 (85.6)\u2003Unlikely55 (22.2)28 (22.8)27 (21.6)\u2003Possible31 (12.5)14 (11.4)17 (13.6)\u2003Probable4 (1.6)2 (1.6)2 (1.6)\u2003Definite228 (91.9)110 (89.4)118 (94.4)Outcome\u2003Death4 (1.6)3 (2.4)1 (0.8)\u2003Ongoing219 (88.3)106 (86.2)113 (90.4)\u2003Recovered with sequelae24 (9.7)14 (11.4)10 (8)\u2003Recovered without sequelae238 (96)121 (99.4)117 (93.6)\u2003Unknown2 (0.8)1 (0.8)1 (0.8)Seriousness\u2003Serious58 (23.4)26 (21.1)32 (25.6)\u2003Not serious243 (98)122 (99.2)121 (96.8)Numerator is participants with at least 1 adverse event; denominator is participants in study/arm.In the 8-week period after newborn MVA85A/control injection and before BCG vaccination, infants in the MVA85A arm were more likely to experience an AE (n = 120) than those in the control arm (n = 84; Table 3). Injection site reactions in this period were more frequent in MVA85A recipients than in controls (n = 119 MVA85A vs n = 32 control; P < .0001); there were more AEs among MVA85A recipients that were mild in severity (n = 116 MVA85A vs n = 75 control; P < .0001). There was no difference in the rate of AEs, including injection site AEs, after BCG vaccination between study arms (Supplementary Materials, Table S2).Table 3.Adverse Events in the Intention-to-Treat Population Occurring in the Period After MVA85A/Candin® Control Injection and Before bacille Calmette-Guérin Vaccination VariableTotal, n (%)MVA85A, n (%)Candin® Control, |n (%)\nP ValueParticipants with ≥1 adverse event204 (82.3)120 (97.6)84 (67.2)Category\u2003Injection site151 (60.9)119 (96.7)32 (25.6)<.0001\u2003Lymphadenopathy11 (4.4)4 (3.3)7 (5.6).369\u2003Systemic148 (59.7)76 (61.8)72 (57.6).501\u2003Laboratory10 (4)7 (5.7)3 (2.4).188Body system\u2003Cardiovascular1 (0.4)0 (0)1 (0.8)\u2003Digestive37 (14.9)16 (13)21 (16.8)\u2003Endocrine3 (1.2)2 (1.6)1 (0.8)\u2003Hematologic/lymphatic14 (5.6)7 (5.7)7 (5.6)\u2003Metabolic/nutritional33 (13.3)18 (14.6)15 (12)\u2003Musculoskeletal0 (0)0 (0)0 (0)\u2003Neurological57 (23)28 (22.8)29 (23.2)\u2003Respiratory28 (11.3)14 (11.4)14 (11.2)\u2003Skin174 (70.2)119 (96.7)55 (44)<.0001\u2003Urogenital2 (0.8)1 (0.8)1 (0.8)Severity\u2003Mild191 (77)116 (94.3)75 (60)<.0001\u2003Moderate67 (27)43 (35)24 (19.2).005\u2003Severe10 (4)4 (3.3)6 (4.8).536\u2003Life-threatening0 (0)0 (0)0 (0)Relationship (MVA85A/control)\u2003Not related75 (30.2)37 (30.1)38 (30.4)\u2003Unlikely73 (29.4)37 (30.1)36 (28.8)\u2003Possible64 (25.8)40 (32.5)24 (19.2)\u2003Probable9 (3.6)7 (5.7)2 (1.6)\u2003Definite135 (54.4)105 (85.4)30 (24)Outcome\u2003Recovered without sequelae199 (80.2)81 (65.9)118 (94.4)\u2003Recovered with sequelae12 (4.8)6 (4.9)6 (4.8)\u2003Ongoing11 (4.4)8 (6.5)3 (2.4)\u2003Death1 (0.4)1 (0.8)0 (0)\u2003Unknown0 (0)0 (0)0 (0)Seriousness\u2003Serious24 (9.7)10 (8.1)14 (11.2)\u2003Not serious201 (81)120 (97.6)81 (64.8)Numerator is participants with at least 1 adverse event; denominator is participants in study/arm.HIV and M. tuberculosis Acquisition, Diagnosis of Tuberculosis DiseaseOne infant (<1%; control arm) was diagnosed as HIV PCR positive at age 6 weeks and, per protocol, did not receive BCG vaccination at week 8. One (breastfed) infant (<1%; MVA85A arm) was HIV PCR negative at age 6 weeks and received BCG vaccine but subsequently tested HIV PCR positive at age 1 year.Five infants tested QFT positive at age 1 year (n = 1 MVA85A arm; n = 4 control arm). Eight infants were found to have tuberculosis within the 1-year follow-up period (n = 5 MVA85A; n = 3 control), of whom 1 was M. tuberculosis culture positive and 7 were diagnosed on clinical/radiographic grounds and tuberculosis contact history. Two of the tuberculosis cases were QFT positive.Ag85A and BCG-Specific T-Cell ResponsesTo evaluate the immunogenicity of MVA85A and BCG, we measured frequencies of cytokine-producing T cells (expressing combinations of interferon gamma [IFNγ], tumor necrosis factor alpha [TNFɑ], interleukin [IL] 2, IL17, and/or IL22) and their differentiation (based on coexpression of CD45RA and CCR7) after 12-hour stimulation of whole blood with Ag85A or BCG, respectively.MVA85A induced higher frequencies of Ag85A-specific IFNγ+ CD4+ T cells 4 and 8 weeks post-vaccination compared to control (Figure 2A). BCG-induced Ag85A-specific CD4+ T cells in placebo recipients were of similar magnitude to those induced by MVA85A. BCG vaccination did not boost Ag85A-specific CD4+ T cells induced by MVA85A (Figure 2B).Figure 2.Ag85A-specific CD4 cytokine responses. Fresh whole blood was stimulated with Ag85A peptides for 12 hours prior to intracellular cytokine staining and flow cytometry analysis. A, Cross-sectional comparison of frequencies of Ag85A-specific CD4+ T cells expressing interferon gamma (IFNγ) in participants who were vaccinated with MVA85A (red) or control (black) at birth. Bacille Calmette-Guérin was administered to all participants at age 8 weeks. B, Longitudinal changes of Ag85A-specific CD4+ T cells expressing IFNγ are indicated by arrows (red for MVA85A arm and black for control arm). Medians and 95% confidence intervals (for the medians) are shown. C, Frequencies of Ag85A-specific CD4+ T cells expressing different combinations of IFNγ, tumor necrosis factor alpha, and interleukin 2 were compared between MVA85A arm (solid boxes) and control arm (clear boxes) at weeks 4 (blue), 8 (purple), 16 (green), and 52 (orange). Box and whiskers denote median, interquartile range, and minimum/maximum. Unadjusted P values were calculated by mixed effects models in A and B and by Mann-Whitney test in C. Abbreviations: BCG, bacille Calmette-Guérin; IFNγ, interferon gamma; IL, interleukin; TNFα, tumor necrosis factor alpha.MVA85A induced mainly IFNγ-expressing CD4+ T cells, many of which coexpressed IL2 and TNFɑ (Figure 2C). There was no detectable IL17 or IL22 production by Ag85A-specific CD4+ T cells before BCG vaccination (data not shown).BCG vaccination induced markedly increased and durable CD4+ T-cell responses in the MVA85A prime and control groups (Figure 3A). The cytokine coexpression profiles of BCG-specific CD4+ T cells were different during the effector (week 16) and memory (week 52) phases of the response and were not affected by MVA85A prime (Figure 3B). At week 52 most BCG-specific CD4+ T cells were monofunctional (Figure 3B, blue slice), and the predominant subset of these cells expressed IL22 alone (Figure 3B, purple arc).Figure 3.Bacille Calmette-Guérin (BCG)-specific CD4 cytokine responses. Fresh whole blood was stimulated with BCG for 12 hours prior to intracellular cytokine staining and flow cytometry analysis. A, Longitudinal changes of BCG-specific CD4+ T cells expressing any combination of interferon gamma (IFNγ), tumor necrosis factor alpha (TNFα), interleukin (IL) 2, IL17, and/or IL22 are indicated by arrows (red for MVA85A arm and black for control arm). Medians and 95% confidence intervals (CIs; for the medians) are shown. Unadjusted P values were calculated by mixed effects models. B, Cytokine coexpression patterns of BCG-specific CD4 responses at week 16 (left) and week 52 (right) in the MVA85A (top) and control (bottom) arms by permutation test. Pies represent total BCG-specific CD4+ T cells expressing any cytokine; slices show the relative proportion of cells coexpressing 1 (blue), 2 (green), 3 (yellow), or 4 (orange) cytokines, identified by the external arcs: IFNγ (red), IL2 (black), IL17 (orange), IL22 (purple), and TNFα (dark green). C, Differentiation profiles were defined based on expression patterns of CD45RA and CCR7 as follows: naive-like (TNL, CD45RA+ CCR7+), central memory (TCM, CD45RA- CCR7+), effector (TE, CD45RA- CCR7-), and terminal effector (TTE, CD45RA+ CCR7-). Representative flow cytometry plot of BCG-specific cytokine+ CD4+ T cells (pink) overlaid on total CD4+ T cells (black). D, Longitudinal changes of BCG-specific cytokine+ CD4+ T cells expressing TNL (maroon), TCM (blue), TE (orange), or TTE (green) phenotype in MVA85A (left) or control (right) recipients. Medians and 95% CIs (for the medians) are shown. The number of participants meeting cutoff criteria for this analysis (see methods) is shown for each visit. Frequencies of all subsets significantly increased (P < .025) upon BCG vaccination (week 8 vs week 16) and decreased (P < .025) between week 16 and 52, with the exception of TCM in the MVA85A arm. Unadjusted P values were calculated by Wilcoxon matched-pairs test; week 4 and 8 were not compared due to low numbers of paired samples (less than 10). No significant differences were observed when comparing frequencies of each subset at each visit between study arms. Abbreviations: BCG, bacille Calmette-Guérin; IFNγ, interferon gamma; IL, interleukin; TNFα, tumor necrosis factor alpha.We also measured memory phenotype of cytokine-expressing, BCG-specific CD4+ T cells (Figure 3C). Frequencies of naive-like (TNL), central memory (TCM), effector (TE), and terminal effector (TTE) BCG-specific CD4+ T cells were not different between study arms at any visit, although BCG administration induced all subsets significantly (week 8 vs 16; P < .025 for all subsets in both study arms). Central memory T cells were maintained at similar levels between week 16 and week 52 only in the MVA85A arm, while all other subsets decreased (P < .025).Ag85A- and BCG-specific CD8+ T cells were detected at low levels, predominantly expressed IFNγ or TNFα, and were not different between the study groups (Supplementary Materials, Figure S3A, S3B and data not shown).T-Cell Proliferative Responses to Ag85A and BCGT-cell proliferation is a sensitive measurement of vaccine immunogenicity. BCG-specific proliferative responses are typically not persistently affected by HIV exposure [26] or delayed BCG administration [23]. Long-term recall and effector potential of MVA85A and BCG-induced T-cell responses were assessed by measuring proliferative capacity (expression of cell cycle–associated marker Ki67) of antigen-specific T cells and their cytotoxic potential (upregulation of cytotoxic mediators granzyme A, granzyme B, granzyme K, granulysin, and perforin) upon 7-day stimulation of whole blood with Ag85A or BCG, respectively.MVA85A and BCG induced similar low CD4 proliferative responses to Ag85, which was lost by age 1 year (Figure 4A). BCG administration did not further boost proliferative responses primed by MVA85A.Figure 4.CD4+ T cell proliferation in response to Ag85A and bacille Calmette-Guérin (BCG). Fresh whole blood was stimulated with Ag85A peptides or BCG for 7 days prior to intracellular staining of Ki67 and cytotoxic markers and flow cytometric analysis. Frequencies of Ag85A-specific (A) and BCG-specific (B) CD4+ T cells expressing the proliferation marker Ki67 were analyzed longitudinally in MVA85A (red lines and arrows) and control (black lines and arrows) arms. Medians and 95% confidence intervals (for the medians) are shown. Unadjusted P values were calculated by mixed effects models. C, Cytotoxic mediator coexpression patterns of BCG-specific CD4 responses were compared across study weeks in MVA85A arm (top) and control arm (bottom) by permutation test. No significant differences between study arms were observed at any visit. Pies represent total BCG-specific CD4+ T cells expressing Ki67, and slices represent the relative proportion of cells coexpressing cytotoxic markers identified by the external arcs: granzyme A (blue), granzyme B (red), granulysin (green), granzyme K (orange), and perforin (purple). Black slices denote the proportion of proliferating cells that do not express any cytotoxic marker. The number of participants meeting cutoff criteria for this analysis (see methods) is shown within each pie. Abbreviations: BCG, bacille Calmette-Guérin.BCG vaccination induced a strong CD4 proliferative response to BCG, which did not differ by study arm and was not sustained above prevaccination levels by age 1 year (Figure 4B).During the effector phase of BCG-induced responses (week 16), the majority of proliferating CD4+ T cells upregulated expression of cytotoxic mediators (Figure 4C), mostly granzyme A (blue arc), granzyme B (red arc), and granulysin (green arc). Proportions of proliferating CD4+ T cells expressing cytotoxic mediators had decreased by week 52 but still comprised approximately one third of BCG-specific CD4+ T cells (Figure 4C). No differences in the cytotoxic potential were observed between study arms at any time point (Figure 4C).DISCUSSIONNewborn administration of a viral-vectored prime vaccine (MVA85A), followed by BCG vaccine boost at age 8 weeks, had an acceptable safety and reactogenicity profile; induced modest, antigen-specific responses before BCG administration; and did not interfere with or enhance subsequent BCG immunogenicity. These findings demonstrate proof of principle that a novel tuberculosis vaccination strategy based on a newborn priming vaccine other than BCG, including candidates that are potentially more immunogenic than MVA85A, can be administered safely to HIV-exposed newborns. Such a strategy would avoid the risks associated with administration of live BCG vaccine to infants with undiagnosed perinatal HIV infection. We infer from these findings that a new efficacious subunit or viral-vectored tuberculosis vaccine might also be given safely to newborns to provide protection against tuberculosis disease in the early weeks of life.It is notable that the rate of HIV acquisition (<1%) was low compared to historical perinatal HIV transmission rates in South Africa (2.7% in 2012 [17]). This is due in part to systemic improvements in the perinatal HIV prevention (prevention of mother-to-child transmission [PMTCT]) and because maternal ART or perinatal prophylaxis was a requirement for infant enrollment. Therefore, this alternative tuberculosis vaccination strategy would be expected to have even greater impact on BCG vaccine safety in countries where PMTCT programs are weaker and perinatal HIV transmission rates are higher.It is also striking that the rate of QFT conversion in HIV-exposed infants at age 1 year (2.5%) was lower than that reported for HIV-unexposed infants in these communities (6%–7%) [28, 36]. While the overall incidence of tuberculosis (3.3%) was similar to what has been described in previous reports [28], clinical diagnoses are likely to have resulted in overestimation of the true disease rate. It is likely that the exclusion criterion for household tuberculosis contact reduced the risk for tuberculosis transmission and disease in study infants, as evidenced by the maternal QFT positive rate (43%), which is considerably lower than that observed in HIV-uninfected young adults in the same community [36].We and others have shown that deferring BCG administration from birth to age 6–18 weeks does not impair long-term BCG immunogenicity [21–24]. Here, we evaluated the effects of administering a newborn prime tuberculosis vaccine on the immunogenicity of deferred BCG vaccination. MVA85A was weakly immunogenic, inducing mainly IFNγ+ Ag85A-specific cells before BCG administration. In BCG-vaccinated infants, higher abundance of cells releasing IFNγ upon BCG stimulation was associated with lower risk of progression to tuberculosis disease [37]. Whether the low IFNγ+ T-cell responses induced by MVA85A could be sufficient to protect against tuberculosis before BCG administration is unknown. Our findings differ from those in previous observations in HIV-exposed and HIV-unexposed infants [38, 39] in which MVA.HIVA was poorly immunogenic, due possibly to differences in study design, lower dose of MVA.HIVA, age at administration, and the assay used to measure immunogenicity. Nevertheless, these trials showed no interference by MVA administration with immunogenicity of routine childhood vaccines, further supporting the clinical development of this strategy.Remarkably, BCG did not further boost MVA85A-primed Ag85A-specific T-cell responses. These findings differ from observations made using the converse vaccination strategy, in which MVA85A significantly enhanced Ag85A-specific CD4 T-cell responses primed by BCG [28]. These observations suggest that either MVA85A is more immunogenic when used as a boost vaccine after BCG priming or, alternatively, that BCG cannot further boost Ag85A-specific T-cell responses that have been maximally primed by MVA85A. Regardless, BCG vaccination induced similar magnitudes of Ag85A-specific T-cell responses in the control and MVA85A groups. We deduce that for a given antigen, MVA is as good a vector as BCG, but that the immune response to Ag85A in this newborn population is weak. Importantly, MVA85A prime did not interfere with BCG immunogenicity with respect to the magnitude, functional quality, memory phenotype, and proliferative capacity of antigen-specific CD4+ T cells.T-cell proliferation was measured to assess relevant immune functions other than cytokine production, such as long-term recall responses and cytotoxic potential, with a more sensitive assay. Unlike cytokine production, T-cell proliferative responses to Ag85A and BCG were not sustained at age 1 year. Similarly, we previously reported that IFNγ release measured upon a 7-day whole blood stimulation with BCG was mostly undetectable by age 1 year, irrespective of age at BCG administration (birth vs 14 weeks) and HIV exposure [40]. While the underlying reasons for the loss of proliferative potential remain to be determined, it is clear that measuring T-cell functions other than IFNγ production is important to assess immunogenicity of novel vaccination strategies.Interpretation of our findings is limited by the lack of HIV-unexposed and BCG-naive control groups, both of which would not be ethically permissible in a highly tuberculosis-endemic setting. Further, the study sample size was selected to assess safety and immunogenicity and was not powered to test efficacy against M. tuberculosis infection or tuberculosis disease. Finally, although MVA85A has an excellent safety track record that is ideal for an experimental medicine study, further studies are needed to test this principle for potentially more efficacious tuberculosis vaccine candidates.In conclusion, the acceptable safety and reactogenicity profile, modest immunogenicity, and lack of interference with immunogenicity of BCG support further testing of alternative newborn prime vaccines, including other vector-based and protein-adjuvant candidates with additional antigens to enhance immunogenicity. This novel strategy should be pursued in order to provide protective immunity against M. tuberculosis in the first months of life, while being safe for all HIV-exposed infants.Supplementary DataSupplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.Supplementary MaterialSupplementary Figure 1Click here for additional data file.Supplementary Figure 2Click here for additional data file.Supplementary Figure 3Click here for additional data file.Supplementary Table 1Click here for additional data file.Supplementary Table 2Click here for additional data file.Supplementary InformationClick here for additional data file.Notes\nAcknowledgments. We thank study participants, their families, and the communities of Cape Winelands East district and Khayelitsha; personnel at the South African Tuberculosis Vaccine Initiative and the Desmond Tutu TB Center; and the study Safety Monitor (Zaynab Waggie) and Data Safety Monitoring Committee (Prakash Jeena, Brian Eley, Lewellys Barker, and Margaret Snowden).\nFinancial support. This work was supported by the UK Medical Research Council, Department for International Development, and Wellcome Trust Joint Global Health Trials programme (grant G1100570/1) and by AERAS. H. Mc. S. is a Wellcome senior clinical research fellow.\nPotential conflicts of interest. The authors declare no conflict of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. 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BMJ Open2011; 1:e000223.31.\nScribaTJ, TamerisM, SmitE\nA phase IIa trial of the new tuberculosis vaccine, MVA85A, in HIV- and/or Mycobacterium tuberculosis-infected adults. Am J Respir Crit Care Med2012; 185:769–78.2228183132.\nNdiayeBP, ThienemannF, OtaM; MVA85A 030 Trial Investigators\nSafety, immunogenicity, and efficacy of the candidate tuberculosis vaccine MVA85A in healthy adults infected with HIV-1: a randomised, placebo-controlled, phase 2 trial. Lancet Respir Med2015; 3:190–200.2572608833.\nDieyeTN, NdiayeBP, DiengAB\nTwo doses of candidate TB vaccine MVA85A in antiretroviral therapy (ART) naïve subjects gives comparable immunogenicity to one dose in ART+ subjects. PLoS One2013; 8:e67177.2384061834.\nKaginaBM, MansoorN, KpameganEP\nQualification of a whole blood intracellular cytokine staining assay to measure mycobacteria-specific CD4 and CD8 T cell immunity by flow cytometry. J Immunol Methods2015; 417:22–33.2552392335.\nSoaresA, GovenderL, HughesJ\nNovel application of Ki67 to quantify antigen-specific in vitro lymphoproliferation. J Immunol Methods2010; 362:43–50.2080006636.\nMahomedH, HughesEJ, HawkridgeT\nComparison of mantoux skin test with three generations of a whole blood IFN-gamma assay for tuberculosis infection. Int J Tuberc Lung Dis2006; 10:310–6.1656271237.\nFletcherHA, SnowdenMA, LandryB\nT-cell activation is an immune correlate of risk in BCG vaccinated infants. Nat Commun2016; 7:11290.2706870838.\nNjugunaIN, AmblerG, ReillyM\nPedVacc 002: a phase I/II randomized clinical trial of MVA.HIVA vaccine administered to infants born to human immunodeficiency virus type 1-positive mothers in Nairobi. Vaccine2014; 32:5801–8.2517348439.\nAfolabiMO, NdureJ, DrammehA\nA phase I randomized clinical trial of candidate human immunodeficiency virus type 1 vaccine MVA.HIVA administered to Gambian infants. PLoS One2013; 8:e78289.2420518540.\nHesselingAC, JaspanHB, BlackGF, NeneN, WalzlG\nImmunogenicity of BCG in HIV-exposed and non-exposed infants following routine birth or delayed vaccination. Int J Tuberc Lung Dis2015; 19:454–62.25860002Appendix\nMVA029 Study Team. Charmaine Abrahams, Deborah Abrahams, Hadn Africa, Veronica Baartman, Beauty Bavuma, Nicole Bilek, Natasja Botes, Yolande Brown, Yolundi Cloete, Margareth Damons, Ronel De Vos, Portia Dlakavu, Karen Du Preez, Mzwandile Erasmus, Claudia Francis, Hendrik Geldenhuys, Mandy Geldenhuys, Katriena Goedeman, Sandra Golliath, Angelique Hendricks Mouton, Christiaan Hopley, Ruwijda Jansen, Carolynne Jones, Alana Keyser, Benjamin Kagina, Gloria Khomba, Fazlin Kola–Cassiem, Sandra Kruger, Daphne Leukes, Loyiso Louw, Angelique Luabeya, Theresa Maart, Lebohang Makhethe, Simbarashe Mbabwe, Eunice Mtshamba, Boniswa Mvinjelwa, Lungisa Nkantsu, Julia Noble, Sizwe Nqweniso, Fajwa Opperman, Christel Petersen, Patiswa Plaatjie, Susan Rossouw, Roxanne Solomoms, Marcia Steyn, Liticia Swanepoel, Asma Toefy, Heidi van Deventer, Elma van Rooyen, Daphne van Ster, Bongiwe Vazana, Ashley Veldsman, Noncedo Xoyana.', 'title': 'Safety and Immunogenicity of Newborn MVA85A Vaccination and Selective, Delayed Bacille Calmette-Guerin for Infants of Human Immunodeficiency Virus-Infected Mothers: A Phase 2 Randomized, Controlled Trial.', 'date': '2017-10-14'}}
| 0.666667
|
Public Health, Epidemiology & Health Systems
|
70
|
Is the risk of starting on tuberculosis treatment higher, lower, or the same when comparing MVA85A added to BCG to BCG alone?
|
no difference
|
moderate
|
yes
|
['25726088', '23391465', '29028973']
| 31,038,197
| 2,019
|
{'25726088': {'article_id': '25726088', 'content': "Lancet Respir MedLancet Respir MedThe Lancet. Respiratory Medicine2213-26002213-2619Elsevier257260884648060S2213-2600(15)00037-510.1016/S2213-2600(15)00037-5ArticlesSafety, immunogenicity, and efficacy of the candidate tuberculosis vaccine MVA85A in healthy adults infected with HIV-1: a randomised, placebo-controlled, phase 2 trialNdiayeBirahim PierreMDa*ThienemannFriedrichMDbd*OtaMartinFWACPeLandryBernard SMPHfCamaraMakhtarPhDaDièyeSiryMDaDieyeTandakha NdiayePhDaEsmailHanifMRCPbjGoliathReneBScbHuygenKrisPhDgJanuaryVanessabNdiayeIbrahimaMDaOniToluMDbcRaineMichaelBScfRomanoMartaPhDgSattiImanPhDiSuttonSharonBSfThiamAminataMDhWilkinsonKatalin APhDbdkMboupSouleymaneProfPhDaWilkinsonRobert JProfFRCPbdjk†McShaneHelenProfFRCPhelen.mcshane@ndm.ox.ac.uki*†for the MVA85A 030 trial investigators‡aLaboratoire de Bactériologie–Virologie, Centre Hospitalier Universitaire Le Dantec, Dakar, SenegalbClinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South AfricacDivision of Public Health Medicine, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South AfricadDepartment of Medicine, University of Cape Town, Cape Town, South AfricaeMedical Research Council Unit, Fajara, The GambiafAeras, Rockville, MD, USAgImmunology Service, Scientific Institute of Public Health (WIV-ISP), Brussels, BelgiumhCentre de Traitement Ambulatoire, Centre Hospitalier Universitaire de Fann, Dakar, SenegaliJenner Institute, University of Oxford, Oxford, UKjDepartment of Medicine, Imperial College London, London, UKkMRC National Institute for Medical Research, London, UK*Correspondence to: Prof Helen McShane, Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK helen.mcshane@ndm.ox.ac.uk*Joint first authors†Joint last authors‡Listed in appendix1320153201533190200© 2015 Ndiaye et al. Open Access article distributed under the terms of CC BY2015This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).SummaryBackgroundHIV-1 infection is associated with increased risk of tuberculosis and a safe and effective vaccine would assist control measures. We assessed the safety, immunogenicity, and efficacy of a candidate tuberculosis vaccine, modified vaccinia virus Ankara expressing antigen 85A (MVA85A), in adults infected with HIV-1.MethodsWe did a randomised, double-blind, placebo-controlled, phase 2 trial of MVA85A in adults infected with HIV-1, at two clinical sites, in Cape Town, South Africa and Dakar, Senegal. Eligible participants were aged 18–50 years, had no evidence of active tuberculosis, and had baseline CD4 counts greater than 350 cells per μL if they had never received antiretroviral therapy or greater than 300 cells per μL (and with undetectable viral load before randomisation) if they were receiving antiretroviral therapy; participants with latent tuberculosis infection were eligible if they had completed at least 5 months of isoniazid preventive therapy, unless they had completed treatment for tuberculosis disease within 3 years before randomisation. Participants were randomly assigned (1:1) in blocks of four by randomly generated sequence to receive two intradermal injections of either MVA85A or placebo. Randomisation was stratified by antiretroviral therapy status and study site. Participants, nurses, investigators, and laboratory staff were masked to group allocation. The second (booster) injection of MVA85A or placebo was given 6–12 months after the first vaccination. The primary study outcome was safety in all vaccinated participants (the safety analysis population). Safety was assessed throughout the trial as defined in the protocol. Secondary outcomes were immunogenicity and vaccine efficacy against Mycobacterium tuberculosis infection and disease, assessed in the per-protocol population. Immunogenicity was assessed in a subset of participants at day 7 and day 28 after the first and second vaccination, and M tuberculosis infection and disease were assessed at the end of the study. The trial is registered with ClinicalTrials.gov, number NCT01151189.FindingsBetween Aug 4, 2011, and April 24, 2013, 650 participants were enrolled and randomly assigned; 649 were included in the safety analysis (324 in the MVA85A group and 325 in the placebo group) and 645 in the per-protocol analysis (320 and 325). 513 (71%) participants had CD4 counts greater than 300 cells per μL and were receiving antiretroviral therapy; 136 (21%) had CD4 counts above 350 cells per μL and had never received antiretroviral therapy. 277 (43%) had received isoniazid prophylaxis before enrolment. Solicited adverse events were more frequent in participants who received MVA85A (288 [89%]) than in those given placebo (235 [72%]). 34 serious adverse events were reported, 17 (5%) in each group. MVA85A induced a significant increase in antigen 85A-specific T-cell response, which peaked 7 days after both vaccinations and was primarily monofunctional. The number of participants with negative QuantiFERON-TB Gold In-Tube findings at baseline who converted to positive by the end of the study was 38 (20%) of 186 in the MVA85A group and 40 (23%) of 173 in the placebo group, for a vaccine efficacy of 11·7% (95% CI −41·3 to 44·9). In the per-protocol population, six (2%) cases of tuberculosis disease occurred in the MVA85A group and nine (3%) occurred in the placebo group, for a vaccine efficacy of 32·8% (95% CI −111·5 to 80·3).InterpretationMVA85A was well tolerated and immunogenic in adults infected with HIV-1. However, we detected no efficacy against M tuberculosis infection or disease, although the study was underpowered to detect an effect against disease. Potential reasons for the absence of detectable efficacy in this trial include insufficient induction of a vaccine-induced immune response or the wrong type of vaccine-induced immune response, or both.FundingEuropean & Developing Countries Clinical Trials Partnership (IP.2007.32080.002), Aeras, Bill & Melinda Gates Foundation, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium.Research in contextEvidence before this studyOne previous study assessed the efficacy of several doses of the saprophyte Mycobacterium vaccae against tuberculosis disease in adults infected with HIV-1, and showed a decreased risk of protocol-defined pulmonary tuberculosis. A previous study with the MVA85A, the candidate vaccine under assessment here, has showed that boosting with MVA85A did not enhance protective efficacy in BCG-vaccinated infants. Adults infected with HIV-1 are an important target population for a new tuberculosis vaccine, and in earlier studies, vaccine-induced immunogenicity in adults infected with HIV-1 was higher than in infants.Added value of this studyThis is the first time that a candidate tuberculosis vaccine has been assessed for efficacy against Mycobacterium tuberculosis infection in people infected with HIV-1. The results show that vaccinating adults infected with HIV-1 with MVA85A is safe, but does not confer protection against infection with M tuberculosis.Implications of all the available evidenceThe safety of MVA85A in this large study population of adults with HIV infection is an important finding for tuberculosis vaccine development. The vector is safe to give to people without HIV testing; these safety data provide some generic reassurance that new candidate tuberculosis vaccines are safe in this higher risk population. Additionally, this study has shown that high-quality, multicentre tuberculosis vaccine trials in vulnerable populations are possible. The absence of efficacy despite immunogenicity in this and previous clinical trials of MVA85A suggests that the current parameters for selection of tuberculosis vaccine candidates are inadequate. Standardised preclinical animal models that better represent human infection and disease, and a greater understanding of immune mechanisms of protection in human tuberculosis are both urgently needed. Alternative approaches to vaccine development, including the delivery of candidate vaccines direct to the respiratory mucosa, merit assessment. Other lessons learnt from this trial include the characterisation of the epidemiology of M tuberculosis infection and disease associated with HIV-1 infection in a setting of antiretroviral therapy and isoniazid chemoprophylaxis.IntroductionTuberculosis is a substantial global cause of mortality and morbidity, with 9 million new cases of active tuberculosis and 1·5 million deaths occurring in 2013.1 One third of the world's population is infected with Mycobacterium tuberculosis.1 HIV-1 co-infection is one of the most important risk factors for both infection with M tuberculosis and active tuberculosis disease,2 with an estimated 1·1 million of all new tuberculosis cases in 2013 occurring in people co-infected with HIV-1.1 The WHO African region accounts for 80% of HIV-1-associated tuberculosis.1 Additionally, the growing incidence of drug-resistant tuberculosis is associated with poor treatment outcome and increased mortality.3 The global Stop TB Partnership aims to eliminate tuberculosis as a public health problem by 2050. An agreed major component to advance this aim would be an effective vaccine.4 BCG is the only licensed tuberculosis vaccine—it provides protection against severe childhood tuberculosis,5, 6 but the protection conferred against pulmonary tuberculosis in adults and adolescents is highly variable.7, 8At least 16 candidate tuberculosis vaccines have advanced to clinical testing.9 The modified vaccinia virus Ankara expressing the major M tuberculosis antigen 85A (MVA85A) is a clinically advanced candidate vaccine.10, 11, 12 MVA85A is well tolerated and immunogenic in adults infected and not infected with HIV-1, and in infants not exposed to HIV-1.10, 11, 12, 13, 14 MVA85A adds to BCG-induced protection against mycobacterial challenge in some preclinical animal models.15, 16, 17, 18, 19 However, boosting BCG with MVA85A in South African infants not infected with HIV-1 did not confer additional protection against tuberculosis disease or M tuberculosis infection.10Administration of several doses of the saprophyte Mycobacterium vaccae to adults infected with HIV-1 was associated with a decreased risk of protocol-defined pulmonary tuberculosis,20 suggesting that vaccination might be effective in people infected with HIV-1. Here we report the results of a multisite, randomised, placebo-controlled, phase 2 trial to assess the safety, immunogenicity, and efficacy of MVA85A in healthy adults infected with HIV-1.MethodsStudy design and participantsWe did a proof-of-concept, randomised, double-blind, placebo-controlled, phase 2 trial of MVA85A at two clinical sites, in Cape Town, South Africa and Dakar, Senegal. In Cape Town, participants were recruited in the community and from primary care clinics in Khayelitsha by use of radio and newspaper advertisements, flyers, pamphlets, and information campaigns at the clinics. Khayelitsha is a densely populated, low-income, peri-urban township. In 2010, antenatal HIV-1 prevalence was 33% and the tuberculosis case notification rate was at least 1500 per 100\u2008000 population per year.21 In Dakar, participants were recruited from public service HIV clinics at the Centre de Traitement Ambulatoire and the Centre de Recherche Clinique et de Formation, Centre Hospitalier Universitaire de Fann. Senegal had an estimated HIV-1 prevalence in adults of less than 1% in 2012, and a reported tuberculosis incidence rate of 0·14% in 2013.1 The annual rate of M tuberculosis infection has not previously been estimated at either site. Eligibility criteria included participants aged 18–50 years with no evidence of active tuberculosis, and baseline CD4 counts greater than 350 cells per μL if they were not receiving antiretroviral therapy, or greater than 300 cells per μL (and with undetectable viral load before randomisation) if they were receiving antiretroviral therapy. Participants with latent tuberculosis infection were eligible for enrolment if they had completed at least 5 months of isoniazid preventive therapy, unless they had completed treatment for tuberculosis disease within 3 years before randomisation. The complete inclusion criteria are listed in the study protocol (appendix).The trial adhered to International Conference on Harmonisation Good Clinical Practice guidelines, and was approved by the University of Cape Town's Faculty of Health Sciences Human Research Ethics Committee and the Medicines Control Council of South Africa; the Senegalese National Ethics Committee for Research in Health; and the Oxford University Tropical Research Ethics Committee. All participants provided written informed consent before any study procedure.Randomisation and maskingParticipants were randomly assigned (1:1) in blocks of four by a randomly generated sequence of participant identification numbers via an interactive voice response system to receive two intradermal injections of either 1\u2008×\u2008108 pfu MVA85A or placebo (Candida skin test antigen [Candin], Allermed Laboratories, San Diego, CA, USA). Randomisation was stratified by antiretroviral therapy status and study site. A statistician uninvolved with study analyses prepared the interactive voice response system randomisation schedule. Doses of vaccines were prepared and labelled in masked syringes by a pharmacist unmasked to group allocation. Participants, nurses (who were involved in assessment and follow-up), investigators, and laboratory staff were masked to group allocation. The second (booster) injection of MVA85A or placebo was given 6–12 months after the first vaccination and participants were actively followed up every 3 months until the last participant enrolled had completed 6 months of follow-up after the booster vaccination.ProceduresWe collected data for the incidence of solicited and unsolicited adverse events, including both local injection-site reactions and systemic reactions. Participants reported solicited adverse events on diary cards for 7 days after each vaccination and in response to direct questioning by trained study staff on days 7 and 28 after each injection. Phlebotomy for routine haematological and biochemical analysis was done at screening, before booster vaccination, and on days 7 and 28 after each vaccination. Peripheral CD4 cell count and HIV-1 viral load were also measured at these timepoints and every 3 months until 6 months after booster vaccination. Serious adverse events were monitored by active surveillance throughout and until the end of the trial. The site investigators and local medical monitors determined the severity and seriousness of adverse events and the relation of these to the vaccine. An independent data monitoring committee assessed masked group safety data after 200 participants had been enrolled and unmasked after 600 participants had been enrolled.In a prespecified subset of 70 participants (35 from each group), immunology samples were obtained before each vaccination and on days 7 and 28 after each vaccination. All immunology tests were done masked to group allocation. We assessed vaccine immunogenicity with three assays. First, ex vivo interferon γ enzyme-linked immunospot (ELISPOT) analysis was done on fresh peripheral blood mononuclear cells.22 Cells were stimulated overnight with a single pool of 66 peptides of the antigen 85A (Ag85A), ESAT-6, and CFP-10. Second, Ag85A-specific intracellular cytokine staining assay was done on whole blood.23 Stimulated fixed whole blood samples were stained for CD3-positive, CD4-positive, CD8-positive, CD14-positive, and CD19-positive cells, interferon γ, tumour necrosis factor α, interleukin 17, and interleukin 2. Third, Ag85A-specific antibody response was measured on plasma. Ag85A-specific immunoglobulin G (IgG) antibodies were measured by ELISA on eight serial two-fold dilutions of plasma (1:25–1:3200), by use of affinity purified recombinant, histidine-tagged Ag85A24 (microwell plates coated with 50 ng per well of recombinant Ag85A in borate buffer, overnight at 4°C). Alkaline phosphatase-labelled goat anti-human IgG (Sigma, St Louis, MO, USA) was used as secondary antibody at a dilution of 1:1000 and optical density was read at 405 nm after development with phosphatase substrate (Sigma). Results were expressed in arbitrary units per mL (AU/mL), as compared with values of an internal tuberculosis serum standard of 2500 AU/mL.Participants were screened to exclude active tuberculosis by symptom screen and chest radiography at both sites before enrolment. In Cape Town, participants also underwent sputum collection for tuberculosis smear microscopy, GeneXpert MTB/RIF (Cepheid, Sunnyvale, CA, USA), and mycobacterial liquid culture (MGIT; Becton Dickinson, Sparks, MD, USA) because of previously documented high frequencies of asymptomatic disease at this site.25 Latent M tuberculosis infection was defined as either a positive QuantiFERON-TB Gold In-Tube (QFT) test or a tuberculin purified protein derivative skin test (tuberculin skin test) reaction greater than 5 mm.Participants were monitored throughout the trial for possible tuberculosis. Tuberculosis investigations were done in participants who had been in contact with a known case of active tuberculosis, in those who presented with at least one of cough for more than 1 week, fever for more than 1 week, drenching night sweats, unintentional weight loss of more than 3 kg, pleuritic chest pains, haemoptysis, or shortness of breath; and in those who converted to a positive QFT or tuberculin skin test (≤5 mm to >5 mm). Investigations included clinical examination, chest radiography, and collection of at least two sputum samples on which tuberculosis smear microscopy, GeneXpert MTB/RIF, and mycobacterial liquid culture were done. Chest radiographs were reviewed by two physicians, with a third reading to achieve consensus in the event of disagreement. QFT and tuberculin skin tests were repeated at the final study visit.OutcomesTuberculosis disease endpoint 1 was defined as culture or GeneXpert MTB/RIF positivity; endpoint 2 included endpoint 1 and a composite clinical endpoint (which included a single acid-fast bacilli smear from a sterile body site; two smears from pulmonary and gastric sampling, and compatible clinical symptoms and radiological signs); and endpoint 3 was participant commencement on anti-tubercular chemotherapy (see the study protocol for more information; appendix). The M tuberculosis infection endpoint was defined as conversion from negative QFT at baseline to positive QFT at the final visit.The primary study outcome was the safety of MVA85A in all participants who received at least one dose of study vaccine or placebo (the safety analysis population) as determined by the numbers and percentages of adverse events (including solicited, unsolicited, and serious adverse events).The secondary outcome was the efficacy of MVA85A for the prevention of active tuberculosis in the per-protocol population (all randomly allocated participants who received at least one dose of study vaccine or placebo and had no major protocol deviations and no tuberculosis case definition endpoints within 28 days after study day 0 [first vaccination]), which was determined by the incidence of active tuberculosis meeting the definition of endpoint 1, calculated as the number of new cases of active tuberculosis with a date of diagnosis from 28 days after the first vaccination until the end of the study follow-up (May 19, 2014). An intention-to-treat analysis was also done for disease efficacy. In the per-protocol population, we also examined the efficacy of MVA85A by antiretroviral therapy status at the time of randomisation and by baseline isoniazid preventive therapy status.Other secondary outcomes were to assess CD4-positive lymphocyte counts and HIV-1 viral load before and after administration of MVA85A compared with placebo; to assess the immunogenicity of MVA85A compared with placebo as measured by the ex-vivo interferon γ ELISPOT assay; to assess the immunogenicity of MVA85A compared with placebo as measured by flow cytometric intracellular cytokine staining of CD4-positive and CD8-positive T cells after stimulation with a peptide pool of mycobacterial antigens; to identify potential immunological correlates of protection from tuberculosis in participants vaccinated with MVA85A and to assess the QFT conversion rate at final study assessment in MVA85A recipients compared with controls without a diagnosis of tuberculosis during the trial.Statistical analysisAll sample size calculations assumed a loss to follow-up and death rate of 2%. The initial planned sample size for this trial was 1400 adult participants, to be followed up for 2 years after the last participant was enrolled. This sample size provided 80% power to detect a vaccine efficacy of 60% against tuberculosis disease. However, after review of the phase 2 infant efficacy data,10 the trial design was revised with safety as the primary objective and a smaller sample size and shorter follow-up of a minimum of 6 months. The revised sample size for this study was selected as adequate for a review of the safety profile. With 325 participants assigned to receive MVA85A, the revised sample would have a 90% probability of detecting at least one adverse event occurring at a rate of 0·71%. Because of the expected effect of antiretroviral therapy on tuberculosis disease, an estimated tuberculosis disease incidence ranging between 1·5% and 2% per year was used to estimate the power of the revised sample size for efficacy. Calculations were based on a one-sided log-rank test at a significance level of 0·10 and assumed completion of enrolment in 21 months, a follow-up period of about 15 months for the last patient enrolled, and a maximum of 36 months for the first patient enrolled. If the true efficacy was about 70%, 325 patients per treatment group (650 patients total) provided 81% power to show positive efficacy given an incidence rate of 2·0% in the control group per year, or 71% power given an incidence rate of 1·5% in the control group per year. At a true efficacy of about 60%, 325 patients per treatment group provided 67% power to show positive efficacy given an incidence rate of 2·0% per year, or 57% power given an incidence rate of 1·5% per year. Vaccine efficacy to prevent infection was a secondary endpoint: the recorded QFT conversion rate in the study provided 80% power to detect a vaccine efficacy of 50%.Statistical analyses were done using SAS version 9.2. All analyses were prespecified in the statistical analysis plan before locking of the database. For the safety analysis, we compared the proportion of participants with at least one adverse event in the MVA85A group versus those in the placebo using Fisher's exact test. We also calculated two-sided 95% CIs for proportions of adverse events within treatment groups and the differences between groups.The main statistical method used in the analysis of tuberculosis disease endpoints 1–3 was vaccine efficacy, estimated as 1 minus the estimated hazard ratio, based on a Cox regression analysis of time (days) to initial tuberculosis diagnosis, based on the per-protocol population. As supportive confirmatory analysis, we used the conditional binomial (Clopper-Pearson) method to estimate vaccine efficacy and its corresponding two-sided 95% CIs and p values. Time to initial diagnosis for each endpoint was compared by use of a two-sided log-rank test, stratified by study site and antiretroviral therapy status at randomisation. Analyses were summarised by antiretroviral therapy and treatment group for participants in the per-protocol population. Vaccine efficacy against M tuberculosis infection and the corresponding 95% CI, and p value were calculated with the conditional binomial method (Clopper-Pearson), identical to the tuberculosis case definition endpoint analysis.Other secondary endpoints were analysed in various ways. Median CD4 cell counts and associated two-sided 95% CIs were summarised by antiretroviral therapy status at randomisation, study site, treatment group, and timepoint. HIV-1 viral load (copies per mL) was summarised with medians (and associated 95% CIs) by antiretroviral therapy status at randomisation, study site, and treatment group, at each available timepoint. Both the CD4 cell counts and HIV-1 viral load values were log-transformed before any analysis was done. We used Wilcoxon paired analysis to compare within group before and after vaccination responses.Quintiles (Blomfontein, South Africa) did the statistical analysis, and Aeras paid for this service. The trial was registered with ClinicalTrials.gov, number NCT01151189.Role of the funding sourceAeras was the trial sponsor and contributed to study design and data analysis. The other funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. BPN, FT, BSL, RJW, and HM had full access to all the data in the study. HM had final responsibility for the decision to submit for publication.ResultsBetween Aug 4, 2011, and April 24, 2013, 1233 adults infected with HIV-1 were screened and 650 were randomly assigned; 649 were included in the safety analysis and 645 in the per-protocol analysis (figure 1). 513 (71%) participants had CD4 counts greater than 300 cells per μL and were receiving antiretroviral therapy; 136 (21%) had CD4 counts above 350 cells per μL and had never received antiretroviral therapy. The results of the intention-to-treat analysis were not different and are not reported. 311 (96%) participants in the placebo group and 298 (92%) in the MVA85A group received the booster vaccination. One participant was randomly assigned to placebo but received MVA85A; this participant was included in the safety population for MVA85A but not in the per-protocol efficacy population. One participant was randomly assigned to MVA85A but withdrew consent before vaccination and was not vaccinated. This participant was excluded from both the safety and per-protocol populations. Baseline demographic characteristics were similar in the two study groups and across the two study sites (table 1; appendix). 625 participants completed the study; 14 participants were lost to follow-up (nine placebo, five MVA85A), five withdrew consent (two placebo, three MVA85A), and six died (four placebo, two MVA85A).In the per-protocol population, median follow-up was 655 days for the 320 recipients of MVA85A and 654 days for the 325 placebo participants. Other than the four participants shown in figure 1, all participants were included in the analysis.At least one adverse event was reported in 312 (96%) of placebo recipients and 321 (99%) of MVA85A recipients (table 2). Solicited adverse events were more common in participants who received MVA85A than placebo (table 2). Most of these events were local injection-site reactions; other solicited adverse events included mild influenza-like symptoms and regional lymphadenopathy. We noted no significant difference between study groups in the frequency of serious adverse events. 34 serious adverse events occurred during the study, 17 in the placebo group and 17 in the MVA85A group (table 2; appendix). All but one of these events were judged to be unrelated to vaccination; a case of probable tuberculous meningitis that occurred 6 days after vaccination was judged to be possibly related to vaccination. The data monitoring committee reviewed this case, did not request unmasking, and recommended continuing with the study. The participant was treated for tuberculous meningitis and made a full recovery. At study completion, this participant was identified as having received MVA85A. 13 serious adverse events in the infections and infestations category occurred during the study (the only category with more than five serious adverse events in either group), eight in the placebo group and five in the MVA85A group; this difference was not significant (Fisher's exact test, p=0·58).The frequency of severe adverse events did not differ significantly between study groups (table 2). We noted no significant changes in CD4 cell count or HIV-1 viral load throughout the course of the trial in either study group (data not shown). Routine haematological and biochemical test results did not differ between study groups (data not shown).ELISPOT responses to Ag85A were significantly higher in participants from Dakar than in those from Cape Town at baseline (p=0·0016), but at no other timepoint. This difference was not seen with the less sensitive whole blood intracellular cytokine staining assay. MVA85A induced an Ag85A-specific T-cell response that peaked 7 days after the first and booster vaccinations (median spots per million: day 0 [first vaccination], 9·0 [IQR 2·3–51·0]; day 7 [first vaccination], 337·0 [139·3–993·8]; day 0 [booster vaccination], 103·5 [14·8–223·8]; day 7 [booster vaccination], 426·0 [150·0–745·0]; figure 2). Responses at each timepoint after vaccination did not differ by study site or by antiretroviral therapy status. Medians in the placebo group did not exceed 20 spots per million at any timepoint.Whole blood intracellular cytokine staining showed the most commonly measured cytokine from CD4 T cells was interferon γ, in agreement with the ELISPOT data. Tumour necrosis factor α and low concentrations of interleukins 2 and 17 were also detected (table 3, figure 2). Overall, numbers of antigen-specific CD8 T cells were very low and were only positive for interferon γ and tumour necrosis factor α. Multiparameter flow-cytometric analysis showed that mainly monofunctional Ag85A-specific CD4 T cells were present before and after vaccination (figure 3). Ag85A-specific antibody responses were less than twice the baseline value after vaccination in all but three participants.In the per-protocol population, the overall number of tuberculosis cases and incidence during study follow-up of tuberculosis cases (endpoint 1) was six (2%) in the MVA85A group and nine (3%) in the placebo group, for a vaccine efficacy of 32·8% (95% CI −111·5 to 80·3; table 4). Figure 4 shows the Kaplan-Meier time-to-disease analysis for endpoint 1. Stratification by antiretroviral therapy status showed no significant difference between treatment groups. Eight of the 15 endpoint 1 cases were QFT positive at enrolment. No additional participants met endpoint 2 who did not already meet endpoint 1. Vaccine efficacy for endpoint 3 was 10·5% (−161·3 to 70.0). Disease incidence did not differ by site. Median time to diagnosis of endpoint 1 was 249 days in the MVA85A group and 236 days in the placebo group. 159 (50%) of 320 MVA85A recipients and 148 (46%) of 325 placebo recipients were investigated for tuberculosis during the study. The study was insufficiently powered to assess the efficacy of MVA85A for the prevention of tuberculosis disease in the subset of participants receiving antiretroviral therapy or isoniazid prophylaxis. The absence of efficacy also made it impossible to identify potential immunological correlates of protection from tuberculosis in participants vaccinated with MVA85A.The number of QFT-negative participants who converted to QFT positive by the end of the study was 38 (20%) in the MVA85A group and 40 (23%) in the placebo group, for a vaccine efficacy of 11·7% (95% CI −41·3 to 44·9). QFT conversion did not differ by antiretroviral therapy status (data not shown), but it did differ by site. In Cape Town, 41 (31%) of 132 participants converted, whereas in Dakar, 37 (16%) of 227 converted (χ2 10·89, p=0·001). Frequency of QFT reversion (participants who were positive at baseline and negative at end of study) was similar in the two treatment groups (17 [14%] of 124 for MVA85A and 27 [19%] of 139 for placebo; p=0·22), and did not differ by antiretroviral therapy status (data not shown). Tuberculin skin test conversion was not a prespecified endpoint and is not reported here, but will be the subject of further analysis.DiscussionThis phase 2 trial in 650 adult participants infected with HIV-1 showed that MVA85A was well tolerated and immunogenic, with safety and immunogenicity profiles similar to those reported elsewhere for other populations in which this candidate vaccine has been assessed.10, 11, 12, 13, 14 However, we did not identify any significant efficacy against tuberculosis disease or M tuberculosis infection.Both first and booster vaccination with MVA85A induced a significant increase in Ag85A-specific T cells. Responses did not differ by antiretroviral therapy status. A probable explanation for this finding is the high baseline median CD4 count (571 cells per mm3; table 1, appendix) in participants who had not received antiretroviral therapy. Unlike the previously reported infant efficacy trial of MVA85A,10 baseline ELISPOT responses were detected in this trial and were significantly higher in participants from Dakar than in those from Cape Town. This result might be due to greater exposure to environmental mycobacteria; and the finding is unlikely to be due to a technical issue because it was only recorded at this timepoint, and there was a robust quality control programme in place for these assays. Furthermore, the median response 7 days after vaccination in this trial exceeded that seen in the infant trial (337 vs 136 spots per million).10 Additionally, the functional phenotype of the dominant T-cell population in this trial was monofunctional by contrast with the infant trial, in which the dominant phenotype was polyfunctional.10 In both trials, the recorded response was insufficient to be associated with protection. It is not clear whether a quantitatively greater or a qualitatively different immune response is needed for protection. Alternative approaches, including the delivery of candidate vaccines direct to the respiratory mucosa, might be more potent routes of immunisation. For example, we have previously reported that delivery of MVA85A by aerosol to HIV-negative, BCG-vaccinated adults in the UK is well tolerated and induces potent mucosal and systemic immunity.26 Further assessment is needed before this route can be examined in countries with a high burden of tuberculosis. This approach, together with other strategies to improve the immunogenicity of MVA85A, are currently under investigation.The recorded annual incidence of tuberculosis (endpoint 1) was substantial (1·43% across treatment groups) and did not differ between sites. However, this incidence was lower than previously reported in Cape Town.27 The numbers of participants receiving antiretroviral therapy was greater than originally envisaged, because of the increased availability of this therapy during the study period and the change in national and international guidelines on the provision of antiretroviral therapy. These factors, combined with the redesign of this study upon availability of the infant trial results,10 led to a reduction in statistical power to detect a difference in tuberculosis disease incidence between treatment groups, leading to wide CIs for our estimates of vaccine efficacy.In this trial, the incidence of infection determined by QFT conversion was much higher than the incidence of tuberculosis disease, so CIs around the estimates of efficacy against infection are narrower. The overall recorded annual QFT conversion rate of about 12% meant that we had about 80% power to detect a vaccine efficacy of 50% against M tuberculosis infection. In view of the cost and complexity of human efficacy studies, there is now increased focus on infection as an endpoint rather than disease in proof-of-concept studies before progression to prevention-of-disease efficacy trials.9 However, this approach presupposes that the immune mechanisms needed to prevent infection and disease are similar. Our poor understanding of the biology underlying dynamic QFT conversion and reversion further complicates this shift in emphasis. The rate of QFT reversion was almost as high as the rate of conversion: whether this finding represents a true biological effect or technical variability in the assay cannot be determined from these data.In this study, we have shown that high-quality, multicentre tuberculosis vaccine trials are possible in Africa, and have succeeded in the characterisation of the epidemiology of tuberculosis associated with HIV-1 in two African cities. Nevertheless, the disappointing finding with respect to vaccine efficacy for MVA85A suggests the need for standardised preclinical animal models that better represent human disease and an improved understanding of immune mechanisms of protection in human tuberculosis. Such advances would greatly enhance the ability to efficiently translate clinical research capacity into the development and deployment of an effective vaccine.References1WHOGlobal tuberculosis report2014World Health OrganizationGeneva2WalkerNFMeintjesGWilkinsonRJHIV-1 and the immune response to TBFuture Virol820135780236536643FalzonDWeyerKRaviglioneMCDrug-resistant tuberculosis: latest advancesLancet Respir Med12013e910243218184BrennanMJTholeJTuberculosis vaccines: a strategic blueprint for the next decadeTuberculosis92suppl 12012S613224411605RodriguesLCDiwanVKWheelerJGProtective effect of BCG against tuberculous meningitis and miliary tuberculosis: a meta-analysisInt J Epidemiol2219931154115881442996TrunzBBFinePDyeCEffect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectivenessLancet367200611731180166165607MangtaniPAbubakarIAritiCProtection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trialsClin Infect Dis582014470480243369118ColditzGABrewerTFBerkeyCSEfficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literatureJAMA271199469870283090349HawnTRDayTAScribaTJTuberculosis vaccines and prevention of infectionMicrobiol Mol Biol Rev7820146506712542893810TamerisMDHatherillMLandryBSSafety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trialLancet3812013102110282339146511McShaneHPathanAASanderCRRecombinant modified vaccinia virus Ankara expressing antigen 85A boosts BCG-primed and naturally acquired antimycobacterial immunity in humansNat Med102004124012441550283912HawkridgeTScribaTJGelderbloemSSafety and immunogenicity of a new tuberculosis vaccine, MVA85A, in healthy adults in South AfricaJ Infect Dis19820085445521858219513SanderCRPathanAABeveridgeNESafety and immunogenicity of a new tuberculosis vaccine, MVA85A, in Mycobacterium tuberculosis-infected individualsAm J Respir Crit Care Med17920097247331915119114MinassianAMRowlandRBeveridgeNEA phase I study evaluating the safety and immunogenicity of MVA85A, a candidate TB vaccine, in HIV-infected adultsBMJ Open12011e00022315WilliamsAGoonetillekeNPMcShaneHBoosting with poxviruses enhances Mycobacterium bovis BCG efficacy against tuberculosis in guinea pigsInfect Immun732005381438161590842016VordermeierHMVillarreal-RamosBCocklePJViral booster vaccines improve Mycobacterium bovis BCG-induced protection against bovine tuberculosisInfect Immun772009336433731948747617VerreckFAVervenneRAKondovaIMVA.85A boosting of BCG and an attenuated, phoP deficient M. tuberculosis vaccine both show protective efficacy against tuberculosis in rhesus macaquesPLoS One42009e52641936733918GoonetillekeNPMcShaneHHannanCMAndersonRJBrookesRHHillAVEnhanced immunogenicity and protective efficacy against Mycobacterium tuberculosis of bacille Calmette–Guérin vaccine using mucosal administration and boosting with a recombinant modified vaccinia virus AnkaraJ Immunol1712003160216091287425519McShaneHWilliamsAA review of preclinical animal models utilised for TB vaccine evaluation in the context of recent human efficacy dataTuberculosis9420141051102436998620von ReynCFMteiLArbeitRDPrevention of tuberculosis in Bacille Calmette-Guérin-primed, HIV-infected adults boosted with an inactivated whole-cell mycobacterial vaccineAIDS2420106756852011876721CoxHHughesJDanielsJCommunity-based treatment of drug-resistant tuberculosis in Khayelitsha, South AfricaInt J Tuberc Lung Dis1820144414482467070022ScribaTJTamerisMMansoorNModified vaccinia Ankara-expressing Ag85A, a novel tuberculosis vaccine, is safe in adolescents and children, and induces polyfunctional CD4+ T cellsEur J Immunol4020102792902001718823HanekomWAHughesJMavinkurveMNovel application of a whole blood intracellular cytokine detection assay to quantitate specific T-cell frequency in field studiesJ Immunol Methods29120041851951534531624GartnerTBaetenMOtienoSRevetsHDe BaetselierPHuygenKMucosal prime-boost vaccination for tuberculosis based on TLR triggering OprI lipoprotein from Pseudomonas aeruginosa fused to mycolyl-transferase Ag85AImmunol Lett111200726351757053525RangakaMXGideonHPWilkinsonKAInterferon release does not add discriminatory value to smear-negative HIV-tuberculosis algorithmsEur Respir J3920121631712171948726SattiIMeyerJHarrisSASafety and immunogenicity of a candidate tuberculosis vaccine MVA85A delivered by aerosol in BCG-vaccinated healthy adults: a phase 1, double-blind, randomised controlled trialLancet Infect Dis1420149399462515122527RangakaMXWilkinsonRJBoulleAIsoniazid plus antiretroviral therapy to prevent tuberculosis: a randomised double-blind, placebo-controlled trialLancet384201468269024835842Supplementary MaterialSupplementary appendixAcknowledgmentsThe study was funded by the European & Developing Countries Clinical Trials Partnership (IP.07.32080.002), Aeras, Bill & Melinda Gates Foundation, the Wellcome Trust (095780, 084323, and 088316), and the Oxford-Emergent Tuberculosis Consortium. Quintiles (Bloemfontein, South Africa) were used for the statistical analysis, and Aeras paid for this service. The appendix includes a complete list of acknowledgments. We dedicate this study to the memory of Robyn Louw.ContributorsBPN, FT, SD, HE, RG, VJ, IN, TO, AT, MRa, BSL, SM, and RJW were responsible for implementation of the study and supervision at the study sites. MC, TND, KH, MRo, IS, and KAW did the immunological analysis. MO, RJW, SM, and HM raised the funding and wrote the protocol. All authors contributed to data analysis and contributed to the writing of the report.Declaration of interestsHM was previously a shareholder in the Oxford-Emergent Tuberculosis Consortium (OETC), a joint venture established for the development of MVA85A (OETC no longer exists). KH has a patent (US 5736524 A) related to the development of a DNA vaccine against Mycobacterium tuberculosis. RJW received grants from the European & Developing Countries Clinical Trials Partnership, the Wellcome Trust, the UK Medical Research Council, and the European Union during the conduct of the study, and personal fees from GlaxoSmithKline unrelated to this work. All other authors declare no competing interests.Figure 1Trial profileFigure 2Vaccine immunogenicity (both study sites combined)(A) Antigen 85A (Ag85A) interferon γ enzyme-linked immunospot analysis responses. Data are presented as spot-forming cells (SFC) per million peripheral blood mononuclear cells (PBMCs). p values were calculated with Wilcoxon matched-pair signed-rank tests. Box and whisker plots show median, IQR, and minimum and maximum values. (B) Whole blood intracellular cytokine staining assay of total cytokines. Data are presented as frequency of CD4 and CD8 T cells producing cytokines. Box and whisker plots show median, IQR, and minimum and maximum values. IFNγ=interferon γ. TNFα=tumour necrosis factor α. IL=interleukin. V1=vaccination 1. V2=vaccination 2.Figure 3Polyfunctional CD4 T cellsPlots show frequency of CD4 T cells producing combinations of the studied cytokines. Bars are median values and dots represent individual volunteers. IFNγ=interferon γ. TNFα=tumour necrosis factor α. IL=interleukin. V1=vaccination 1. V2=vaccination 2.Figure 4Cumulative incidence of diagnosis of tuberculosis endpoint 1 by treatment groupEndpoint 1 was defined as a positive finding from culture or GeneXpert MTB/RIF assay.Table 1Demographic and baseline characteristics (safety analysis population)Placebo (n=325)MVA85A (n=324)Median age, years (range)39·0 (22–41)38·0 (21–49)Women255 (78%)265 (82%)Ethnic originBlack304 (94%)302 (93%)Mixed21 (6%)22 (7%)QFT test resultPositive150 (46%)135 (42%)Negative173 (53%)188 (58%)Indeterminate2 (1%)1 (<1%)TST result>5 mm128 (39%)124 (38%)≤5 mm191 (59%)190 (59%)Missing data6 (2%)10 (3%)Latent tuberculosis infection178 (55%)164 (51%)5–6 months IPT before enrolment144 (44%)133 (41%)Receiving antiretroviral therapy256 (79%)257 (79%)CD4 count (cells per mm3)Participants not receiving antiretroviral therapy564 (169·8)571 (187·5)Participants receiving antiretroviral therapy599 (199·6)598 (220·7)HIV viral load (copies per mL)Participants not receiving antiretroviral therapy41\u2008371 (92\u2008456·9)62\u2008168 (166\u2008912·1)Participants receiving antiretroviral therapy29 (27·1)34 (63·7)Data are n (%) or mean (SD), unless otherwise stated. QFT=QuantiFERON-TB Gold In-Tube. TST=tuberculin skin test. IPT=isoniazid preventive therapy.Table 2Overview of adverse events (safety analysis population)OverallParticipants not receiving antiretroviral therapyParticipants receiving antiretroviral therapyPlacebo (n=325)MVA85A (n=324)Difference (MVA85A minus placebo) (95% CI)Placebo (n=69)MVA85A (n=67)Difference (MVA85A minus placebo) (95% CI)Placebo (n=256)MVA85A (n=257)Difference (MVA85A minus placebo) (95% CI)Any adverse event312 (96·0%; 93·3–97·7)321 (99·1%; 97·3–99·7)3·1 (0·7 to 5·4)67 (97·1%; 90·0–99·2)66 (98·5%; 92·0–99·7)1·4 (−3·5 to 6·3)245 (95·7%; 92·5–97·6)255 (99·2%; 97·2–99·8)3·5 (0·8 to 6·2)Solicited adverse event235 (72·3%; 67·2–76·9)288 (88·9%; 85·0–91·9)16·6 (10·6 to 22·5)50 (72·5%; 61·0–81·6)63 (94·0%; 85·6–97·7)21·6 (9·6 to 33·5)185 (72·3%; 66·5–77·4)225 (87·5%; 83·0–91·0)15·3 (8·5 to 22·1)Serious adverse event17 (5·2%; 3·9–8·2)17 (5·2%; 3·3–8·2)0·02 (−3·4 to 3·4)2 (2·9%; 0·8–10·0)9 (13·4%; 7·2–23·6)10·5 (1·5 to 19·6)15 (5·9%; 3·6–9·4)8 (3·1%; 1·6–6·0)−2·7 (−6·3 to 0·8)Related adverse event307 (94·5%; 91·4–96·5)318 (98·1%; 96·0–99·2)3·7 (0·8 to 6·6)66 (95·7%; 88·0–98·5)66 (98·5%; 92·0–99·7)2·9 (−2·8 to 8·5)241 (94·1%; 90·6–96·4)252 (98·1%; 95·5–99·1)3·9 (0·6 to 7·2)Severe adverse event84 (25·8%; 21·4–30·9)100 (30·9%; 26·1-36·1)5·0 (−1·9 to 11·9)15 (21·7%; 13·6–32·8)22 (32·8%; 22·8–44·8)11·1 (−3·8 to 26)69 (27·0%; 21·7–32·9)78 (30·4%; 25·1–36·2)3·4 (−4·4 to 11·2)Data are n (%; 95% CI), unless otherwise stated. Serious adverse events were coded with Medical Dictionary for Regulatory Activities version 14.0. Patients with multiple events in each category are counted only once in each category.Table 3Total intracellular cytokine response, presented as frequency of CD4 T cells and CD8 T cells producing specific cytokinesMVA85A (n=28)MVA85A timepoint comparisons (p values)Placebo (n=29)Day 0 (vaccination 1)Day 7 (vaccination 1)Day 0 (vaccination 2)Day 7 (vaccination 2)Day 0 (vaccination 1) vs day 7 (vaccination 1)Day 0 (vaccination 1) vs day 0 (vaccination 2)Day 0 (vaccination 1) vs day 7 (vaccination 2)Day 0 (vaccination 2) vs day 7 (vaccination 2)Day 0 (vaccination 1)Day 7 (vaccination 1)Day 0 (vaccination 2)Day 7 (vaccination 2)CD4 IFNγ0·01 (0–0·07)0·1 (0–1·12)0·03 (0–0·28)0·11 (0·02–0·82)<0·00010·0015<0·0001<0·00010·02 (0–0·12)0·01 (0–0·08)0 (0–0·08)0·01 (0–0·18)CD4 TNFα0·02 (0–0·12)0·11 (0–0·53)0·05 (0–0·57)0·11 (0–0·46)<0·00010·0403<0·0001<0·00010·02 (0–0·15)0·02 (0-0·14)0·02 (0–0·11)0·02 (0–0·23)CD4 IL-20·021 (0–0·11)0·07 (0–0·68)0·04 (0–0·27)0·1 (0·03–0·44)<0·00010·0421<0·0001<0·00010·02 (0–0·08)0·017 (0–0·08)0·02 (0–0·09)0·018 (0–0·06)CD4 IL-170·09 (0·01–0·28)0·12 (0·03–0·27)0·09 (0–0·37)0·1 (0·03–0·23)0·09460·54250·40470·28430·07 (0–0·27)0·06 (0·02–0·27)0·08 (0·01–0·26)0·078 (0–0·25)CD8 IFNγ0 (0–0·21)0·02 (0–0·94)0 (0–0·58)0·01 (0–0·3)0·01010·54990·22640·28970 (0–0·35)0 (0–0·19)0 (0–0·33)0 (0–0·24)CD8 TNFα0 (0–0·28)0 (0–0·24)0 (0–0·48)0 (0–0·05)0·45130·76150·73370·39530 (0–0·09)0 (0–0·38)0 (0–0·2)0 (0–0·13)Data are median (minimum to maximum) of total cytokines at each of the study timepoints, unless otherwise stated. Population is the immunology substudy (the first 70 participants), of which complete data were available for 57 participants. Statistical comparison of total cytokine responses in MVA85A study group used Wilcoxon matched-pairs signed-rank test. IL=interleukin. IFNγ=interferon γ. TNFα=tumour necrosis factor α.Table 4Primary and secondary efficacy results (per-protocol population)OverallParticipants not receiving antiretroviral therapyParticipants receiving antiretroviral therapyPlaceboMVA85AVaccine efficacy (95% CI)PlaceboMVA85AVaccine efficacy (95% CI)PlaceboMVA85AVaccine efficacy (95% CI)Disease endpoint 1 (primary efficacy endpoint)9/325 (2·8%)6/320 (1·9%)32·8%(−111·5 to 80·3)1/69 (1·4%)2/65 (3·1%)−114·1%(−12\u2008528·3 to 88·9)8/256 (3·1%)4/255 (1·6%)50·3%(−85·4 to 89·1)Disease endpoint 39/325 (2·8%)8/320 (2·5%)10·5%(−161·3 to 70·0)1/69 (1·4%)3/65 (4·6%)−224·7%(−16\u2008947·7 to 73·9)8/256 (3·1%)5/255 (2·0%)38·2%(−114·1 to 84·1)QFT positive conversion40/173 (23·1%)38/186 (20·4%)11·7%(−41·3 to 44·9)11/36 (30·6%)6/38 (15·8%)44·2%(−64·8 to 83·0)29/137 (21·2%)32/148 (21·6%)−0·1%(−71·5 to 41·4)Data are n/N (%), unless otherwise stated. Disease endpoint 1 was defined as culture or GeneXpert MTB/RIF positivity; disease endpoint 2 included endpoint 1 and a composite clinical endpoint; and disease endpoint 3 was commencement on anti-tubercular chemotherapy. No additional participants met endpoint 2 who did not already meet endpoint 1. QFT=QuantiFERON-TB Gold In-Tube.", 'title': 'Safety, immunogenicity, and efficacy of the candidate tuberculosis vaccine MVA85A in healthy adults infected with HIV-1: a randomised, placebo-controlled, phase 2 trial.', 'date': '2015-03-03'}, '23391465': {'article_id': '23391465', 'content': "LancetLancetLancet (London, England)0140-67361474-547XElsevier233914655424647S0140-6736(13)60177-410.1016/S0140-6736(13)60177-4ArticlesSafety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trialTamerisMichele DDrMBChBmichele.tameris@uct.ac.zaa**HatherillMarkFCPa*LandryBernard SMPHbScribaThomas JPhDaSnowdenMargaret AnnMPHbLockhartStephenDMcdSheaJacqueline EPhDcMcClainJ BruceMDbHusseyGregory DProfFFCHafHanekomWillem AProfFCPaMahomedHassanMMedag†McShaneHelenProfFRCPhelen.mcshane@ndm.ox.ac.uke†**the MVA85A 020 Trial Study TeamaSouth African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and School of Child and Adolescent Health, University of Cape Town, Cape Town, South AfricabAeras, Rockville, MD, USAcOxford-Emergent Tuberculosis Consortium, Wokingham, Berkshire, UKdEmergent Product Development UK, Wokingham, Berkshire, UKeJenner Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UKfVaccines for Africa, Institute of Infectious Disease and Molecular Medicine and Department of Medical Microbiology, University of Cape Town, Cape Town, South AfricagDepartment of Health, Western Cape and Division of Community Health, Stellenbosch University, Stellenbosch, South Africa*Correspondence to: Dr Michele D Tameris, South African Tuberculosis Vaccine Initiative (SATVI), Brewelskloof Hospital, Haarlem Street, Worcester 6850, South Africa michele.tameris@uct.ac.za**Prof Helen McShane, University of Oxford, Jenner Institute, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK helen.mcshane@ndm.ox.ac.uk*Contributed equally†Senior authors422013422013381987110211028© 2013 Published by Elsevier Ltd.2013Elsevier LtdSummaryBackgroundBCG vaccination provides incomplete protection against tuberculosis in infants. A new vaccine, modified Vaccinia Ankara virus expressing antigen 85A (MVA85A), was designed to enhance the protective efficacy of BCG. We aimed to assess safety, immunogenicity, and efficacy of MVA85A against tuberculosis and Mycobacterium tuberculosis infection in infants.MethodsIn our double-blind, randomised, placebo-controlled phase 2b trial, we enrolled healthy infants (aged 4–6 months) without HIV infection who had previously received BCG vaccination. We randomly allocated infants (1:1), according to an independently generated sequence with block sizes of four, to receive one intradermal dose of MVA85A or an equal volume of Candida skin test antigen as placebo at a clinical facility in a rural region near Cape Town, South Africa. We actively followed up infants every 3 months for up to 37 months. The primary study outcome was safety (incidence of adverse and serious adverse events) in all vaccinated participants, but we also assessed efficacy in a protocol-defined group of participants who received at least one dose of allocated vaccine. The primary efficacy endpoint was incident tuberculosis incorporating microbiological, radiological, and clinical criteria, and the secondary efficacy endpoint was M tuberculosis infection according to QuantiFERON TB Gold In-tube conversion (Cellestis, Australia). This trial was registered with the South African National Clinical Trials Register (DOH-27-0109-2654) and with ClinicalTrials.gov on July 31, 2009, number NCT00953927FindingsBetween July 15, 2009, and May 4, 2011, we enrolled 2797 infants (1399 allocated MVA85A and 1398 allocated placebo). Median follow-up in the per-protocol population was 24·6 months (IQR 19·2–28·1), and did not differ between groups. More infants who received MVA85A than controls had at least one local adverse event (1251 [89%] of 1399 MVA85A recipients and 628 [45%] of 1396 controls who received the allocated intervention) but the numbers of infants with systemic adverse events (1120 [80%] and 1059 [76%]) or serious adverse events (257 [18%] and 258 (18%) did not differ between groups. None of the 648 serious adverse events in these 515 infants was related to MVA85A. 32 (2%) of 1399 MVA85A recipients met the primary efficacy endpoint (tuberculosis incidence of 1·15 per 100 person-years [95% CI 0·79 to 1·62]; with conversion in 178 [13%] of 1398 infants [95% CI 11·0 to 14·6]) as did 39 (3%) of 1395 controls (1·39 per 100 person-years [1·00 to 1·91]; with conversion in 171 [12%] of 1394 infants [10·6 to 14·1]). Efficacy against tuberculosis was 17·3% (95% CI −31·9 to 48·2) and against M tuberculosis infection was −3·8% (–28·1 to 15·9).InterpretationMVA85A was well tolerated and induced modest cell-mediated immune responses. Reasons for the absence of MVA85A efficacy against tuberculosis or M tuberculosis infection in infants need exploration.FundingAeras, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium (OETC).IntroductionTuberculosis is a major global health problem, with an estimated 8·7 million cases and 1·4 million deaths in 2011.1 The Stop TB Partnership developed the Global Plan to Stop TB: 2006–2015, with a goal of tuberculosis elimination by 2050.2 One of the long-term strategies essential for control of the epidemic is effective vaccination. The existing BCG vaccine protects against disseminated tuberculosis in young children,3, 4 but protection against pulmonary tuberculosis is very variable.4, 5, 6 Efficacy against infection with Mycobacterium tuberculosis has only been reported in observational studies in low-burden settings.7 In endemic countries such as South Africa, the incidence of tuberculosis in infants and young children is very high despite high BCG coverage.8, 9 An improved infant tuberculosis vaccination regimen is urgently needed.12 candidate vaccines are being tested in clinical trials.10 MVA85A is a recombinant strain of modified Vaccinia Ankara virus expressing the immunodominant M tuberculosis protein, antigen 85A.11 MVA85A has been developed as a heterologous boost for BCG.11 Boosting BCG with MVA85A improved BCG-induced protection against mycobacterial challenge in animals.12, 13, 14, 15 MVA85A was well tolerated in clinical trials in infants.11, 16, 17 Furthermore, a BCG prime-MVA85A boost immunisation regimen in infants induced antigen-specific Th1 and Th17 cells,16 which are regarded as important in protection against tuberculosis.18, 19We aimed to further assess safety of MVA85A in HIV-negative infants who were previously vaccinated with BCG. As secondary endpoints, we also aimed to assess efficacy of MVA85A against tuberculosis and M tuberculosis infection beyond that of BCG alone, assess immunogenicity of MVA85A, and identify correlates of protection. To our knowledge, our investigation was the first infant efficacy trial of a new tuberculosis vaccine since BCG was last assessed in infants as part of the Chingleput-Madras trial that started in 1968.20MethodsStudy design and participantsWe undertook a parallel-group, randomised, placebo-controlled, double-blind phase 2b trial at the South African Tuberculosis Vaccine Initiative (SATVI) site in a rural region near Cape Town, South Africa. The region has a population of about 290\u2008000 people and an annual birth cohort of about 7000 babies. The overall incidence of tuberculosis in South Africa in 2011 was estimated to be almost 1% (993 per 100\u2008000 individuals).1 The incidence of tuberculosis in children younger than 2 years was about 3% at our trial site.21Parents of recently born infants were approached at local immunisation clinics or at home about study participation. We enrolled healthy infants, aged 4–6 months and who had received BCG (Danish 1331, Statens Serum Institut, Denmark) within 7 days of birth. Infants had to have received all age-appropriate routine immunisations, and two doses of pneumococcal conjugate vaccine at least 28 days before study vaccination (amended to 14 days during enrolment). All infants had to be HIV ELISA negative, QuantiFERON-TB Gold In-tube test (QFT; Cellestis, Australia) negative, and have had no substantial exposure to a patient with known tuberculosis. The appendix contains the study protocol.The trial was approved by the University of Cape Town Faculty of Health Sciences Human Research Ethics Committee, Oxford University Tropical Research Ethics Committee, and the Medicines Control Council of South Africa. Parents or legal guardians provided written, informed consent.Randomisation and maskingWe randomly allocated infants in a 1:1 ratio, with a block size of four, by use of an interactive voice/online response system to receive one intradermal dose of MVA85A (1×108 plaque-forming units in 0·06 mL) or an equal volume of Candida skin test antigen (Candin, AllerMed, USA) as placebo. Doses were prepared and labelled in masked syringes by an unmasked study pharmacist. An independent statistician prepared the randomisation schedule. The parents or legal guardians of study participants, study staff administering vaccinations or undertaking follow-up clinic assessments, and laboratory staff were masked to intervention group assignment.ProceduresThe study design included specific cohorts for specialised analyses, but all participants were followed up for assessment of efficacy and incidence of serious adverse events. Peripheral blood for routine haematological and biochemical tests was taken at screening and on day 7 and day 28 after vaccination in an initial safety cohort of at least 330 infants (study group 1). We assessed immunogenicity in three subsequent cohorts of up to 60 participants with an enzyme-linked immunosorbent spot analysis (study group 2), an intracellular cytokine staining (ICS) assay for peripheral blood mononuclear cell (PBMCs) counts (study group 3), and a whole blood ICS assay (study group 4). We enrolled remaining infants into a fifth cohort (study group 5). PBMCs obtained from all infants before and after vaccination were cryopreserved for future correlates analyses. We did QFT testing at screening, day 336, at the end of study visit, and for infants admitted to a dedicated study ward for investigation for tuberculosis.21We obtained data for incidence of solicited and unsolicited local (injection site) and systemic adverse events reported by parents or guardians on diary cards for 7 days after vaccination and by direct questioning by study staff for 28 days after vaccination. We also obtained data for serious adverse events throughout follow-up by active surveillance. Adverse events were assessed by the trial investigators and serious adverse events were assessed by the trial investigators and a local medical monitor, acting on behalf of the sponsor, to determine relation to vaccination. The trial investigators and local medical monitor were masked to intervention group throughout the trial. The safety monitoring committee (SMC) did not determine the association or severity of the adverse events. When the last infant in the safety cohort completed day 84, the SMC reviewed unmasked safety data to determine if a pattern of adverse events related to MVA85A or other safety concerns existed so as to advise on further enrolments. The SMC also conducted a second unmasked analysis-by-group safety and risk review after the 1000th infant completed their visit at study day 84.We actively followed up infants every 3 months to identify any signs, symptoms, or exposure that merited further investigation. Participants who had a persistent cough, failure to thrive, weight loss crossing a major centile band, QFT or tuberculin skin test conversion, household tuberculosis contact, or any other condition causing investigator concern were admitted to the study ward. Standardised investigations involved assessments with chest radiography, tuberculin skin test, QFT, HIV-ELISA, two consecutive early morning gastric lavage samples, and two induced sputa. Gastric lavage and sputum samples underwent auramine smear microscopy, GeneXpert MTB/RIF (Cepheid, USA; routinely from January, 2011, onwards), and MGIT (Becton Dickinson, Sparks, USA) liquid culture and sensitivity testing. Positive samples were speciated by PCR. We developed a hierarchy of three disease endpoint definitions. Endpoint 1 (panel 1) and endpoint 2 (appendix p 49) were based on the presence of specific clinical, radiological, and microbiological findings.22 Endpoint 2 (which included all infants who met endpoint 1 criteria) had marginally less stringent criteria to define tuberculosis infection and household exposure. Endpoint 3 included all participants placed on treatment for tuberculosis by a health professional. This approach allowed objective case classification without the need for an adjudication committee.The endpoint of infection with M tuberculosis was defined as conversion to a positive QFT test at any time during follow-up. We assessed rates of QFT conversion 1 year after vaccination and at end of study in those participants not previously started on anti-tuberculous treatment.We measured immunological sensitisation to M tuberculosis antigens, suggesting M tuberculosis infection, by QFT during screening, 1 year after vaccination, and at the close-out visit. We obtained blood samples from study groups 2–4 for immunogenicity analyses 7 days before vaccination and 7 days or 28 days after vaccination. We assessed immunogenicity with an ex-vivo interferon γ enzyme-linked immunosorbent spot assay, together with PBMC and whole blood ICS assays done as previously described.23 Further details of the methods are available in the appendix.Statistical analysesThe primary study outcome was safety in all vaccinated participants (safety population), including all solicited, unsolicited, and serious adverse events. We compared the proportion of participants with at least one such adverse event in the placebo and MVA85A groups with Fisher's exact test, and we calculated two-sided exact 95% CIs for proportions of individual events within treatment groups. We did immunogenicity analyses for all vaccinated participants enrolled in study groups 2–4. Statistical analyses were prespecified in a statistical analysis plan, signed off prior to study database lock and unmasking of data (appendix).The primary efficacy outcome was incidence of endpoint 1 and the secondary efficacy outcome was infection with M tuberculosis. Endpoints 2 and 3 were exploratory efficacy outcomes. All efficacy analyses were based on the per-protocol population, consisting of all randomly allocated participants who received at least one dose of study vaccine as randomised, and who had no major protocol deviations.The primary statistical method for analysis of endpoint 1 was vaccine efficacy, defined as 1 minus the estimated hazard ratio based on a Cox regression analysis of time to first diagnosis of endpoint 1. The Cox model contained one indicator variable for treatment group. To investigate the potential effect of variable follow-up times, we also did this analysis with a predefined cutoff of 2 years after vaccination. Analysis of endpoint 1 also included time (months) to initial tuberculosis diagnosis from day of vaccination in each treatment group with the Kaplan-Meier estimate of the survival function by treatment group, and the exact binomial method to estimate vaccine efficacy and its corresponding 95% CI (Clopper-Pearson with mid-p adjustment) conditional on the total number of events. We included participants with more than one diagnosis (eg, a diagnosis of tuberculosis endpoint 2 that was subsequently diagnosed as endpoint 1) in analyses separately for each diagnostic level. For the analysis of secondary and exploratory efficacy endpoints, no adjustment for multiplicity was done. We regarded a two-sided p value of less than 0·05 as significant. Summaries were presented for all cases reported during the study, and also, all cases with a diagnosis during the first 2 years of individual follow-up.For efficacy analyses, we based the sample size calculation on the primary efficacy endpoint of tuberculosis (endpoint 1). We assumed a cumulative tuberculosis incidence of 3% after a median of 18 months' follow-up in the placebo group,21 with an estimated 7·5% loss to follow-up.24 Thus, 1392 participants per intervention group would provide a 90% chance of detection of a 60% reduction between the intervention and control groups based on a two-sided log-rank test at a significance level of 0·05. We implemented a 6 month extension to the planned follow-up to achieve the target case accrual.For safety analyses, the sample size of 1392 participants receiving MVA85A would provide a greater than 75% chance of observing an adverse event that had an approximately one in 1000 actual rate of occurrence.The trial was registered with the South African National Clinical Trials Register on Nov, 4, 2008 (DOH-27-0109-2654), and with ClinicalTrials.gov on July 31, 2009, number NCT00953927.Role of the funding sourceAeras was the trial sponsor. Aeras and the Oxford-Emergent Tuberculosis Consortium (OETC) contributed to study design, data interpretation, and writing of the manuscript. MDT, MH, BSL, TJS, MAS, SL, HM, and HMcS had complete access to the data. HMcS had final responsibility for the decision to submit for publication.ResultsBetween July 15, 2009, and May 4, 2011, we obtained consent for 4754 infants. We enrolled 2797 infants who had completed screening when the enrolment target of 2784 was met (figure 1). Reasons for screening failure have been reported elsewhere.22 363 infants were entered into study group 1 (initial safety cohort; 182 in MVA85A group and 181 in the placebo group); 54 into group 2 (27 and 27), 54 into group 3 (27 and 27), and 39 into group 4 (19 and 20; immunogenicity groups); and 2287 in group 5 (1144 and 1143; correlates of protection). Follow-up was completed in October, 2012. The per-protocol population was 2794, excluding three participants from the intention-to-treat population (figure 1). The intention-to-treat analysis is not reported.Demographic and baseline clinical characteristics of the study participants were much the same between groups (table 1). In the per-protocol population, median follow-up for 1399 recipients of MVA85A was 24·6 months (range 0·2–37·3; IQR 19·2–27·8) and for 1395 controls was 24·6 months (0·3–37·3; 19·2–30·1). The number of participants discontinuing the study did not differ between the two treatment groups (figure 1). 126 infants (5%) were lost to follow-up, 11 died (<1%), and 62 (2%) had consent withdrawn.At least one local adverse event was reported in 628 (45%) of 1396 controls who received the allocated intervention and 1251 (89%) of 1399 recipients of MVA85A. At least one systemic adverse event was reported in 1059 (76%) controls and 1120 (80%) of recipients of MVA85A. At least one serious adverse event was reported in 258 (18%) controls and 257 (18%) recipients of MVA85A (appendix). No serious adverse events related to vaccine were reported in the MVA85A group, but one serious adverse event regarded as related to placebo occurred in the placebo group (short admission to hospital for fever 4 days after vaccination). 417 (64%) of 648 serious adverse events were acute lower-respiratory-tract infections or gastroenteritis (appendix). Seven (1%) infants died in the vaccine group (two from kwashiorkor, two from non-tuberculous meningitis, one from gastroenteritis, one from asphyxia due to drowning, and one from sudden death) and four (<1%) infants died in the placebo group (two from gastroenteritis, one from encephalitis, and one from a lower-respiratory-tract infection). During follow-up, 510 (37%) of 1395 recipients of placebo and 507 (36%) of 1399 recipients of MVA85A were admitted to the study ward for investigation.MVA85A induced an Ag85-specific T-cell response as measured by ex-vivo interferon γ enzyme-linked immunosorbent spot (median 136 spot-forming cells per million PBMCs, IQR 87–362; figure 2). Whole blood ICS showed that these cells were CD4-positive T cells predominantly expressing interferon γ, TNFα, and interleukin 2 (figure 2). We also detected CD4-positive interleukin 17-positive T cells (figure 2), some of which co-expressed Th1 cytokines (data not shown). These responses were not detected in recipients of placebo. No CD8-positive T-cell responses were detectable and no responses were detected with ICS completed on cryopreserved PBMCs (data not shown).Table 2 shows vaccine efficacy and numbers of infants who met endpoints 1, 2, or 3 by intervention group. For analysis with follow-up data truncated at 2 years after vaccination, vaccine efficacy was 23·9% (95% CI −27·9 to 54·7) for endpoint 1, −0·7% (–52·3 to 33·4) for endpoint 2, and −3·6% (–29·0 to 16·8) for endpoint 3. A post-hoc review of case distribution in the first year showed 16 recipients of placebo met endpoint 1 as did ten MVA85A recipients. Figure 3 shows the Kaplan-Meier survival analysis for endpoint 1.39 (3%) of 1395 infants assessed in the placebo group had incident tuberculosis (1·39 per 100 person-years [95% CI 1·00 to 1·91]) as did 32 (2%) of 1399 infants in the MVA85A group (1·15 per 100 person-years [0·79 to 1·62]). 171 (12% [95% CI 10·6 to 14·1]) infants assessed in the placebo group and 178 (13% [95% CI 11·0 to 14·6]) infants in the MVA85A group became infected with M tuberculosis as defined by QFT conversion during the course of the study. Vaccine efficacy against infection was −3·8% (95% CI −28·1 to 15·9). Efficacy was much the same when the comparison was restricted to QFT conversion at day 336 and end of study visit (data not shown).DiscussionWe report completion of a phase 2b safety and efficacy trial for infants with a new tuberculosis vaccine strategy (panel 2). In this trial, MVA85A was well tolerated and immunogenic in healthy infants who had previously been vaccinated with BCG, with a safety and immunogenicity profile consistent with that reported in other studies of infants.16, 17 However, we noted no significant efficacy against tuberculosis or M tuberculosis infection.This absence of efficacy was not consistent with findings from studies in animals, which suggested potential for efficacy,12, 13, 14, 15 and evidence of immunogenicity in previous clinical trials16, 17, 23 that measured immune responses regarded as important for protection.18, 19 Our results suggest that the CD4-positive T cells induced by MVA85A—at least at the modest frequencies noted in this trial—do not correlate with protection against tuberculosis or M tuberculosis infection. Frequencies of antigen-specific Th1 cells observed in infants with MVA85A were up to a tenth of the frequencies noted in adults.16, 25Our efficacy trial was undertaken in infants. However, this group is not responsible for most transmission of M tuberculosis. Thus, MVA85A could potentially protect adolescents or adults against pulmonary tuberculosis, in view of the fact that immunologically immature infants do not respond as well to this vaccine as adults do. MVA85A could also potentially have high efficacy in people of all ages against severe forms of tuberculosis, including pulmonary tuberculosis, without preventing infection or mild forms of disease. A high efficacy against severe disease could be masked in a trial that predominantly detects mild forms of tuberculosis. The sample size of a trial powered to detect only severe or disseminated disease would be prohibitively large. The safety and immunogenicity of MVA85A alone in infants exposed to HIV is currently being assessed.26 BCG-specific Th1 and Th17 responses were recently shown not to correlate with risk of tuberculosis in infants after BCG vaccination.27 Whether a substantially greater magnitude of response, a response that is qualitatively different, or a completely new immunological response would be necessary for protection is unclear. In our study, frequencies of BCG-primed Ag85A-specific T cells detected before MVA85A vaccination were very low or undetectable (figure 2). Conversely, adults and adolescents have significantly higher Ag85A-specific responses before vaccination,16 which might be an important factor in the stronger responses induced by MVA85A in older individuals. MVA85A was designed to boost BCG-primed responses, and the low frequencies of BCG-induced cells in infants might restrict the immunogenicity, and potentially the efficacy, of MVA85A in this age group. Ongoing assessment of study samples for potential correlates of risk might also yield important insights into why MVA85A did not confer protection in this trial and could add to the design and assessment of the next generation of tuberculosis vaccine candidates. Identification of immune correlates of protection would greatly aid vaccine design and assessment. However such correlates can only be identified in trials in which efficacy was shown. Identification and optimisation of animal models that accurately predict efficacy in human beings is also needed. Other efficacy trials of new HIV and malaria vaccines have reported early but waning efficacy.28, 29 In this trial, a post-hoc analysis of distribution of case accrual in the first year suggested a possible early effect on disease that merits further study of route of administration, regimen, and dosing strategies with MVA85A and other vaccines.Despite concerns about potential immunopathology induced by new tuberculosis vaccines,30 we noted no evidence for this effect. The high incidence of respiratory and gastrointestinal serious adverse events recorded in this trial reflects the known burden of childhood morbidity in this community.24 High numbers of unrelated serious adverse events should be expected in clinical trials in infant populations in developing countries. The high frequency of mild, self-limiting local reactions in MVA85A recipients is consistent with previous studies.16, 17 These local reactions were only partially controlled for by Candin, a placebo selected for its local reactogenicity profile. The overall safety profile supports modified Vaccinia Ankara virus as a suitable vector for infant vaccination strategies.The high incidence of disease noted in our study was comparable to the high rates noted in previous trials.21, 23 We noted no confirmed cases of disseminated tuberculosis (two cases of tuberculous meningitis met the definition for endpoint 2) and no deaths from tuberculosis, supporting our previous observation that disseminated and severe tuberculosis are uncommon in a setting of modern trials with active surveillance, effective isoniazid prophylaxis, and effective anti-tuberculous treatment.21 The high overall rate of M tuberculosis infection noted in this trial (349 [13%] of 2792) suggests a high level of exposure and transmission in this community. This infection burden suggests that M tuberculosis infection might be a suitable endpoint for future trials of new tuberculosis vaccines that aim to prevent infection and subsequent disease. Because BCG is regarded as less effective for prevention of infection than prevention of disease, our finding that MVA85A did not prevent infection is unsurprising and should be interpreted separately from the findings about efficacy against disease. We recognise that QFT has not been validated as a diagnostic test for M tuberculosis infection in infants and young children; however, a previous study31 done by our group showed good correlation between QFT and the tuberculin skin test.Our study showed that a large efficacy trial of a new tuberculosis vaccine in a high-burden setting is feasible with a stringent and objective case definition that incorporated the primary elements proposed in a recent consensus statement.32 We have also shown that standardised investigation for tuberculosis with multiple respiratory sampling, microbiological confirmation of disease, and masked expert panel review of digital radiograph images is feasible in a developing country setting where tuberculosis vaccine efficacy trials are likely to be done. We recognise that there is no gold standard definition of childhood tuberculosis,33 but we believe that the hierarchal endpoint definition used in this trial is robust and might be suitable for future tuberculosis vaccine trials.Cohort retention was very high in this trial, and no evidence was noted that the rate of loss to follow-up had a differential effect on case accrual. Similarly, exclusion of three enrolled infants in the per-protocol analysis did not affect the results.In conclusion, MVA85A was well tolerated, modestly immunogenic but unable to confer significant protection against tuberculosis or M tuberculosis infection. The information gained from the successful execution of this study will aid the planning of future trials and vaccination strategies. Substantial global efforts to develop an improved vaccine against tuberculosis must continue.References1WHOGlobal tuberculosis report 2012http://apps.who.int/iris/bitstream/10665/75938/1/9789241564502_eng.pdf(accessed Jan 2, 2013).2Stop TB PartnershipThe global plan to stop TB 2011–2015http://www.stoptb.org/global/plan/(accessed Jan 2, 2013).3TrunzBFinePDyeCEffect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectivenessLancet367200611731180166165604RodriguesLDiwanVWheelerJProtective effect of BCG against tuberculous meningitis and miliary tuberculosis: a meta-analysisInt J Epidemiol2219931154115881442995FinePVariation in protection by BCG: implications of and for heterologous immunityLancet34619951339134574757766ColditzGABerkeyCSMostellerFThe efficacy of bacillus Calmette-Guerin vaccination of newborns and infants in the prevention of tuberculosis: meta-analyses of the published literaturePediatrics961995293575967187Basu RoyRSotgiuGAltet-GomezNIdentifying predictors of interferon-gamma release assay results in pediatric latent tuberculosis: a protective role of bacillus Calmette-Guerin?: a pTB-NET collaborative studyAm J Respir Crit Care Med1862012378384227008628MahomedHKibelMHawkridgeTThe impact of a change in bacille Calmette-Guerin vaccine policy on tuberculosis incidence in children in Cape Town, South AfricaPediatr Infect Dis J25200611671172171331649MoyoSVerverSMahomedHAge-related tuberculosis incidence and severity in children under 5 years of age in Cape Town, South AfricaInt J Tuberc Lung Dis1420101491542007440410BrennanMJTholeJTuberculosis vaccines: a strategic blueprint for the next decadeTuberculosis (Edinb)92suppl 12012S6132244116011McShaneHPathanASanderCRecombinant modified vaccinia virus Ankara expressing antigen 85A boosts BCG-primed and naturally acquired antimycobacterial immunity in humansNat Med102004124012441550283912VordermeierHVillarreal-RamosBCocklePViral booster vaccines improve Mycobacterium bovis BCG-induced protection against bovine tuberculosisInfect Immun772009336433731948747613VerreckFVervenneRKondovaIMVA85A boosting of BCG and an attenuated, phoP deficient M tuberculosis vaccine both show protective efficacy against tuberculosis in rhesus macaquesPloS One42009e52641936733914GoonetillekeNMcShaneHHannanCAndersonRBrookesRHillAEnhanced immunogenicity and protective efficacy against Mycobacterium tuberculosis of bacille Calmette-Guerin vaccine using mucosal administration and boosting with a recombinant modified vaccinia virus AnkaraJ Immunol1712003160216091287425515WilliamsAGoonetillekeNPMcShaneHBoosting with poxviruses enhances Mycobacterium bovis BCG efficacy against tuberculosis in guinea pigsInfect Immun732005381438161590842016ScribaTJTamerisMMansoorNDose-finding study of the novel tuberculosis vaccine, MVA85A, in healthy BCG-vaccinated infantsJ Infect Dis2032011183218432160654217OtaMOdutolaAOwiafePImmunogenicity of the tuberculosis vaccine MVA85A is reduced by coadministration with EPI vaccines in a randomized controlled trial in Gambian infantsSci Transl Med3201188ra5618KaufmannSHFact and fiction in tuberculosis vaccine research: 10 years laterLancet Infect Dis1120116336402179846319HanekomWDockrellHOttenhoffTImmunological outcomes of new tuberculosis vaccine trials: WHO panel recommendationsPLoS Med52008e1451859755120BailyGVTuberculosis prevention trial, MadrasIndian J Med Res72suppl1980174700508621HawkridgeAHatherillMLittleFEfficacy of percutaneous versus intradermal BCG in the prevention of tuberculosis in South African infants: randomised trialBMJ33720081275128222Tameris M, McShane H, McClain J, et al. Lessons learnt from the first efficacy trial of a new infant tuberculosis vaccine since BCG. Tuberculosis (Edin) (in press).23ScribaTJTamerisMMansoorNModified vaccinia Ankara-expressing Ag85A, a novel tuberculosis vaccine, is safe in adolescents and children, and induces polyfunctional CD4+ T cellsEur J Immunol4020102792902001718823MoyoSVerverSHawkridgeATuberculosis case finding for vaccine trials in young children in high-incidence settings: a randomised trialInt J Tuberc Lung Dis1620121851912223691825MeyerJHarrisSSattiIComparing the safety and immunogenicity of a candidate TB vaccine MVA85A administered by intramuscular and intradermal deliveryVaccine312013102610332326634226HatherillMSafety and immunogenicity of MVA85A prime and bacille Calmette-Guérin boost vaccination (MVA(TB)029)http://www.clinicaltrials.gov/ct2/show/NCT1650389(accessed Jan 29, 2013).27KaginaBAbelBScribaTSpecific T cell frequency and cytokine expression profile do not correlate with protection against tuberculosis after bacillus Calmette-Guerin vaccination of newbornsAm J Resp Crit Care Med1822010107310792055862728Rerks-NgarmSPitisuttithumPNitayaphanSVaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in ThailandN Engl J Med3612009220922201984355729RtsSCTPAgnandjiSLellBA phase 3 trial of RTS,S/AS01 malaria vaccine in African infantsN Engl J Med3672012228422952313690930TaylorJTurnerOBasarabaRBelisleJHuygenKOrmeIPulmonary necrosis resulting from DNA vaccination against tuberculosisInfect Immun712003219221981265484131MoyoSIsaacsFGelderbloemSTuberculin skin test and QuantiFERON® assay in young children investigated for tuberculosis in South AfricaInt J Tuberc Lung Dis152011117611812194384132GrahamSAhmedTAmanullahFEvaluation of tuberculosis diagnostics in children: 1. Proposed clinical case definitions for classification of intrathoracic tuberculosis disease. Consensus from an expert panelJ Infect Dis205Suppl 22012S199S2082244802333HatherillMVerverSMahomedHConsensus statement on diagnostic end points for infant tuberculosis vaccine trialsClin Infect Dis54201249350122144538Supplementary MaterialSupplementary appendixAcknowledgmentsWe thank study participants and their families, the community of Cape Winelands East district, and South African Tuberculosis Vaccine Initiative (SATVI) personnel (Tony Hawkridge and Zainab Waggie [medical monitors]; Savvas Andronikou, Tracy Kilborn, and Nicky Wieselthaler [radiograph reviewers]; Andre Burger, Lizette Phillips, Danie Theron, Luise Lunnon [Cape Winelands Department of Health], staff of Cape Winelands East public health clinics and hospitals, Andrew Whitelaw and staff of National Health Laboratory Service, Groote Schuur Hospital, Cape Town; Jasur Ishmukhamedov, Sharon Sutton, Amy Lwin, Michael Raine, Christine Fattore, Wasima Rida, and E Martin Stals [Aeras]; and Andreas Diacon [Chair], James Balsley, Prakash Jeena, Neil Cameron, Alison Elliot, and Gil Price [safety monitoring committee]).ContributorsAll authors, on behalf of the MVA85A 020 Trial Study Team, contributed to study design, data analysis and interpretation, and writing and approval of the manuscript. MDT, MH, TJS, and HM contributed to the implementation of the study and supervision at the study site. MDT, GDH, and HM were the principal investigators. MAS designed and led the statistical analysis.The MVA85A 020 Trial Study TeamLinda Van Der Merwe, E Jane Hughes, Hennie Geldenhuys, Angelique K K Luabeya, Susan Rossouw, Erica Smit, Yolande Browne, Frances Ratangee, Cynthia Ontong, Marwou De Kock, Humphrey Mulenga, Ashley Veldsman, Stephanie Abrahim, Lilly Denation, Veronica Baartman, Amaryl Van Schalkwyk, Mariana Jacks, Colleen Krohn, Fazlin Kafaar, Marcia Steyn, Lebohang Makhete, Fatima Isaacs, Julia Noble, and Welile Sikhondze from the South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and School of Child and Adolescent Health, University of Cape Town, Cape Town, South Africa. Thomas Evans and Jerald Sadoff from Aeras, Rockville, MD, USA. Adrian V S Hill, Alison M Lawrie, Nathaniel J Brittain, and Samantha Vermaak from the Jenner Institute, Nuffield Department of Clinical Medicine, University of Oxford, UK.Conflicts of interestSL and JES are employees of Emergent BioSolutions and own shares and stock options in the company. HMcS is a shareholder in the Oxford-Emergent Tuberculosis Consortium (a joint venture between Emergent BioSolutions and the University of Oxford). All other authors declare that they have no conflicts of interest.Figure 1Trial profile*One infant developed gastroenteritis that precluded inclusion and one infant became ineligible after a randomisation error. QFT=QuantiFERON-TB Gold In-tube.Figure 2Vaccine immunogenicity(A) Frequencies of Ag85A-specific T cells measured by interferon-γ enzyme-linked immunosorbent spot assay in infants in study group 2 (27 infants in the MVA85A group and 27 infants in the placebo group) before administration of placebo or MVA85A (day 0) and 7 days after vaccination. (B) Frequencies of cytokine-expressing Ag85A-specific Th1 (CD4-positive T cells expressing IFN-γ, TNFα, or interleukin 2) and (C) frequencies of Ag85A-specific Th17 (CD4-positive T cells expressing interleukin 17) cells, measured by whole blood intracellular cytokine staining 28 days after administration of placebo or MVA85A to infants in study group four (17 infants in the MVA85A group and 19 infants in the placebo group). SFC=spot-forming cells. PBMC=peripheral blood mononuclear cell.Figure 3Cumulative incidence of diagnosis of tuberculosis endpoint 1Table 1Demographics and baseline characteristics of the per-protocol populationPlacebo (n=1395)MVA85A (n=1399)Overall (n=2794)Age, days145·7 (13·5)146·6 (14·3)146·2 (13·9)Sex, male714 (51%)708 (51%)1422 (51%)Ethnic groupBlack267 (19%)287 (21%)554 (20%)Mixed race1126 (81%)1107 (79%)2233 (80%)Asian1 (<1%)3 (<1%)4 (<1%)White1 (<1%)2 (<1%)3 (<1%)WeightInfants assessed1389 (>99%)1394 (>99%)2783 (>99%)Mean, kg6·47 (0·98)6·45 (0·99)6·46 (0·98)Full-term birth (≥38 weeks)983 (70%)1031 (74%)2014 (72%)Data are mean (SD) or n (%).Table 2Primary and secondary efficacy endpointsPlacebo (n=1395)MVA85A (n=1399)Vaccine efficacyEndpoint 1 (primary efficacy endpoint)39 (3%)32 (2%)17·3% (–31·9 to 48·2)Endpoint 2 (exploratory efficacy endpoint)52 (4%)55 (4%)–6·9% (–56·1 to 26·9)Endpoint 3 (exploratory efficacy endpoint)177 (13%)196 (14%)–12·1% (–37·4 to 8·5)Data are n (%) or % (95% CI). Participants with more than one diagnosis were analysed in each level of diagnosis attained. Vaccine efficacy and corresponding 95% CI was estimated with the Cox regression model (1 – estimated hazard ratio).Panel 1Definition of endpoint 1Any of the following criteria:•Isolation of Mycobacterium tuberculosis from any site•Identification of M tuberculosis by an approved molecular diagnostic technique from any site•Histopathology diagnostic for tuberculosis disease (eg, caseating granulomas)•Choroidal tubercle diagnosed by an ophthalmologist•Miliary pattern on chest radiograph in an HIV-negative infant•Clinical diagnosis of tuberculous meningitis (cerebrospinal fluid protein concentrations >0·6 g/L and pleocytosis of >50 cells per μL with >50% mononuclear cells) with features of basal meningeal enhancement and hydrocephalus on head CT•Vertebral spondylosis•One smear or histology specimen positive for auramine-positive bacilli from a normally sterile body site•One of each of the following:•Evidence of mycobacterial infection defined as two acid-fast positive smears (each from a separate collection) that were morphologically consistent with mycobacteria from either sputum or gastric aspirate that were not found to be non-tuberculous mycobacteria bacteria on culture; QuantiFERON-TB Gold In-tube test conversion from negative to positive; or tuberculin skin test ≥15 mmand•Radiographic findings compatible with tuberculosis defined as ≥1 of the following factors identified independently by at least two of three paediatric radiologists serving on a masked review panel: calcified Ghon focus, pulmonary cavity, hilar or mediastinal adenopathy, pleural effusion, or airspace opacificationand•Clinical manifestations compatible with tuberculosis defined as cough without improvement for >2 weeks; weight loss of >10% of bodyweight for >2 months; or failure to thrive, defined as crossing >1 complete major centile band (<97th–90th, <90th–75th, <75th–50th, <50th–25th, <25th–10th, and <10th–3rd weight-for-age centiles) downward for >2 monthsPanel 2Research in contextSystematic reviewTo our knowledge, our trial is the first efficacy study of a novel BCG booster tuberculosis vaccine in infants. A systematic review is not applicable.InterpretationThe safety of MVA85A reported in our large cohort is an important finding for tuberculosis vaccine development. However the absence of efficacy noted, despite studies in animals suggesting potential for efficacy and evidence of immunogenicity in previous clinical trials, was unexpected and suggests that the present parameters for selection of tuberculosis vaccine candidates might be inadequate. The relatively weak immunogenicity we noted in this study makes it difficult to conclude whether a higher magnitude response (ie, one that is qualitatively different or a completely new immunological mechanism) will be required for a protective vaccine. Lessons learnt from this trial, including trial design, execution, and vaccine selection, will be of enormous importance to the broader specialty of vaccine development.", 'title': 'In vivo detection of non-cavitated caries lesions on occlusal surfaces by visual inspection and quantitative light-induced fluorescence.', 'date': '2007-05-22'}, '29028973': {'article_id': '29028973', 'content': 'Clin Infect DisClin. Infect. DiscidClinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America1058-48381537-6591Oxford University PressUS29028973584909010.1093/cid/cix834cix834Articles and CommentariesSafety and Immunogenicity of Newborn MVA85A Vaccination and Selective, Delayed Bacille Calmette-Guerin for Infants of Human Immunodeficiency Virus-Infected Mothers: A Phase 2 Randomized, Controlled TrialNemesElisa1HesselingAnneke C2TamerisMichele1MauffKatya1DowningKatrina1MulengaHumphrey1RosePenelope2van der ZalmMarieke2MbabaSharon2Van AsDanelle1HanekomWillem A1WalzlGerhard3ScribaThomas J1McShaneHelen4HatherillMark1MVA029 Study Team\nAbrahamsCharmaineAbrahamsDeborahAfricaHadnBaartmanVeronicaBavumaBeautyBilekNicoleBotesNatasjaBrownYolandeCloeteYolundiDamonsMargarethDe VosRonelDlakavuPortiaDu PreezKarenErasmusMzwandileFrancisClaudiaGeldenhuysHendrikGeldenhuysMandyGoedemanKatrienaGolliathSandraMoutonAngelique HendricksHopleyChristiaanJansenRuwijdaJonesCarolynneKeyserAlanaKaginaBenjaminKhombaGloriaKola–CassiemFazlinKrugerSandraLeukesDaphneLouwLoyisoLuabeyaAngeliqueMaartTheresaMakhetheLebohangMbabweSimbarasheMtshambaEuniceMvinjelwaBoniswaNkantsuLungisaNobleJuliaNqwenisoSizweOppermanFajwaPetersenChristelPlaatjiePatiswaRossouwSusanSolomomsRoxanneSteynMarciaSwanepoelLiticiaToefyAsmavan DeventerHeidivan RooyenElmavan SterDaphneVazanaBongiweVeldsmanAshleyXoyanaNoncedo1South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease & Molecular Medicine and Division of Immunology, Department of Science & Technology/National Research Foundation, University of Cape Town2Desmond Tutu Tuberculosis Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences3DST/NRF Centre of Excellence for Biomedical Tuberculosis Research/Medical Research Council Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa4Jenner Institute, Oxford University, United KingdomE. N. and A. C. H. contributed equally to this manuscript.The members of the MVA029 Study Team are listed in the Appendix.Correspondence: M. Hatherill, South African Tuberculosis Vaccine Initiative, Room S2.01, Wernher and Beit Building, University of Cape Town Faculty of Health Sciences, Anzio Road, Observatory 7925, Cape Town, South Africa. (mark.hatherill@uct.ac.za).15220182610201726102017664554563056201723102017© The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America.2017This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.Newborn MVA85A prime vaccination was safe and induced an early immune response that did not interfere with immunogenicity of subsequent bacille Calmette-Guérin vaccination. New tuberculosis vaccine candidates should be tested using this strategy, which appears safe regardless of infant human immunodeficiency virus exposure.AbstractBackgroundVaccination of human immunodeficiency virus (HIV)-infected infants with bacille Calmette-Guérin (BCG) is contraindicated. HIV-exposed newborns need a new tuberculosis vaccination strategy that protects against tuberculosis early in life and avoids the potential risk of BCG disease until after HIV infection has been excluded.MethodsThis double-blind, randomized, controlled trial compared newborn MVA85A prime vaccination (1 × 108 PFU) vs Candin® control, followed by selective, deferred BCG vaccination at age 8 weeks for HIV-uninfected infants and 12 months follow-up for safety and immunogenicity.ResultsA total of 248 HIV-exposed infants were enrolled. More frequent mild–moderate reactogenicity events were seen after newborn MVA85A vaccination. However, no significant difference was observed in the rate of severe or serious adverse events, HIV acquisition (n = 1 per arm), or incident tuberculosis disease (n = 5 MVA85A; n = 3 control) compared to the control arm. MVA85A vaccination induced modest but significantly higher Ag85A-specific interferon gamma (IFNγ)+ CD4+ T cells compared to control at weeks 4 and 8 (P < .0001). BCG did not further boost this response in MVA85A vaccinees. The BCG-induced Ag85A-specific IFNγ+ CD4+ T-cell response at weeks 16 and 52 was of similar magnitude in the control arm compared to the MVA85A arm at all time points. Proliferative capacity, functional profiles, and memory phenotype of BCG-specific CD4 responses were similar across study arms.ConclusionsMVA85A prime vaccination of HIV-exposed newborns was safe and induced an early modest antigen-specific immune response that did not interfere with, or enhance, immunogenicity of subsequent BCG vaccination. New protein-subunit and viral-vectored tuberculosis vaccine candidates should be tested in HIV-exposed newborns.Clinical Trials RegistrationNCT01650389.HIV-exposed infantsMVA85ABCGvaccinationtuberculosisBacille Calmette-Guérin (BCG) vaccination of infants remains a key tool to protect young children against tuberculosis [1]. Given young children’s high risk of progression from Mycobacterium tuberculosis infection to disease and disseminated forms of tuberculosis, which is associated with severe morbidity and mortality, tuberculosis prevention strategies are of great importance in this population [2, 3]. Infant BCG vaccination offers partial protection against pulmonary, miliary, and meningitic tuberculosis in children [4, 5].In settings with high tuberculosis burden, all children born to human immunodeficiency virus (HIV)-infected mothers are at increased risk of tuberculosis, including those who remain HIV uninfected [6–8]. A safe and effective tuberculosis vaccine for infants with perinatal HIV exposure is needed urgently, since BCG vaccination of infants known to be HIV infected is contraindicated due to the risk of local, regional, and disseminated BCG disease as well as BCG immune reconstitution inflammatory syndrome following antiretroviral therapy (ART) initiation [9–13]. However, delay in BCG vaccination to allow exclusion of perinatal HIV acquisition would put infants at risk of acquiring tuberculosis in the first weeks of life, in the period before BCG could be administered without safety concerns. These competing risks and benefits have resulted in a pragmatic approach to continued BCG vaccination of HIV-exposed newborns whose HIV infection status is not yet known in settings where rates of childhood tuberculosis and maternal HIV infection are high [13, 14]. For example, approximately one fifth of South African women of reproductive age were HIV infected in 2017 [15]. Despite recent reductions in perinatal HIV transmission [16], the HIV infection rate at age 18 months is considerably higher than at 8 weeks due to high-risk mixed feeding practices [17]. There were an estimated 320 000 South African children living with HIV in 2016 [18]; 50% of deaths among children aged <5 years were associated with HIV infection [19]. Although early HIV polymerase chain reaction (PCR) testing is being introduced, this advance does not solve the BCG safety dilemma because routine BCG is usually given at birth. Also, since HIV-exposed infants in sub-Saharan Africa are often exclusively breast fed, HIV infection may be acquired subsequent to negative PCR testing at age 2 weeks.Given the high risk of both tuberculosis and BCG-associated adverse events (AEs) in HIV-infected infants, we hypothesized that delaying routine newborn BCG vaccination until HIV infection had been excluded, but preceded by a novel tuberculosis vaccine given at birth, would be safe and more immunogenic than delayed BCG vaccination alone for HIV-exposed infants [20]. We previously showed that delayed BCG vaccination of HIV-unexposed South African infants induces a long-lasting polyfunctional T-cell response, with higher frequencies and better quality of BCG-specific CD4 T cells at age 1 year compared to newborn BCG vaccination [21]. Conflicting studies have shown no significant immunological benefit of delayed BCG [22–24]. However, in utero exposure to maternal HIV and M. tuberculosis infection does not appear to alter long-term immune responses of HIV-uninfected infants to BCG vaccination when given at age 6 weeks [25, 26].New tuberculosis vaccine candidates in clinical development include recombinant and live-attenuated mycobacterial vaccines and viral-vectored or protein-subunit vaccines [27]. A nonreplicating vaccine with a track record of safety in infants and HIV-infected persons would be required to test this novel strategy. Although MVA85A did not confer additional protection when given as a boost vaccine after BCG prime in HIV-uninfected infants [28], MVA85A is an ideal candidate vaccine to test this experimental strategy since MVA85A was safe in this high-risk population [29–33].Here, we report on the safety and immunogenicity of MVA85A vaccination in newborns of HIV-infected mothers, followed by selective deferred BCG vaccination at 8 weeks for HIV-uninfected infants, in a double-blind, randomized, controlled trial.METHODSThe trial was conducted at 2 sites near Cape Town, South Africa. Mothers provided written antenatal and postnatal consent for infant participation. The protocol was approved by the ethics committees of the universities of Cape Town (013/2012), Stellenbosch (M12/03/020), and Oxford (02-12). Eligible infants (see Supplementary Materials) were randomized 1:1 to receive either MVA85A vaccine (1 × 108 PFU) or Candin® control within 96 hours of birth in blinded fashion (Figure 1A). BCG was administered (1–4 × 105 cfu) at age 8 weeks only to infants documented to be HIV-uninfected at age 6 weeks by negative HIV DNA PCR (Roche Diagnostic COBAS AmpliPrep COBAS Taqman HIV-1 Qual test version 2.0)[Figure 1A]. HIV DNA PCR testing prior to age 6 weeks was not routine at the time. All infants were followed for safety endpoints at weeks 1, 4, 6, and 8 after MVA85A/control vaccination and thereafter at weeks 9, 12, and 16 (corresponding to weeks 1, 4, and 8 following delayed BCG vaccination at 8 age weeks) and at week 52. All infants underwent safety monitoring for solicited and unsolicited local, regional, and systemic AEs. For immunogenicity analyses, blood was collected at weeks 4, 8, 16, and 52 (Figure 1A).Figure 1.Study design (A) and CONSORT diagram (B). Abbreviations: BCG, bacille Calmette-Guérin; CONSORT, Consolidated Standards of Reporting Trials; HIV, human immunodeficiency virus; PCR, polymerase chain reaction; TB, tuberculosis.QuantiFERON-TB Gold (QFT, Qiagen) was performed on mothers at enrollment of newborns and on infants at age 1 year. Infants who reported a new household tuberculosis contact or developed symptoms or signs of tuberculosis were investigated for tuberculosis as previously described [28]. HIV-uninfected infants with a household tuberculosis contact or positive QFT or tuberculin skin test were referred for isoniazid preventive therapy after exclusion of active tuberculosis. All infants diagnosed with tuberculosis started tuberculosis treatment for disease as per national guidelines.Whole Blood Functional AssaysVenous blood was collected in sodium heparin–containing tubes for short- (12 hours) and long-term (7 days) functional assays to measure antigen-specific T-cell responses and proliferative capacity, respectively. Whole blood was left unstimulated (negative control) or stimulated with Ag85A peptide pool, BCG, and phytohemagglutinin (positive control). Assays were conducted as previously described [34, 35] (see Supplementary Materials). Samples were stained with optimized panels of monoclonal antibodies (Supplementary Materials, Table S1) and analyzed using flow cytometry (Supplementary Materials, Figures S1 and S2).Statistical AnalysesIn the intention-to-treat (ITT) population for safety analysis, the number of AEs was compared between study arms for the periods prior to and following BCG vaccination and for the entire observation period. In each period, counts and percentages of AEs were determined per arm, per category of interest. Tests of proportions per category were used to compare the number of AEs between arms for each type of AE and categories. The Bonferroni correction was applied to account for multiple testing.Linear mixed-effect models were used to assess the impact of study arm and time and their interaction on the (logged) frequencies of cytokine-producing or cytokine-proliferating T cells. In cases where the distributional assumptions of the model were not met, nonparametric tests were used to assess differences between arms at each time point and changes over time between arms (Wilcoxon rank sum test) and changes over time within arms (Wilcoxon signed rank test).The ITT population for safety analysis included all infants who received either MVA85A or control. The modified ITT (mITT) population for immunology analysis included all infants who received either MVA85A or control and BCG vaccine and who were not HIV infected, including data from all available sampling time points.RESULTSParticipantsAfter screening 261 infants, 248 were randomized and included in the ITT safety analysis; 213 infants were analyzed per protocol (Figure 1B). MVA85A and BCG immunogenicity was assessed in 65 infants in the mITT population who received MVA85A (n = 32) or control (n = 33) at birth and BCG at age 8 weeks (n = 65). The median age of infants’ mothers was 28 years; 80% of mothers were receiving long-term ART with median CD4 cell count 424 cells/mm3; and 43% of mothers tested QFT positive. Median gestational age of infants was 40 weeks; 48% were male; median birth weight was 3.2 kg; and 61% were breastfed as the initial feeding choice. Baseline demographics by study arm are shown in Table 1.Table 1.Baseline DemographicsCharacteristicMVA85A (n = 123)Candin® Control (n = 125)Median birth weight, g (IQR)3220 (2970–3420)3170 (2880–3410)Median gestational age, weeks (IQR)39 (39–40)40 (39–40)Gender female, n (%)63 (51)64 (51)Breastfed, n (%)70 (57)75 (60)Median maternal age, years (IQR)29 (26–32)28 (25–33)Mother receiving antiretroviral therapy, n (%)98 (80)101 (81)Median maternal CD4 count, cells/mm3 (IQR)442 (306–607)400 (262–554.5)Maternal QuantiFERON-tuberculosis Gold + n (%)51 (42)55 (44)Abbreviation: IQR, interquartile range.SafetyAll AEs are shown in Table 2. At least 1 AE was experienced by 243 infants including 239 infants with injection site AEs. The majority of infants experienced mild or moderate AEs. Twenty-five infants experienced at least 1 severe AE, with no difference in rate between the MVA85A (n = 11) and control (n = 14) arms. No life-threatening AEs were observed. Fifty-eight infants had at least 1 serious AE (SAE; n = 26 MVA85A; n = 32 control), including 4 deaths (n = 3 MVA85A; n = 1 control), none of which were classified as related to the investigational product. SAE diagnoses reflected the pattern of respiratory and gastroenteritic illnesses typically observed in the study communities.Table 2.All Adverse Events in the Intention-to-Treat Population Throughout Follow-up VariableTotal, n (%)MVA85A, n (%)Candin® Control, n (%)\nP ValueParticipants with ≥1 adverse event243 (98)122 (99.2)121 (96.8)Category\u2003Injection site239 (96.4)121 (98.4)118 (94.4).094\u2003Lymphadenopathy13 (5.2)4 (3.3)9 (7.2).163\u2003Systemic210 (84.7)106 (86.2)104 (83.2).515\u2003Laboratory27 (10.9)14 (11.4)13 (10.4).804Body system\u2003Cardiovascular3 (1.2)1 (0.8)2 (1.6)\u2003Digestive74 (29.8)35 (28.5)39 (31.2)\u2003Endocrine15 (6)6 (4.9)9 (7.2)\u2003Hematologic/lymphatic21 (8.5)10 (8.1)11 (8.8)\u2003Metabolic/nutritional80 (32.3)42 (34.1)38 (30.4)\u2003Musculoskeletal1 (0.4)1 (0.8)0 (0)\u2003Neurological69 (27.8)34 (27.6)35 (28)\u2003Respiratory87 (35.1)42 (34.1)45 (36)\u2003Skin241 (97.2)121 (98.4)120 (96).259\u2003Urogenital5 (2)2 (1.6)3 (2.4)Severity\u2003Mild243 (98)122 (99.2)121 (96.8).181\u2003Moderate116 (46.8)62 (50.4)54 (43.2).255\u2003Severe25 (10.1)11 (8.9)14 (11.2).555\u2003Life-threatening0 (0) 0 (0) 0 (0)Vaccine relationship (MVA85A/control)\u2003Not related236 (95.2)116 (94.3)120 (96)\u2003Unlikely98 (39.5)50 (40.7)48 (38.4)\u2003Possible66 (26.6)41 (33.3)25 (20)\u2003Probable9 (3.6)7 (5.7)2 (1.6)\u2003Definite138 (55.6)105 (85.4)33 (26.4)Vaccine relationship (bacille Calmette-Guérin)\u2003Not related229 (92.3)122 (99.2)107 (85.6)\u2003Unlikely55 (22.2)28 (22.8)27 (21.6)\u2003Possible31 (12.5)14 (11.4)17 (13.6)\u2003Probable4 (1.6)2 (1.6)2 (1.6)\u2003Definite228 (91.9)110 (89.4)118 (94.4)Outcome\u2003Death4 (1.6)3 (2.4)1 (0.8)\u2003Ongoing219 (88.3)106 (86.2)113 (90.4)\u2003Recovered with sequelae24 (9.7)14 (11.4)10 (8)\u2003Recovered without sequelae238 (96)121 (99.4)117 (93.6)\u2003Unknown2 (0.8)1 (0.8)1 (0.8)Seriousness\u2003Serious58 (23.4)26 (21.1)32 (25.6)\u2003Not serious243 (98)122 (99.2)121 (96.8)Numerator is participants with at least 1 adverse event; denominator is participants in study/arm.In the 8-week period after newborn MVA85A/control injection and before BCG vaccination, infants in the MVA85A arm were more likely to experience an AE (n = 120) than those in the control arm (n = 84; Table 3). Injection site reactions in this period were more frequent in MVA85A recipients than in controls (n = 119 MVA85A vs n = 32 control; P < .0001); there were more AEs among MVA85A recipients that were mild in severity (n = 116 MVA85A vs n = 75 control; P < .0001). There was no difference in the rate of AEs, including injection site AEs, after BCG vaccination between study arms (Supplementary Materials, Table S2).Table 3.Adverse Events in the Intention-to-Treat Population Occurring in the Period After MVA85A/Candin® Control Injection and Before bacille Calmette-Guérin Vaccination VariableTotal, n (%)MVA85A, n (%)Candin® Control, |n (%)\nP ValueParticipants with ≥1 adverse event204 (82.3)120 (97.6)84 (67.2)Category\u2003Injection site151 (60.9)119 (96.7)32 (25.6)<.0001\u2003Lymphadenopathy11 (4.4)4 (3.3)7 (5.6).369\u2003Systemic148 (59.7)76 (61.8)72 (57.6).501\u2003Laboratory10 (4)7 (5.7)3 (2.4).188Body system\u2003Cardiovascular1 (0.4)0 (0)1 (0.8)\u2003Digestive37 (14.9)16 (13)21 (16.8)\u2003Endocrine3 (1.2)2 (1.6)1 (0.8)\u2003Hematologic/lymphatic14 (5.6)7 (5.7)7 (5.6)\u2003Metabolic/nutritional33 (13.3)18 (14.6)15 (12)\u2003Musculoskeletal0 (0)0 (0)0 (0)\u2003Neurological57 (23)28 (22.8)29 (23.2)\u2003Respiratory28 (11.3)14 (11.4)14 (11.2)\u2003Skin174 (70.2)119 (96.7)55 (44)<.0001\u2003Urogenital2 (0.8)1 (0.8)1 (0.8)Severity\u2003Mild191 (77)116 (94.3)75 (60)<.0001\u2003Moderate67 (27)43 (35)24 (19.2).005\u2003Severe10 (4)4 (3.3)6 (4.8).536\u2003Life-threatening0 (0)0 (0)0 (0)Relationship (MVA85A/control)\u2003Not related75 (30.2)37 (30.1)38 (30.4)\u2003Unlikely73 (29.4)37 (30.1)36 (28.8)\u2003Possible64 (25.8)40 (32.5)24 (19.2)\u2003Probable9 (3.6)7 (5.7)2 (1.6)\u2003Definite135 (54.4)105 (85.4)30 (24)Outcome\u2003Recovered without sequelae199 (80.2)81 (65.9)118 (94.4)\u2003Recovered with sequelae12 (4.8)6 (4.9)6 (4.8)\u2003Ongoing11 (4.4)8 (6.5)3 (2.4)\u2003Death1 (0.4)1 (0.8)0 (0)\u2003Unknown0 (0)0 (0)0 (0)Seriousness\u2003Serious24 (9.7)10 (8.1)14 (11.2)\u2003Not serious201 (81)120 (97.6)81 (64.8)Numerator is participants with at least 1 adverse event; denominator is participants in study/arm.HIV and M. tuberculosis Acquisition, Diagnosis of Tuberculosis DiseaseOne infant (<1%; control arm) was diagnosed as HIV PCR positive at age 6 weeks and, per protocol, did not receive BCG vaccination at week 8. One (breastfed) infant (<1%; MVA85A arm) was HIV PCR negative at age 6 weeks and received BCG vaccine but subsequently tested HIV PCR positive at age 1 year.Five infants tested QFT positive at age 1 year (n = 1 MVA85A arm; n = 4 control arm). Eight infants were found to have tuberculosis within the 1-year follow-up period (n = 5 MVA85A; n = 3 control), of whom 1 was M. tuberculosis culture positive and 7 were diagnosed on clinical/radiographic grounds and tuberculosis contact history. Two of the tuberculosis cases were QFT positive.Ag85A and BCG-Specific T-Cell ResponsesTo evaluate the immunogenicity of MVA85A and BCG, we measured frequencies of cytokine-producing T cells (expressing combinations of interferon gamma [IFNγ], tumor necrosis factor alpha [TNFɑ], interleukin [IL] 2, IL17, and/or IL22) and their differentiation (based on coexpression of CD45RA and CCR7) after 12-hour stimulation of whole blood with Ag85A or BCG, respectively.MVA85A induced higher frequencies of Ag85A-specific IFNγ+ CD4+ T cells 4 and 8 weeks post-vaccination compared to control (Figure 2A). BCG-induced Ag85A-specific CD4+ T cells in placebo recipients were of similar magnitude to those induced by MVA85A. BCG vaccination did not boost Ag85A-specific CD4+ T cells induced by MVA85A (Figure 2B).Figure 2.Ag85A-specific CD4 cytokine responses. Fresh whole blood was stimulated with Ag85A peptides for 12 hours prior to intracellular cytokine staining and flow cytometry analysis. A, Cross-sectional comparison of frequencies of Ag85A-specific CD4+ T cells expressing interferon gamma (IFNγ) in participants who were vaccinated with MVA85A (red) or control (black) at birth. Bacille Calmette-Guérin was administered to all participants at age 8 weeks. B, Longitudinal changes of Ag85A-specific CD4+ T cells expressing IFNγ are indicated by arrows (red for MVA85A arm and black for control arm). Medians and 95% confidence intervals (for the medians) are shown. C, Frequencies of Ag85A-specific CD4+ T cells expressing different combinations of IFNγ, tumor necrosis factor alpha, and interleukin 2 were compared between MVA85A arm (solid boxes) and control arm (clear boxes) at weeks 4 (blue), 8 (purple), 16 (green), and 52 (orange). Box and whiskers denote median, interquartile range, and minimum/maximum. Unadjusted P values were calculated by mixed effects models in A and B and by Mann-Whitney test in C. Abbreviations: BCG, bacille Calmette-Guérin; IFNγ, interferon gamma; IL, interleukin; TNFα, tumor necrosis factor alpha.MVA85A induced mainly IFNγ-expressing CD4+ T cells, many of which coexpressed IL2 and TNFɑ (Figure 2C). There was no detectable IL17 or IL22 production by Ag85A-specific CD4+ T cells before BCG vaccination (data not shown).BCG vaccination induced markedly increased and durable CD4+ T-cell responses in the MVA85A prime and control groups (Figure 3A). The cytokine coexpression profiles of BCG-specific CD4+ T cells were different during the effector (week 16) and memory (week 52) phases of the response and were not affected by MVA85A prime (Figure 3B). At week 52 most BCG-specific CD4+ T cells were monofunctional (Figure 3B, blue slice), and the predominant subset of these cells expressed IL22 alone (Figure 3B, purple arc).Figure 3.Bacille Calmette-Guérin (BCG)-specific CD4 cytokine responses. Fresh whole blood was stimulated with BCG for 12 hours prior to intracellular cytokine staining and flow cytometry analysis. A, Longitudinal changes of BCG-specific CD4+ T cells expressing any combination of interferon gamma (IFNγ), tumor necrosis factor alpha (TNFα), interleukin (IL) 2, IL17, and/or IL22 are indicated by arrows (red for MVA85A arm and black for control arm). Medians and 95% confidence intervals (CIs; for the medians) are shown. Unadjusted P values were calculated by mixed effects models. B, Cytokine coexpression patterns of BCG-specific CD4 responses at week 16 (left) and week 52 (right) in the MVA85A (top) and control (bottom) arms by permutation test. Pies represent total BCG-specific CD4+ T cells expressing any cytokine; slices show the relative proportion of cells coexpressing 1 (blue), 2 (green), 3 (yellow), or 4 (orange) cytokines, identified by the external arcs: IFNγ (red), IL2 (black), IL17 (orange), IL22 (purple), and TNFα (dark green). C, Differentiation profiles were defined based on expression patterns of CD45RA and CCR7 as follows: naive-like (TNL, CD45RA+ CCR7+), central memory (TCM, CD45RA- CCR7+), effector (TE, CD45RA- CCR7-), and terminal effector (TTE, CD45RA+ CCR7-). Representative flow cytometry plot of BCG-specific cytokine+ CD4+ T cells (pink) overlaid on total CD4+ T cells (black). D, Longitudinal changes of BCG-specific cytokine+ CD4+ T cells expressing TNL (maroon), TCM (blue), TE (orange), or TTE (green) phenotype in MVA85A (left) or control (right) recipients. Medians and 95% CIs (for the medians) are shown. The number of participants meeting cutoff criteria for this analysis (see methods) is shown for each visit. Frequencies of all subsets significantly increased (P < .025) upon BCG vaccination (week 8 vs week 16) and decreased (P < .025) between week 16 and 52, with the exception of TCM in the MVA85A arm. Unadjusted P values were calculated by Wilcoxon matched-pairs test; week 4 and 8 were not compared due to low numbers of paired samples (less than 10). No significant differences were observed when comparing frequencies of each subset at each visit between study arms. Abbreviations: BCG, bacille Calmette-Guérin; IFNγ, interferon gamma; IL, interleukin; TNFα, tumor necrosis factor alpha.We also measured memory phenotype of cytokine-expressing, BCG-specific CD4+ T cells (Figure 3C). Frequencies of naive-like (TNL), central memory (TCM), effector (TE), and terminal effector (TTE) BCG-specific CD4+ T cells were not different between study arms at any visit, although BCG administration induced all subsets significantly (week 8 vs 16; P < .025 for all subsets in both study arms). Central memory T cells were maintained at similar levels between week 16 and week 52 only in the MVA85A arm, while all other subsets decreased (P < .025).Ag85A- and BCG-specific CD8+ T cells were detected at low levels, predominantly expressed IFNγ or TNFα, and were not different between the study groups (Supplementary Materials, Figure S3A, S3B and data not shown).T-Cell Proliferative Responses to Ag85A and BCGT-cell proliferation is a sensitive measurement of vaccine immunogenicity. BCG-specific proliferative responses are typically not persistently affected by HIV exposure [26] or delayed BCG administration [23]. Long-term recall and effector potential of MVA85A and BCG-induced T-cell responses were assessed by measuring proliferative capacity (expression of cell cycle–associated marker Ki67) of antigen-specific T cells and their cytotoxic potential (upregulation of cytotoxic mediators granzyme A, granzyme B, granzyme K, granulysin, and perforin) upon 7-day stimulation of whole blood with Ag85A or BCG, respectively.MVA85A and BCG induced similar low CD4 proliferative responses to Ag85, which was lost by age 1 year (Figure 4A). BCG administration did not further boost proliferative responses primed by MVA85A.Figure 4.CD4+ T cell proliferation in response to Ag85A and bacille Calmette-Guérin (BCG). Fresh whole blood was stimulated with Ag85A peptides or BCG for 7 days prior to intracellular staining of Ki67 and cytotoxic markers and flow cytometric analysis. Frequencies of Ag85A-specific (A) and BCG-specific (B) CD4+ T cells expressing the proliferation marker Ki67 were analyzed longitudinally in MVA85A (red lines and arrows) and control (black lines and arrows) arms. Medians and 95% confidence intervals (for the medians) are shown. Unadjusted P values were calculated by mixed effects models. C, Cytotoxic mediator coexpression patterns of BCG-specific CD4 responses were compared across study weeks in MVA85A arm (top) and control arm (bottom) by permutation test. No significant differences between study arms were observed at any visit. Pies represent total BCG-specific CD4+ T cells expressing Ki67, and slices represent the relative proportion of cells coexpressing cytotoxic markers identified by the external arcs: granzyme A (blue), granzyme B (red), granulysin (green), granzyme K (orange), and perforin (purple). Black slices denote the proportion of proliferating cells that do not express any cytotoxic marker. The number of participants meeting cutoff criteria for this analysis (see methods) is shown within each pie. Abbreviations: BCG, bacille Calmette-Guérin.BCG vaccination induced a strong CD4 proliferative response to BCG, which did not differ by study arm and was not sustained above prevaccination levels by age 1 year (Figure 4B).During the effector phase of BCG-induced responses (week 16), the majority of proliferating CD4+ T cells upregulated expression of cytotoxic mediators (Figure 4C), mostly granzyme A (blue arc), granzyme B (red arc), and granulysin (green arc). Proportions of proliferating CD4+ T cells expressing cytotoxic mediators had decreased by week 52 but still comprised approximately one third of BCG-specific CD4+ T cells (Figure 4C). No differences in the cytotoxic potential were observed between study arms at any time point (Figure 4C).DISCUSSIONNewborn administration of a viral-vectored prime vaccine (MVA85A), followed by BCG vaccine boost at age 8 weeks, had an acceptable safety and reactogenicity profile; induced modest, antigen-specific responses before BCG administration; and did not interfere with or enhance subsequent BCG immunogenicity. These findings demonstrate proof of principle that a novel tuberculosis vaccination strategy based on a newborn priming vaccine other than BCG, including candidates that are potentially more immunogenic than MVA85A, can be administered safely to HIV-exposed newborns. Such a strategy would avoid the risks associated with administration of live BCG vaccine to infants with undiagnosed perinatal HIV infection. We infer from these findings that a new efficacious subunit or viral-vectored tuberculosis vaccine might also be given safely to newborns to provide protection against tuberculosis disease in the early weeks of life.It is notable that the rate of HIV acquisition (<1%) was low compared to historical perinatal HIV transmission rates in South Africa (2.7% in 2012 [17]). This is due in part to systemic improvements in the perinatal HIV prevention (prevention of mother-to-child transmission [PMTCT]) and because maternal ART or perinatal prophylaxis was a requirement for infant enrollment. Therefore, this alternative tuberculosis vaccination strategy would be expected to have even greater impact on BCG vaccine safety in countries where PMTCT programs are weaker and perinatal HIV transmission rates are higher.It is also striking that the rate of QFT conversion in HIV-exposed infants at age 1 year (2.5%) was lower than that reported for HIV-unexposed infants in these communities (6%–7%) [28, 36]. While the overall incidence of tuberculosis (3.3%) was similar to what has been described in previous reports [28], clinical diagnoses are likely to have resulted in overestimation of the true disease rate. It is likely that the exclusion criterion for household tuberculosis contact reduced the risk for tuberculosis transmission and disease in study infants, as evidenced by the maternal QFT positive rate (43%), which is considerably lower than that observed in HIV-uninfected young adults in the same community [36].We and others have shown that deferring BCG administration from birth to age 6–18 weeks does not impair long-term BCG immunogenicity [21–24]. Here, we evaluated the effects of administering a newborn prime tuberculosis vaccine on the immunogenicity of deferred BCG vaccination. MVA85A was weakly immunogenic, inducing mainly IFNγ+ Ag85A-specific cells before BCG administration. In BCG-vaccinated infants, higher abundance of cells releasing IFNγ upon BCG stimulation was associated with lower risk of progression to tuberculosis disease [37]. Whether the low IFNγ+ T-cell responses induced by MVA85A could be sufficient to protect against tuberculosis before BCG administration is unknown. Our findings differ from those in previous observations in HIV-exposed and HIV-unexposed infants [38, 39] in which MVA.HIVA was poorly immunogenic, due possibly to differences in study design, lower dose of MVA.HIVA, age at administration, and the assay used to measure immunogenicity. Nevertheless, these trials showed no interference by MVA administration with immunogenicity of routine childhood vaccines, further supporting the clinical development of this strategy.Remarkably, BCG did not further boost MVA85A-primed Ag85A-specific T-cell responses. These findings differ from observations made using the converse vaccination strategy, in which MVA85A significantly enhanced Ag85A-specific CD4 T-cell responses primed by BCG [28]. These observations suggest that either MVA85A is more immunogenic when used as a boost vaccine after BCG priming or, alternatively, that BCG cannot further boost Ag85A-specific T-cell responses that have been maximally primed by MVA85A. Regardless, BCG vaccination induced similar magnitudes of Ag85A-specific T-cell responses in the control and MVA85A groups. We deduce that for a given antigen, MVA is as good a vector as BCG, but that the immune response to Ag85A in this newborn population is weak. Importantly, MVA85A prime did not interfere with BCG immunogenicity with respect to the magnitude, functional quality, memory phenotype, and proliferative capacity of antigen-specific CD4+ T cells.T-cell proliferation was measured to assess relevant immune functions other than cytokine production, such as long-term recall responses and cytotoxic potential, with a more sensitive assay. Unlike cytokine production, T-cell proliferative responses to Ag85A and BCG were not sustained at age 1 year. Similarly, we previously reported that IFNγ release measured upon a 7-day whole blood stimulation with BCG was mostly undetectable by age 1 year, irrespective of age at BCG administration (birth vs 14 weeks) and HIV exposure [40]. While the underlying reasons for the loss of proliferative potential remain to be determined, it is clear that measuring T-cell functions other than IFNγ production is important to assess immunogenicity of novel vaccination strategies.Interpretation of our findings is limited by the lack of HIV-unexposed and BCG-naive control groups, both of which would not be ethically permissible in a highly tuberculosis-endemic setting. Further, the study sample size was selected to assess safety and immunogenicity and was not powered to test efficacy against M. tuberculosis infection or tuberculosis disease. Finally, although MVA85A has an excellent safety track record that is ideal for an experimental medicine study, further studies are needed to test this principle for potentially more efficacious tuberculosis vaccine candidates.In conclusion, the acceptable safety and reactogenicity profile, modest immunogenicity, and lack of interference with immunogenicity of BCG support further testing of alternative newborn prime vaccines, including other vector-based and protein-adjuvant candidates with additional antigens to enhance immunogenicity. This novel strategy should be pursued in order to provide protective immunity against M. tuberculosis in the first months of life, while being safe for all HIV-exposed infants.Supplementary DataSupplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.Supplementary MaterialSupplementary Figure 1Click here for additional data file.Supplementary Figure 2Click here for additional data file.Supplementary Figure 3Click here for additional data file.Supplementary Table 1Click here for additional data file.Supplementary Table 2Click here for additional data file.Supplementary InformationClick here for additional data file.Notes\nAcknowledgments. We thank study participants, their families, and the communities of Cape Winelands East district and Khayelitsha; personnel at the South African Tuberculosis Vaccine Initiative and the Desmond Tutu TB Center; and the study Safety Monitor (Zaynab Waggie) and Data Safety Monitoring Committee (Prakash Jeena, Brian Eley, Lewellys Barker, and Margaret Snowden).\nFinancial support. This work was supported by the UK Medical Research Council, Department for International Development, and Wellcome Trust Joint Global Health Trials programme (grant G1100570/1) and by AERAS. H. Mc. S. is a Wellcome senior clinical research fellow.\nPotential conflicts of interest. The authors declare no conflict of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.References1.\nZwerlingA, BehrMA, VermaA, BrewerTF, MenziesD, PaiM\nThe BCG world atlas: a database of global BCG vaccination policies and practices. PLoS Med2011; 8:e1001012.214453252.\nMaraisBJ, GieRP, SchaafHS\nThe clinical epidemiology of childhood pulmonary tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis2004; 8:278–85.151394653.\nMaraisBJ, GieRP, SchaafHS\nThe natural history of childhood intra-thoracic tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis2004; 8:392–402.151417294.\nColditzGA, BerkeyCS, MostellerF\nThe efficacy of bacillus Calmette-Guérin vaccination of newborns and infants in the prevention of tuberculosis: meta-analyses of the published literature. 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Int J Tuberc Lung Dis2009; 13:1331–44.1986100315.\nKanabusA.\nInformation about Tuberculosis: TB Statistics-Global, Regional and High Burden. Global Health Education (GHE), 2017\nwww.tbfacts.org. Accessed 14 October 2017.16.\nBhardwajS, BarronP, PillayY\nElimination of mother-to-child transmission of HIV in South Africa: rapid scale-up using quality improvement. S Afr Med J2014; 104:239–43.2489350017.\nJoint review of HIV, TB and PMTCT programmes in South Africa. Department of Health, Republic of South Africa, 2014.18.\nSouth Africa. HIV and AIDS estimates, 2016\nwww.unaids.org. Accessed 14 October 2017.19.\nBarronP, PillayY, DohertyT\nEliminating mother-to-child HIV transmission in South Africa. Bull World Health Organ2013; 91:70–4.2339735320.\nHatherillM, MahomedH, HanekomW\nNovel vaccine prime and selective BCG boost: a new tuberculosis vaccine strategy for infants of HIV-infected mothers. Vaccine2010; 28:4550–2.2047079721.\nKaginaBM, AbelB, BowmakerM\nDelaying BCG vaccination from birth to 10 weeks of age may result in an enhanced memory CD4 T cell response. Vaccine2009; 27:5488–95.1961649422.\nBurlS, AdetifaUJ, CoxM\nDelaying bacillus Calmette-Guérin vaccination from birth to 4½ months of age reduces postvaccination Th1 and IL-17 responses but leads to comparable mycobacterial responses at 9 months of age. J Immunol2010; 185:2620–8.2064416023.\nTchakouteCT, HesselingAC, KidzeruEB\nDelaying BCG vaccination until 8 weeks of age results in robust BCG-specific T-cell responses in HIV-exposed infants. J Infect Dis2015; 211:338–46.2510802724.\nLutwamaF, KaginaBM, WajjaA\nDistinct T-cell responses when BCG vaccination is delayed from birth to 6 weeks of age in Ugandan infants. J Infect Dis2014; 209:887–97.2417911125.\nMansoorN, ScribaTJ, de KockM\nHIV-1 infection in infants severely impairs the immune response induced by Bacille Calmette-Guérin vaccine. J Infect Dis2009; 199:982–90.1923628026.\nJonesCE, HesselingAC, Tena-CokiNG\nThe impact of HIV exposure and maternal Mycobacterium tuberculosis infection on infant immune responses to bacille Calmette-Guérin vaccination. AIDS2015; 29:155–65.2553575227.\nRowlandR, McShaneH\nTuberculosis vaccines in clinical trials. Expert Rev Vaccines2011; 10:645–58.2160498528.\nTamerisMD, HatherillM, LandryBS; MVA85A 020 Trial Study Team\nSafety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial. Lancet2013; 381:1021–8.2339146529.\nScribaTJ, TamerisM, MansoorN\nDose-finding study of the novel tuberculosis vaccine, MVA85A, in healthy BCG-vaccinated infants. J Infect Dis2011; 203:1832–43.2160654230.\nMinassianAM, RowlandR, BeveridgeNE\nA phase I study evaluating the safety and immunogenicity of MVA85A, a candidate TB vaccine, in HIV-infected adults. BMJ Open2011; 1:e000223.31.\nScribaTJ, TamerisM, SmitE\nA phase IIa trial of the new tuberculosis vaccine, MVA85A, in HIV- and/or Mycobacterium tuberculosis-infected adults. Am J Respir Crit Care Med2012; 185:769–78.2228183132.\nNdiayeBP, ThienemannF, OtaM; MVA85A 030 Trial Investigators\nSafety, immunogenicity, and efficacy of the candidate tuberculosis vaccine MVA85A in healthy adults infected with HIV-1: a randomised, placebo-controlled, phase 2 trial. Lancet Respir Med2015; 3:190–200.2572608833.\nDieyeTN, NdiayeBP, DiengAB\nTwo doses of candidate TB vaccine MVA85A in antiretroviral therapy (ART) naïve subjects gives comparable immunogenicity to one dose in ART+ subjects. PLoS One2013; 8:e67177.2384061834.\nKaginaBM, MansoorN, KpameganEP\nQualification of a whole blood intracellular cytokine staining assay to measure mycobacteria-specific CD4 and CD8 T cell immunity by flow cytometry. J Immunol Methods2015; 417:22–33.2552392335.\nSoaresA, GovenderL, HughesJ\nNovel application of Ki67 to quantify antigen-specific in vitro lymphoproliferation. J Immunol Methods2010; 362:43–50.2080006636.\nMahomedH, HughesEJ, HawkridgeT\nComparison of mantoux skin test with three generations of a whole blood IFN-gamma assay for tuberculosis infection. Int J Tuberc Lung Dis2006; 10:310–6.1656271237.\nFletcherHA, SnowdenMA, LandryB\nT-cell activation is an immune correlate of risk in BCG vaccinated infants. Nat Commun2016; 7:11290.2706870838.\nNjugunaIN, AmblerG, ReillyM\nPedVacc 002: a phase I/II randomized clinical trial of MVA.HIVA vaccine administered to infants born to human immunodeficiency virus type 1-positive mothers in Nairobi. Vaccine2014; 32:5801–8.2517348439.\nAfolabiMO, NdureJ, DrammehA\nA phase I randomized clinical trial of candidate human immunodeficiency virus type 1 vaccine MVA.HIVA administered to Gambian infants. PLoS One2013; 8:e78289.2420518540.\nHesselingAC, JaspanHB, BlackGF, NeneN, WalzlG\nImmunogenicity of BCG in HIV-exposed and non-exposed infants following routine birth or delayed vaccination. Int J Tuberc Lung Dis2015; 19:454–62.25860002Appendix\nMVA029 Study Team. Charmaine Abrahams, Deborah Abrahams, Hadn Africa, Veronica Baartman, Beauty Bavuma, Nicole Bilek, Natasja Botes, Yolande Brown, Yolundi Cloete, Margareth Damons, Ronel De Vos, Portia Dlakavu, Karen Du Preez, Mzwandile Erasmus, Claudia Francis, Hendrik Geldenhuys, Mandy Geldenhuys, Katriena Goedeman, Sandra Golliath, Angelique Hendricks Mouton, Christiaan Hopley, Ruwijda Jansen, Carolynne Jones, Alana Keyser, Benjamin Kagina, Gloria Khomba, Fazlin Kola–Cassiem, Sandra Kruger, Daphne Leukes, Loyiso Louw, Angelique Luabeya, Theresa Maart, Lebohang Makhethe, Simbarashe Mbabwe, Eunice Mtshamba, Boniswa Mvinjelwa, Lungisa Nkantsu, Julia Noble, Sizwe Nqweniso, Fajwa Opperman, Christel Petersen, Patiswa Plaatjie, Susan Rossouw, Roxanne Solomoms, Marcia Steyn, Liticia Swanepoel, Asma Toefy, Heidi van Deventer, Elma van Rooyen, Daphne van Ster, Bongiwe Vazana, Ashley Veldsman, Noncedo Xoyana.', 'title': 'Safety and Immunogenicity of Newborn MVA85A Vaccination and Selective, Delayed Bacille Calmette-Guerin for Infants of Human Immunodeficiency Virus-Infected Mothers: A Phase 2 Randomized, Controlled Trial.', 'date': '2017-10-14'}}
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Public Health, Epidemiology & Health Systems
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71
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Is improvement in health status up to 6 months (as measured by improvement on both CCQ and SGRQ) higher, lower, or the same when comparing smart technology for self‐management to face‐to‐face/digital and/or written support for self‐management?
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higher
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low
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yes
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['27502583', '26089656', '24293120']
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{'27502583': {'article_id': '27502583', 'content': "J Med Internet ResJ. Med. Internet ResJMIRJournal of Medical Internet Research1439-44561438-8871JMIR PublicationsToronto, Canada275025834993862v18i8e21510.2196/jmir.5622Original PaperOriginal PaperLong-Term Effects of an Internet-Mediated Pedometer-Based Walking Program for Chronic Obstructive Pulmonary Disease: Randomized Controlled TrialEysenbachGuntherCobbNathanMullerIngridJeromeGeraldRyanDermotGraingerRebeccaPoderThomasMoyMarilyn LMD12http://orcid.org/0000-0002-2471-9218MartinezCarlos HMD3http://orcid.org/0000-0003-2070-4091KadriReemaMLIS45http://orcid.org/0000-0003-0935-3761RomanPiaMA5http://orcid.org/0000-0002-6190-4666HollemanRobert GMPH5http://orcid.org/0000-0003-2300-1842KimHyungjin MyraScD56http://orcid.org/0000-0002-0604-8027NguyenHuong QPhD7http://orcid.org/0000-0002-3650-3705CohenMiriam DMSN8http://orcid.org/0000-0002-8551-0741GoodrichDavid EEdD5http://orcid.org/0000-0003-3232-2189GiardinoNicholas DPhD9http://orcid.org/0000-0002-5026-3859RichardsonCaroline RMD4Department of Family MedicineUniversity of Michigan1018 Fuller St.Ann Arbor, MI, 48104United States1 734 998 7120 ext 3161 734 998 7335caroli@umich.edu5http://orcid.org/0000-0002-1945-60461Pulmonary and Critical Care Medicine SectionVA Boston Healthcare SystemBoston, MAUnited States2Harvard Medical SchoolBoston, MAUnited States3Pulmonary & Critical Care DivisionUniversity of Michigan Health SystemAnn Arbor, MIUnited States4Department of Family MedicineUniversity of MichiganAnn Arbor, MIUnited States5Center for Clinical Management ResearchVA Ann Arbor Healthcare SystemAnn Arbor, MIUnited States6Department of BiostatisticsSchool of Public HealthUniversity of MichiganAnn Arbor, MIUnited States7Department of Research and EvaluationKaiser Permanente Southern CaliforniaPasadena, CAUnited States8Pulmonary Medicine SectionVA New York HarborBrooklyn, NYUnited States9Department of PsychiatryUniversity of MichiganAnn Arbor, MIUnited StatesCorresponding Author: Caroline R Richardson\ncaroli@umich.edu820160882016188e215922016103201621420162452016©Marilyn L Moy, Carlos H Martinez, Reema Kadri, Pia Roman, Robert G Holleman, Hyungjin Myra Kim, Huong Q Nguyen, Miriam D Cohen, David E Goodrich, Nicholas D Giardino, Caroline R Richardson. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 08.08.2016.2016This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in the Journal of Medical Internet Research, is properly cited. The complete bibliographic information, a link to the original publication on http://www.jmir.org/, as well as this copyright and license information must be included.BackgroundRegular physical activity (PA) is recommended for persons with chronic obstructive pulmonary disease (COPD). Interventions that promote PA and sustain long-term adherence to PA are needed.ObjectiveWe examined the effects of an Internet-mediated, pedometer-based walking intervention, called Taking Healthy Steps, at 12 months.MethodsVeterans with COPD (N=239) were randomized in a 2:1 ratio to the intervention or wait-list control. During the first 4 months, participants in the intervention group were instructed to wear the pedometer every day, upload daily step counts at least once a week, and were provided access to a website with four key components: individualized goal setting, iterative feedback, educational and motivational content, and an online community forum. The subsequent 8-month maintenance phase was the same except that participants no longer received new educational content. Participants randomized to the wait-list control group were instructed to wear the pedometer, but they did not receive step-count goals or instructions to increase PA. The primary outcome was health-related quality of life (HRQL) assessed by the St George’s Respiratory Questionnaire Total Score (SGRQ-TS); the secondary outcome was daily step count. Linear mixed-effect models assessed the effect of intervention over time. One participant was excluded from the analysis because he was an outlier. Within the intervention group, we assessed pedometer adherence and website engagement by examining percent of days with valid step-count data, number of log-ins to the website each month, use of the online community forum, and responses to a structured survey.ResultsParticipants were 93.7% male (223/238) with a mean age of 67 (SD 9) years. At 12 months, there were no significant between-group differences in SGRQ-TS or daily step count. Between-group difference in daily step count was maximal and statistically significant at month 4 (P<.001), but approached zero in months 8-12. Within the intervention group, mean 76.7% (SD 29.5) of 366 days had valid step-count data, which decreased over the months of study (P<.001). Mean number of log-ins to the website each month also significantly decreased over the months of study (P<.001). The online community forum was used at least once during the study by 83.8% (129/154) of participants. Responses to questions assessing participants’ goal commitment and intervention engagement were not significantly different at 12 months compared to 4 months.ConclusionsAn Internet-mediated, pedometer-based PA intervention, although efficacious at 4 months, does not maintain improvements in HRQL and daily step counts at 12 months. Waning pedometer adherence and website engagement by the intervention group were observed. Future efforts should focus on improving features of PA interventions to promote long-term behavior change and sustain engagement in PA.ClinicalTrialClinicaltrials.gov NCT01102777; https://clinicaltrials.gov/ct2/show/NCT01102777 (Archived by WebCite at http://www.webcitation.org/6iyNP9KUC)bronchitis, chronicemphysemapulmonary disease, chronic obstructivequality of lifeexercisemotor activityInternetIntroductionPhysical activity (PA) is significantly reduced in persons with chronic obstructive pulmonary disease (COPD), even at the earliest stages of disease [1-3]. Its clinical course is punctuated with acute exacerbations, during and following which persons suffer further reductions in PA [4,5]. As a disease with systemic consequences, COPD increases vulnerability to frailty, immobility, and loss of functional independence. Despite optimal pharmacological therapy, persons with COPD suffer from a downward spiral of breathlessness, deconditioning, and physical inactivity [6]. Comorbidities of cardiovascular disease, diabetes mellitus, and osteoporosis contribute to further reductions in PA [7,8].Physical activity is a modifiable health behavior that affects COPD-specific outcomes [9-14]. It has been shown that a greater quantity of low-intensity PA reduces risk of COPD hospitalizations, whereas high-intensity PA does not result in risk reduction [15]. In a cohort of persons with COPD, those who walk the least have risks that are 2 and 6 times higher for acute exacerbations and COPD-related hospitalizations, respectively, compared to those who walk the most [12]. In addition, persons with COPD with higher PA levels have a significantly lower risk of dying, independent of forced expiratory volume in 1 second (FEV1) [14]. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend regular PA for all persons with stable COPD as part of standard nonpharmacological treatment [6].Despite the evidence and recommendations, effective long-term PA interventions are lacking in the clinical care of patients with COPD. Most studies of long-term exercise interventions have examined methods to maintain exercise in the subset of persons with COPD who have completed a conventional pulmonary rehabilitation program [16-21]. These interventions have combined weekly- or monthly-supervised exercise classes with unsupervised home exercise, support groups, and/or telephone contact with a health care professional, showing mixed results over the long term [16-21]. Strategies that promote behavior change and long-term adherence to effectively sustain PA in all persons with COPD are needed.We developed an automated, Internet-mediated, pedometer-based walking program called Taking Healthy Steps to promote PA in persons with COPD. Taking Healthy Steps combines the Omron HJ-720 ITC pedometer (Omron Healthcare, Inc, Bannockburn, IL, USA) with a disease-specific website accessed via a URL. Taking Healthy Steps provides iterative step-count feedback, individualized step-count goals, education on disease self-management, motivational support, and an online community of social support [22-27]. We studied the efficacy of Taking Healthy Steps in a randomized controlled trial (trial registration: Clinicaltrials.gov NCT01102777) [27]. The conceptual framework, study design, and results at 4 months have been described previously [26,27]. We have shown that Taking Healthy Steps is safe and engaging, and improves health-related quality of life (HRQL) and increases daily step count at 4 months [25-27]. In this study, our primary aim was to assess the long-term efficacy of Taking Healthy Steps on HRQL and daily step counts, a marker for walking behavior change, at 12 months. Our secondary aim was to assess long-term engagement with the PA intervention.MethodsRecruitmentThe study design and methods have been reported previously [26,27]. Participants were enrolled from national patient care databases of US Veterans, between December 2011 and January 2013, who had received any treatment services in the previous year and had a COPD diagnosis. Zip codes were matched with the Rural Urban Commuting Area Codes to determine whether one’s residence was urban or rural [28]. Of the 21 regional Veteran Integrated Service Networks (VISN) across the 50 United States and Puerto Rico, we excluded Veterans from one VISN (VISN-1) where another COPD research study using the Taking Healthy Steps platform was recruiting participants. The coordinating center was located at the Ann Arbor VA Healthcare System, Ann Arbor, MI, USA. Ethical approval for this study was granted by the VA Ann Arbor Healthcare System Human Studies Subcommittee.A random sample of 28,957 Veterans (half rural, half urban) with a COPD diagnosis was sent a recruitment letter. Inclusion criteria included having access to a computer with an Internet connection, a USB port, and Windows XP, Vista, Windows 7, or Windows 8. Our a priori exclusion criteria excluded those who did not upload baseline step-count data or who did not complete the baseline survey to assess HRQL. Per study protocol, participants had to have baseline values for the primary (HRQL) and secondary outcome (daily step count) to be enrolled and randomized. Ultimately, 239 participants were enrolled and randomized in a 2:1 ratio to either Taking Healthy Steps (Internet-mediated, pedometer-based walking program) or wait-list control (pedometer alone), stratified by Modified Medical Research Council (MMRC) dyspnea score and urban versus rural status (Figure 1). All participants were prompted monthly to report new or worsening medical problems; all self-reported adverse events were recorded. There were no face-to-face encounters with staff; all features were automatically delivered via the website.Figure 1CONSORT diagram at 12 months.OutcomesPrimary OutcomeThe St. George’s Respiratory Questionnaire (SGRQ), a disease-specific instrument with 50 items that has been well validated in COPD [29,30] was used to assess HRQL. It has a summary total score (SGRQ-TS) composed of three domain scores: symptoms (frequency and severity), activities (that cause or are limited by breathlessness), and impact (social functioning and psychological disturbances resulting from airways disease). Scores range from 0 to 100 with lower scores indicating better HRQL. A change of four units is the minimum clinically important difference for the SGRQ-TS [31]. Study participants completed the SGRQ online at study entry, 4 months, and 12 months.Secondary OutcomeDaily step count was assessed by the Omron HJ-720 ITC pedometer. Once participants completed the baseline survey, study staff mailed them a pedometer that had an embedded USB port, an upload cable, and detailed written instructions on how to install the Java software and upload pedometer data. For users who did not have Java already installed on their computers, the software installation was a one-time event. Thereafter, participants uploaded step-count data using the cable that connected the pedometer to their home computer. Research staff were available by telephone to assist with software installation and upload of step counts.A wear day with valid step-count data was defined as one having at least 100 steps and 8 hours of step counts recorded [32]. At baseline, participants wore the pedometer covered with a sticker to blind the participant to device feedback. Baseline daily step count was the mean daily step count calculated using at least 5 days of valid data within a period of seven consecutive days. Follow-up daily step counts were calculated within a window of +/-14 days around day 121 for 4-month values, and +/-14 days around day 366 for 12-month values. Follow-up daily step counts were the means of at least 5 days of valid data within a period of seven consecutive days. We also calculated the mean daily step count each month by examining the data in 30-day increments. We used values from the last valid week (at least 5 days of valid data within a period of seven consecutive days) in each of those months.Intervention GroupParticipants randomized to Taking Healthy Steps completed an intensive 4-month intervention period, followed by a distinct 8-month maintenance phase (Table 1). During the first 4 months, participants were instructed to wear the pedometer every day, reminded to upload at least weekly, and were provided access to the website. The website has four key components [26,27]: individualized goal setting was based on uploaded step counts, iterative feedback allowed self-monitoring of step counts, motivational content provided a new educational tip every other day and a new motivational message each week, and an online community forum enhanced social support [22-27]. During the 8-month maintenance phase, participants continued to wear the pedometer, upload daily step counts, receive weekly step-count goals and feedback, and had access to the online community forum. They could view the initial 4 months of educational content and motivational messages, but no longer received new content. Topics on the online community forum included walking in a variety of weather/seasons, health topics (weight management, COPD disease management), injury prevention, barriers to walking, and technical issues with the pedometer and website.Table 1Features available to the Taking Healthy Steps and control groups during the first 4 months versus last 8 months of the study.Features0-4 Months5-12 MonthsTaking Healthy StepsControlTaking Healthy StepsControlWear pedometerYesYesYesYesUpload step-count dataAt least weeklyAt least monthlyAt least weeklyAt least monthlyGoal settingYesNoYesNoFeedbackYesNoYesNoNew educational and motivational contentYesNoNoNoOnline community forumYesNoYesNoWait-List Control GroupParticipants randomized to the wait-list control group were instructed to wear the pedometer every day, reminded monthly to log in to the website to upload step-count data, and asked to report all adverse events. Veterans in the wait-list control group received neither instruction to increase PA nor step-count goals. They had access to a webpage that showed only a checklist of surveys completed and a count of what week they were in the study. After 12 months, they were given the option to use the Internet-mediated intervention.Participant Characteristics, Device Adherence, and Website EngagementAt baseline, participants answered questions online that assessed comorbidities, oxygen use, smoking status, and demographics. At study entry, 4 months, and 12 months, dyspnea was assessed using the MMRC scale (range 0-4 with 4 indicating the most severe level of dyspnea) [33]. Events self-reported during the study were defined a priori as COPD-related if persons experienced a combination of symptoms and/or required treatment with antibiotics and/or systemic corticosteroids. The COPD-related events included acute exacerbations or pneumonia, ascertained by self-reported events and/or review of health care utilization (hospitalizations and emergency room visits) and pharmacy data. To assure independence of individual acute exacerbations, participants were considered to have experienced a new acute exacerbation only if it were reported 21 or more days after the previous acute exacerbation [34].We examined device adherence, overall and by group, by calculating the percentage of days (of 366 days) that were wear days with valid step-count data. For the participants who uploaded valid step-count data at 12 months and completed the study, we also examined percentage of days (of 42 days) that were wear days during the last 6 weeks of the study.In the intervention group, we objectively examined website engagement by recording the number of log-ins to the website by month of study and assessing the frequency of use of the online community forum. In addition, at 4 and 12 months, participants in the Taking Healthy Steps group answered a structured survey eliciting feedback about their commitment to their step-count goals and various aspects of engagement with the intervention, including participants’ ease of finding time to log in to the website, knowledge of step-count goals, and use of the different components of the website.Statistical AnalysisProportions, means, and standard deviations described baseline participant characteristics. Two-sample t tests and chi-square tests compared baseline characteristics between groups. The occurrence of COPD-related events (acute exacerbations or pneumonia), hospitalizations, emergency room visits, deaths, and adverse events during the study were each compared between groups using a logistic regression model. For the count of hospitalizations, a zero-inflated Poisson regression model was also used to assess the difference in the rate of hospitalizations between groups. These models adjusted for age, gender, treatment group, and oxygen use.The primary analysis used the intention-to-treat approach, and used a linear mixed-effects model with baseline, 4-month, and 12-month outcome values (eg, SGRQ-TS or daily step count) as dependent variables. No baseline variable was predictive of missingness in models adjusting for stratification variables and treatment group. Thus, the longitudinal data model included participants who had the dependent variable for at least one time point and was expected to give unbiased estimates of the intervention effect assuming missingness at random. The model included participants as random intercepts to adjust for within-participant correlations of repeated measures, fixed predictors of treatment group, 4- and 12-month time indicators, and treatment group by time indicator interactions, MMRC dyspnea score (dichotomized to 0-1 vs 2-4), and urban versus rural residence. We also analyzed the data excluding those who died. The proportion of participants who had at least a 4-unit improvement in SGRQ-TS at 12 months was compared between groups using a chi-square test [31]. For the analysis of mean daily step count by month of study, we used a linear mixed-effect model similar to that for the primary outcome except data were assessed in 30-day increments over the 12-month study period. Predictors were treatment group, month of study as indicator variables (coded as 1-12), group-by-month indicator variables interactions, dichotomized MMRC dyspnea score, and urban versus rural residence.We assessed website engagement in the intervention group by characterizing the number of log-ins to the website using the mean, median, and interquartile range, and assessed trends over months of study using a linear mixed-effects regression analysis with monthly number of log-ins for each participant as the outcome and time (month since randomization) as the predictor. Trends for device adherence over month of study were examined with percent of days with valid step-count data using a linear mixed-effects model and for use of the online community forum using a generalized mixed-effects model with logit link. The effect of time on participant responses to the online survey about goal commitment and intervention engagement at 4 and 12 months was estimated for each response variable using a mixed-effects model with 4- and 12-month survey data as the dependent variable and predictors including 12-month indicator, baseline dichotomized MMRC dyspnea score, and urban versus rural status. All models, including the model for the number of log-ins, were checked for model assumptions using residuals.One participant in the Taking Healthy Steps group was considered an outlier given that his change in SGRQ-TS was 4.0 standard deviations greater than the mean for change in SGRQ-TS and his change in daily step count was 8.1 standard deviations greater than the mean for change in daily step count. The extremely high step counts more likely reflected his occupational PA rather than any effects of our intervention. Our main analyses excluded the outlying individual, but we also repeated primary and secondary outcome analyses with this participant included. All analyses were performed with Stata 14.0 (StataCorp LP, College Station, TX, USA).ResultsParticipant CharacteristicsNo information is available on the persons to whom we mailed recruitment materials but who were not screened because they did not go to our website and did not call us (Figure 1). The top three reasons for ineligibility of 459 participants were not sedentary (n=202), could not walk a block (n=120), or no compatible computer access (n=161), with some participants having more than one reason (Figure 1). In all, 68 persons consented but were not enrolled and randomized, including 19 who failed to submit a medical clearance form and did not upload step-count data, one who failed to submit a medical clearance form, four who failed to upload step-count data, and nine who failed to complete the baseline SGRQ (Figure 1).Participants’ (N=238) characteristics include: mean age 67 (SD 9) years, male (93.7%, 223/238), rural residence (45.4%, 108/238), MMRC dyspnea score ≥2 (30.7%, 73/238), current smokers (24.8%, 59/238), and supplemental oxygen use (23.5%, 56/238) (Table 2). There were no significant differences in baseline characteristics between study groups, including current smoking history. Overall, 87.8% (209/238) of participants completed the 12-month online HRQL assessment, and 74.4% (177/238) uploaded 12-month valid step-count data. In the intervention group, 87.7% (135/154) of participants completed the HRQL assessment and 76.6% (118/154) uploaded valid step-count data, compared to 88% (74/84) and 70% (59/84), respectively, in the control group.Table 2Baseline participant characteristics (N=238).CharacteristicIntervention (n=154)Control (n=84)Total (N=238)Age (years), mean (SD)67 (8.6)66.4 (9.2)66.8 (8.8)Gender (male), n(%)146 (94.8)77 (92)223 (93.7)Residence, n(%)Urban83 (53.9)47 (56)130 (54.6)Rural71 (46.1)37 (44)108 (45.4)Hispanic (n=235), n(%)5 (3.3)1 (1)6 (2.6)Race, n(%)Black7 (4.6)3 (4)10 (4.2)White142 (92.2)79 (94)221 (92.9)Other5 (3.3)2 (2)7 (2.9)Current smoker, n(%)41 (26.6)18 (21)59 (24.8)Oxygen use, n(%)35 (22.7)21 (25)56 (23.5)SGRQ,a mean (SD)Symptoms57.2 (19.1)56 (19.9)56.8 (19.3)Activities62.3 (20.2)64.2 (18)62.9 (19.5)Impact32.2 (16.5)34.1 (17.9)32.9 (17)Total45.6 (15.4)46.8 (15.6)46 (15.4)Baseline daily step count, mean (SD)3488 (2316)3521 (2058)3499 (2224)MMRC dyspnea score,b n (%)0-1108 (70.1)57 (68)165 (69.3)2-446 (29.9)27 (32)73 (30.7)aSGRQ: St. George’s Respiratory Questionnaire. Data for symptoms, activities, and impact were available from 236 participants; total from 233 participants.bMMRC: Modified Medical Research Council.At 12 months, 29 of 238 (12.2%) participants did not have sufficient data to calculate the SGRQ-TS: 19 Taking Healthy Steps participants and 10 controls. There was no significant difference in baseline SGRQ-TS (mean 49.8, SD 16.1 vs mean 45.6, SD 15.3; P=.18) or baseline daily step count (mean 3410, SD 2667 vs mean 3512, SD 2163; P=.82) between those for whom SGRQ-TS could not be calculated (n=29) versus those for whom SGRQ-TS was calculated at 12 months (n=209).The percent of participants with COPD-related events (acute exacerbations or pneumonia) during the study did not differ between groups (control: 18%, 15/84; intervention: 22.7%, 35/154; logistic regression OR 1.4, 95% CI 0.7-2.8; P=.33). No between-group difference was found in the percent of participants with hospitalizations (control: 17%, 14/84; intervention: 23.4%, 36/154; logistic regression OR 1.6, 95% CI 0.8-3.2; P=.19) or emergency room visits (control: 24%, 20/84; intervention: 29.9%, 46/154; logistic regression OR 1.4, 95% CI 0.8-2.6; P=.27) during the 12-month study. For the count of hospitalizations, a zero-inflated Poisson regression model also found no between-group difference. The percent of participants who died during the study did not differ between groups (control: 2%, 2/84; intervention: 3.9%, 6/154; P=.53). Finding no between-group differences in the percentage of participants who were hospitalized or died provided assurance that the censoring of the outcome variables (SGRQ-TS or daily step counts) due to these events was not likely to confound the assessment of the between-group outcome differences. However, we repeated the analyses with deaths excluded as well.Health-Related Quality of LifeThere was no significant between-group difference in the primary outcome of SGRQ-TS (mean 1.1 units, 95% CI –2.2 to 4.5; P=.50) at 12 months (Table 3). The proportion of participants who achieved at least a 4-unit improvement in SGRQ-TS at 12 months was 45.2% (61/135) in the intervention versus 32% (23/71) in the control group (P=.08). There was no significant between-group difference in the SGRQ domain scores of symptoms (mean 0.5 unit, 95% CI –4.2 to 5.2; P=.84), activities (mean 0.04 unit, 95% CI –4.2 to 4.2; P=.99), and impact (mean 2.3 units, 95% CI –1.6 to 6.1; P=.25) at 12 months.Table 3Within-group changes and between-group differences in SGRQ scores and daily step counts at 12 months.Outcome and armNDifference from baseline to 12 months, mean (95% CI)PBetween-group difference, mean (95% CI)PaSGRQTotal1.1 (–2.2, 4.5).50Taking Healthy Steps154–2.5 (–4.5, –0.6).01Control84–1.4 (–4.1, 1.3).31Symptoms0.5 (–4.2, 5.2).84Taking Healthy Steps154–3.2 (–6.0, –0.4).02Control84–2.7 (–6.5, 1.1).16Activities0.04 (–4.2, 4.2).99Taking Healthy Steps154–1.2 (–3.7, 1.3).36Control84–1.1 (–4.5, 2.3).51Impact2.3 (–1.6, 6.1).25Taking Healthy Steps154–3.4 (–5.6, –1.1).004Control84–1.1 (–4.2, 2.0).48Daily step count–108 (–720, 505).73Taking Healthy Steps154270 (–86, 626).14Control84163 (–336, 661).52a Based on linear mixed-effect models, adjusting for group, 4- and 12-month indicators, group×time indicator interactions, baseline MMRC dyspnea score (dichotomized to 0-1 vs 2-4), and urban versus rural status.Intervention participants showed an improvement in SGRQ-TS of a mean 2.5 units (95% CI –4.5 to –0.6) at 12 months, compared to baseline (P=.01) (Table 3). For domain scores in the intervention group, symptoms improved by a mean 3.2 units (95% CI –6.0 to –0.4, P=.02), and impact improved by a mean 3.4 units (95% CI –5.6 to –1.1, P=.004) at 12 months. The control group showed no significant changes in the SGRQ-TS and domain scores at 12 months compared to baseline (Table 3). When the analysis was repeated with the outlying individual included, no substantive difference was seen in results, except improvement in symptoms within the Taking Healthy Steps group was marginally significant (P=.05). When the analysis excluded the eight deaths, results remained nearly identical.Daily Step CountThere was no significant difference between groups with respect to the secondary outcome of daily step count at 12 months (P=.73) (Table 3). There was no significant change in daily step count in the intervention participants (P=.14) or in the control group (P=.52) at 12 months, compared to baseline (Table 3). Examination of daily step count by month of intervention showed that differences in daily step counts in the intervention group compared to controls were maximal and statistically significant at month 4, but approached zero in months 8 to 12 (Figure 2). Between-group P values were <.001 at 4 months, .28 at 8 months, and .82 at 12 months. Within the intervention group, although daily step counts peaked at 2 months and then declined over the course of the study, daily step counts continued to be higher than baseline values in all months of the study (Figure 2). Analysis including the outlying individual showed improvement in daily step counts at 12 months to be significant in the Taking Healthy Steps group (P=.048). Analysis excluding the eight deaths did not change results.Figure 2Mean daily step count and 95% confidence intervals by month of study. Note: the Taking Healthy Steps (THS) curve is shifted to the right of the control curve on the x-axis for ease of visual display. Baseline data are included at month zero.Device Adherence and Website EngagementDevice adherence during the 12-month study period was significantly higher in the intervention group than the control group, with mean 76.7% (SD 29.5) of the 366 days having valid step-count data in the intervention group versus mean 63.7% (SD 32.9) of the 366 days having valid step-count data in the control group (P=.002). For the 177 participants in both groups who uploaded valid step-count data at 12 months and completed the study, mean 83.1% (SD 21.9) of days in the last 6 weeks of the study had valid step-count data. In these last 6 weeks, mean 87.5% (SD 16.5) of days had valid step-count data in the intervention group, which was significantly higher than the mean 74.1% (SD 28.1) of days observed in the control group (P<.001). In the intervention group, device adherence decreased significantly over time (P<.001), with mean 92.1% (95% CI 86.6-97.6) of days having valid step-count data at month 1 versus 70.3% (95% CI 64.9-75.8) of days at month 12 (Figure 3).In the intervention group, mean number of log-ins to the website decreased significantly over the months of study (P<.001; Figure 4). The number of monthly log-ins was mean 6.8 (SD 3.7; median 6, IQR 3) at month 1, which declined to mean 4.2 (SD 3.5; median 4, IQR 3) by month 9 and mean 3.0 (SD 3.0; median 3, IQR 5) by month 12 (Figure 4). In the intervention group, 83.8% (129/154) of the participants used the online community forum at some point during the 12-month study; 66.2% (102/154) of participants directly viewed an online community forum thread or entry, and an additional 17.5% (27/154) of participants posted a new topic or a reply at least once. More than half of the participants responded “definitely true” (22/121, 18.2%) or “mostly true” (45/121, 37.2%) to the statement: “I learned helpful information when I used the online community forum.” There was a significant trend for decreasing use of the online community forum by month of study (P<.001).Responses to questions regarding participant’s goal commitment were not significantly different at 12 months compared to 4 months (Table 4). When asked, “Overall, how motivated are you to walk each day?” with responses from 1=not motivated and 10=extremely motivated, the mean response was 6.8 (SD 2.3) at 4 months compared to mean 6.5 (SD 2.5) at 12 months (P=.06). Responses to questions about engagement with the use of Taking Healthy Steps were not significantly different at 12 months compared to 4 months (Table 4).Table 4Goal commitment and engagement with Taking Healthy Steps intervention.Goal commitment and engagementNa4 months mean (95% CI)12 months mean (95% CI)PbGoal commitmentcIt’s hard to take my step-count goal seriously.1472.1 (1.9-2.2)2.0 (1.9-2.2).69Quite frankly, I don’t care if I reach my step goal or not.1471.7 (1.6-1.8)1.7 (1.6-1.8).46I am strongly committed to pursuing my step-count goal.1463.8 (3.6-4.0)3.7 (3.5-3.9).52It wouldn’t take much to make me abandon my step-count goal.1471.9 (1.7-2.1)2.0 (1.8-2.2).27I think my step-count goal is a good goal to shoot for.1464.0 (3.8-4.2)3.9 (3.8-4.1).77Engagement in Taking Healthy StepsdI would recommend the Taking Healthy Steps walking program to another person with COPD.1461.3 (1.2-1.4)1.2 (1.1-1.3).01It was easy for me to find the time to log in to the website once a week.1461.8 (1.6-2.0)1.8 (1.6-2.0).92I had technical difficulty uploading step-count data from the pedometer to my computer.1464.0 (3.7-4.2)3.9 (3.7-4.1).75I knew what my step goal should be every day.1471.5 (1.4-1.6)1.5 (1.4-1.6).48I was able to comfortably increase my daily step count every week.1472.6 (2.5-2.8)2.8 (2.6-3.0).10I looked at the graphs of the step counts that I walked.1471.6 (1.4-1.7)1.6 (1.4-1.7).76The motivational messages and educational tips were easy to understand.1431.9 (1.8-2.0)1.8 (1.7-1.9).21I learned helpful information when I used the online community forum.1372.5 (2.3-2.7)2.4 (2.3-2.6).52The daily step-count goals were too high for me to walk each day.1473.4 (3.2-3.5)3.4 (3.2-3.5).98a Participants with responses at 4 and/or 12 months were included in the models.b Based on linear mixed-effect models with 4 and 12 months as the dependent variable and predictors of 12-month indicator, intervention group indicator and baseline MMRC dyspnea score (dichotomized to 0-1 vs 2-4) and urban versus rural status.c Response scale 1-5 with 1=strongly disagree, 2=disagree, 3=neither agree nor disagree, 4=agree, 5=strongly agree.d Response scale 1-5 with 1=definitely true, 2=mostly true, 3=not sure, 4=mostly false, 5=definitely false.Figure 3Percentage and 95% confidence intervals of days with valid step-count data in the intervention group by month of study.Figure 4Mean log-ins and 95% confidence intervals in the intervention group by month of study.SafetyAdverse events were categorized as pulmonary, cardiac, musculoskeletal, or other. A significantly greater percent of participants in the intervention group (27.9%, 43/154) had minor musculoskeletal adverse events than in the control group (10%, 8/84; P<.001). There were no differences between groups with respect to pulmonary, cardiac, or other adverse events during the 12 months.DiscussionWe show that our Internet-mediated, pedometer-based walking intervention does not maintain benefits in HRQL and daily step counts at 12 months, despite demonstrated improvements at 4 months [27]. Although we report negative findings for the study overall, lessons learned about device adherence and website engagement are highly informative for guiding the development of future PA interventions that can effectively promote long-term behavior change and sustain PA.Overall, we found that a COPD population found the study feasible and were engaged. The percentage of participants who completed the 12-month study, providing HRQL and step-count data, was high. In addition, our objective results assessing device adherence and showing that 83% of days for participants in both groups within the last 6 weeks of the study had valid step-count data support that people were not lost to the study and then showing up for the last evaluation period. Importantly, persons in the intervention group had significantly higher device adherence compared to the control group for the study overall and at the end of the study. This finding supports that the goal setting, feedback, educational and motivational content, and online community forum provided on the website significantly increased intervention engagement beyond that observed with the use of a pedometer alone.For the first time, we rigorously elicited participant survey responses about goal commitment and intervention engagement, and objectively assessed device adherence and website engagement during the 12-month study. In the intervention group, responses to questions about engagement at 12 months were the same compared to those at 4 months, with participants finding time to log in to the intervention, knowing their step-count goal, and using the graphs, tips and messages, and forums. They also reported that they were as committed to their step-count goal at 12 months as they were at 4 months. Although participants reported the same levels of goal commitment and intervention engagement at the end of the study compared to the beginning of the study, sustained behavior change was not observed because there were significant decreases in number of days with valid step-count data, number of log-ins to the website, and use of the online community forum over time. Although we can only speculate as to cause and effect, the decrease in daily step count (a marker of intervention efficacy and walking behavior change) over time mirrors the declines in device adherence and website engagement over time.The reasons for the observed decline in daily step counts over time require further exploration. Participants may not have continued to wear the pedometer, log in to the website, and walk over the 12 months for a variety of possible reasons that we did not assess, such as waning interest with the intervention, progression of underlying COPD, flare-up of comorbidities, or occurrence of intercurrent life events (eg, spouse illness). The effect of the intervention on daily step counts could potentially have been greater if the control group had not received a pedometer and monthly reminders to upload step counts. We are confident that battery life did not affect the results because we mailed a new battery with replacement instructions to each participant every 4 months. We replaced lost or broken devices reported to us.These results are similar to published data examining maintenance exercise programs after conventional pulmonary rehabilitation [16-21]. Typically, the unstable clinical course of a chronic lung disease such as COPD makes it difficult for patients to resume or maintain an exercise program [20]. Although we observed no difference in the number of COPD-related events, such as acute exacerbations, between groups, the occurrence of acute exacerbations and flare-up of comorbidities over a period of 12 months may have modified the response to Taking Healthy Steps within the intervention group.The failure to obtain long-term benefits with our PA interventions parallels the literature studying other behavior changes, such as smoking cessation [35] and weight loss [36]. Our 8-month maintenance phase retained the key components of goal setting, feedback, and social support. The main feature omitted beginning at month 5 was new educational and motivational content. These findings support that ongoing behavioral modification techniques are critical to sustain PA [37,38]. We speculate that additional intervention components, such as face-to-face contact with peers and/or health care providers, would enhance the social support and motivation needed to sustain PA as a routine behavior. Use of evolving technology, such as wireless transmission and mobile connectivity with cell phones, smartphones/mobile phones, or tablets, could potentially provide anytime/anywhere access to the PA intervention and enhance its long-term efficacy [37,39,40]. Intensive counseling and support at the time of acute exacerbations and flare-up of comorbidities would address medical barriers to PA and motivate patients to continue to walk after an illness. Finally, incorporating the health care provider, health care institutions, communities, and society at large into PA interventions could enhance long-term behavior change and adherence to effectively sustain PA in persons with COPD [41,42].The exact role of digital walking programs in starting and maintaining exercise in persons with COPD remains to be determined. Both acute and chronic models of digital walking programs are potentially useful. Acute intervention models are needed to initiate and promote PA in the vast majority of patients with COPD who cannot access a conventional pulmonary rehabilitation program [43]. In addition, maintenance models are appropriate and much needed because long-term maintenance of behavior change is challenging. In addition, digital walking programs can potentially be useful adjuncts after conventional pulmonary rehabilitation to maintain benefits, which start to wane as early as 3 to 6 months after program completion [20,21]. They can also be an important component of COPD self-management programs [44]. An interesting future question to address is whether restarting our intervention every 4 to 8 months would be an efficacious long-term strategy.The potential full impact of our intervention can only be appreciated by performing a future cost-effectiveness analysis. Results from cross-sectional data from our group and others have shown that every step counts. We have not found a “threshold” or “optimal” daily step count to obtain clinical benefits. The benefits appear to be linear such that those with higher step counts have lower risks for acute exacerbations, hospitalizations, hospital admissions and readmissions, and death compared to those with lower step counts [9-14]. Future work is needed to examine whether PA interventions such as ours can decrease health care resource utilization and result in cost savings to our health care system.Major strengths of our study include the randomized controlled trial design with balanced groups at baseline, objective data on device adherence and website engagement, and the long-term follow-up of 12 months. Our intervention is based on a theoretical model, and informed by previous work eliciting patient feedback to optimize user acceptability and develop the motivational and educational content [25,45]. Our Internet-mediated, pedometer-based intervention focuses specifically on walking, a low-intensity PA that most patients can do. It has already been shown that a greater quantity of low-intensity PA reduces risk of COPD hospitalizations, whereas high-intensity PA does not result in risk reduction [15].Our study has several limitations. We studied primarily white male Veterans limiting the generalizability of our results. Spirometric confirmation of the COPD diagnosis was not made at study entry. However, any potential misclassification of asthma as COPD was most likely balanced between groups and would not bias the primary results. The vast majority of the patients had MMRC <2. It is justified to include patients with MMRC <2 because patients with newly diagnosed COPD have reduced PA even at the earliest stages of the disease [3]. It is important to promote PA even when patients are not significantly symptomatic, as recommended by the GOLD guidelines for COPD [6]. We found no difference in benefit of the PA intervention in those with MMRC <2 versus MMRC ≥2. We acknowledge the final response rate was likely biased toward responders who had a particular interest in this type of intervention, and the results may not be generalizable to a wider COPD population. Finally, seasonal variation can influence our secondary outcome of daily step counts. We minimized the impact of season by having a 12-month intervention and enrolling participants over all four seasons.An Internet-mediated, pedometer-based PA intervention for persons with COPD does not maintain improvements in HRQL or daily step count at 12 months, despite demonstrated improvements at 4 months. In addition, waning engagement with the PA intervention support that future efforts should focus on improving features of PA interventions to enhance long-term behavior change and sustain engagement with PA. These findings need to be considered when designing future Internet-mediated PA interventions.We thank the Veterans for their participation in this research study. The study was funded by Department of Veterans Affairs, Health Services Research and Development Service (Grant IIR 09-366, Richardson); Department of Veterans Affairs, Rehabilitation Research and Development Service (Career Development Award, F6847W, Moy); and NIH National Heart, Lung and Blood Institute (Grant T32 HL007749-20, Martinez). None of the funding bodies had any role in the design, collection, analysis or interpretation of the data, in writing the manuscript, or in the decision to submit the manuscript for publication.Authors' Contributions: MLM, RK, HQN, MDC, DEG, NDG, and CRR were involved in the conception and design of all stages of the study. MLM, CHM, RK, PR, HQN, MDC, and CRR were involved in study data collection. CHM, HMK, RK, PR, RGH, and NDG conducted study analyses. All authors read and approved the final manuscript. CRR, the study PI, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.Conflicts of Interest: None declared. This study was initiated by the investigators, who do not receive any financial support from Omron Healthcare. The results of this study do not constitute endorsement of the Omron pedometer by the authors.Multimedia Appendix 1CONSORT-EHEALTH checklist.AbbreviationsAEacute exacerbationsCOPDchronic obstructive pulmonary diseaseFEV1forced expiratory volume in 1 secondGOLDGlobal Initiative for Chronic Obstructive Lung DiseaseHRQLhealth-related quality of lifeMMRCModified Medical Research CouncilPAphysical activitySGRQSt George’s Respiratory QuestionnaireSGRQ-TSSt George’s Respiratory Questionnaire Total ScoreVISNVeteran Integrated Service Network1MoyMLDanilackVAWestonNAGarshickEDaily step counts in a US cohort with COPDRespir Med20127106796296910.1016/j.rmed.2012.03.01622521225225212252WaschkiBKirstenAMHolzOMuellerKSchaperMSackAMeyerTRabeKFMagnussenHWatzHDisease progression and changes in physical activity in patients with chronic obstructive pulmonary diseaseAm J Respir Crit Care Med201581192329530610.1164/rccm.201501-0081OC26020495260204953Van RemoortelHHornikxMDemeyerHLangerDBurtinCDecramerMGosselinkRJanssensWTroostersTDaily physical activity in subjects with newly diagnosed COPDThorax201310681096296310.1136/thoraxjnl-2013-20353423604460236044604HurstJRVestboJAnzuetoALocantoreNMüllerovaHTal-SingerRMillerBLomasDAAgustiAMacneeWCalverleyPRennardSWoutersEFWedzichaJAEvaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) InvestigatorsSusceptibility to exacerbation in chronic obstructive pulmonary diseaseN Engl J Med2010916363121128113810.1056/NEJMoa090988320843247208432475PittaFTroostersTProbstVSSpruitMADecramerMGosselinkRPhysical activity and hospitalization for exacerbation of COPDChest20063129353654410.1378/chest.129.3.53616537849165378496VestboJHurdSSAgustíAGJonesPWVogelmeierCAnzuetoABarnesPJFabbriLMMartinezFJNishimuraMStockleyRASinDDRodriguez-RoisinRGlobal strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summaryAm J Respir Crit Care Med2013215187434736510.1164/rccm.201204-0596PP22878278228782787McNamaraRJMcKeoughZJMcKenzieDKAlisonJAPhysical comorbidities affect physical activity in chronic obstructive pulmonary disease: a prospective cohort studyRespirology2014819686687210.1111/resp.1232524909412249094128DivoMCoteCde TorresJPCasanovaCMarinJMPinto-PlataVZuluetaJCabreraCZagacetaJHunninghakeGCelliBComorbidities and risk of mortality in patients with chronic obstructive pulmonary diseaseAm J Respir Crit Care Med2012715186215516110.1164/rccm.201201-0034OC22561964225619649MoyMGouldMLiuILeeJNguyenHPhysical activity assessed in routine care predicts mortality after a COPD hospitalizationERJ Open Res [in press]2016901(forthcoming)10MoyMLTeylanMDanilackVAGagnonDRGarshickEAn index of daily step count and systemic inflammation predicts clinical outcomes in chronic obstructive pulmonary diseaseAnn Am Thorac Soc2014211214915710.1513/AnnalsATS.201307-243OC243085882430858811MoyMLTeylanMWestonNAGagnonDRDanilackVAGarshickEDaily step count is associated with plasma C-reactive protein and IL-6 in a US cohort with COPDChest201431145354255010.1378/chest.13-1052240914822409148212MoyMLTeylanMWestonNAGagnonDRGarshickEDaily step count predicts acute exacerbations in a US cohort with COPDPLoS One201384e6040010.1371/journal.pone.0060400235932112359321113NguyenHQChuLAmyLILeeJSSuhDKorotzerBYuenGDesaiSColemanKJXiangAHGouldMKAssociations between physical activity and 30-day readmission risk in chronic obstructive pulmonary diseaseAnn Am Thorac Soc2014611569570510.1513/AnnalsATS.201401-017OC247130942471309414WaschkiBKirstenAHolzOMüllerKMeyerTWatzHMagnussenHPhysical activity is the strongest predictor of all-cause mortality in patients with COPD: a prospective cohort studyChest20118140233134210.1378/chest.10-2521212732942127329415Donaire-GonzalezDGimeno-SantosEBalcellsEde BatlleJRamonMARodriguezEFarreroEBenetMGuerraSSauledaJFerrerAFerrerJBarberàJARodriguez-RoisinRGeaJAgustíAAntóJMGarcia-AymerichJPAC-COPD Study GroupBenefits of physical activity on COPD hospitalisation depend on intensityEur Respir J2015114651281128910.1183/13993003.01699-2014262068732620687316BrooksDKripBMangovski-AlzamoraSGoldsteinRSThe effect of postrehabilitation programmes among individuals with chronic obstructive pulmonary diseaseEur Respir J200272012029121665711216657117GriffithsTLBurrMLCampbellIALewis-JenkinsVMullinsJShielsKTurner-LawlorPJPayneNNewcombeRGIonescuAAThomasJTunbridgeJLonescuAAResults at 1 year of outpatient multidisciplinary pulmonary rehabilitation: a randomised controlled trialLancet20001293559201362368106655561066555618RingbaekTBrondumEMartinezGThogersenJLangePLong-term effects of 1-year maintenance training on physical functioning and health status in patients with COPD: A randomized controlled studyJ Cardiopulm Rehabil Prev2010301475210.1097/HCR.0b013e3181c9c985200684232006842319BeauchampMKEvansRJanaudis-FerreiraTGoldsteinRSBrooksDSystematic review of supervised exercise programs after pulmonary rehabilitation in individuals with COPDChest20131014441124113310.1378/chest.12-2421234299312342993120RiesALKaplanRMMyersRPrewittLMMaintenance after pulmonary rehabilitation in chronic lung disease: a randomized trialAm J Respir Crit Care Med2003315167688088810.1164/rccm.200204-318OC125058591250585921SpencerLMAlisonJAMcKeoughZJMaintaining benefits following pulmonary rehabilitation: a randomised controlled trialEur Respir J2010335357157710.1183/09031936.00073609196439441964394422RichardsonCRBuisLRJanneyAWGoodrichDESenAHessMLMehariKSFortlageLAResnickPJZikmund-FisherBJStrecherVJPietteJDAn online community improves adherence in an internet-mediated walking program. Part 1: results of a randomized controlled trialJ Med Internet Res2010124e7110.2196/jmir.1338211691602116916023RichardsonCRMehariKSMcIntyreLGJanneyAWFortlageLASenAStrecherVJPietteJDA randomized trial comparing structured and lifestyle goals in an internet-mediated walking program for people with type 2 diabetesInt J Behav Nutr Phys Act200745910.1186/1479-5868-4-59180214111802141124MoyMLJanneyAWNguyenHQMatthessKRCohenMGarshickERichardsonCRUse of pedometer and Internet-mediated walking program in patients with chronic obstructive pulmonary diseaseJ Rehabil Res Dev2010475485496208033922080339225MoyMLWestonNAWilsonEJHessMLRichardsonCRA pilot study of an Internet walking program and pedometer in COPDRespir Med2012910691342135010.1016/j.rmed.2012.06.013227959842279598426MartinezCHMoyMLNguyenHQCohenMKadriRRomanPHollemanRGKimHMGoodrichDEGiardinoNDRichardsonCRTaking Healthy Steps: rationale, design and baseline characteristics of a randomized trial of a pedometer-based Internet-mediated walking program in veterans with chronic obstructive pulmonary diseaseBMC Pulm Med2014141210.1186/1471-2466-14-12244911372449113727MoyMLCollinsRJMartinezCHKadriRRomanPHollemanRGKimHMNguyenHQCohenMDGoodrichDEGiardinoNDRichardsonCRAn Internet-mediated pedometer-based program improves health-related quality-of-life domains and daily step counts in COPD: a randomized controlled trialChest20157148112813710.1378/chest.14-1466258113952581139528WeeksWBKazisLEShenYCongZRenXSMillerDLeeAPerlinJBDifferences in health-related quality of life in rural and urban veteransAm J Public Health200410941017621767154517471545174729JonesPWQuirkFHBaveystockCMLittlejohnsPA self-complete measure of health status for chronic airflow limitation. The St. George's Respiratory QuestionnaireAm Rev Respir Dis1992614561321132710.1164/ajrccm/145.6.13211595997159599730KaplanRMRiesALReillyJMohsenifarZNational Emphysema Treatment Trial Research GroupMeasurement of health-related quality of life in the national emphysema treatment trialChest20049126378178910.1378/chest.126.3.781153647571536475731JonesPWSt. George's Respiratory Questionnaire: MCIDCOPD20053217579171369661713696632MatthewsCEHagströmerMPoberDMBowlesHRBest practices for using physical activity monitors in population-based researchMed Sci Sports Exerc20121441 Suppl 1S68S7610.1249/MSS.0b013e3182399e5b221577772215777733MahlerDAWellsCKEvaluation of clinical methods for rating dyspneaChest198839335805863342669334266934AaronSDFergussonDMarksGBSuissaSVandemheenKLDoucetteSMaltaisFBourbeauJFGoldsteinRSBalterMO'DonnellDFitzgeraldMCanadian Thoracic Society/Canadian Respiratory Clinical Research ConsortiumCounting, analysing and reporting exacerbations of COPD in randomised controlled trialsThorax2008263212212810.1136/thx.2007.082636177027901770279035Jiménez-RuizCAAndreasSLewisKETonnesenPvan SchayckCPHajekPTonstadSDautzenbergBFletcherMMasefieldSPowellPHeringTNardiniSToniaTGratziouCStatement on smoking cessation in COPD and other pulmonary diseases and in smokers with comorbidities who find it difficult to quitEur Respir J20157461617910.1183/09031936.00092614258828052588280536AppelLJClarkJMYehHWangNCoughlinJWDaumitGMillerERDalcinAJeromeGJGellerSNoronhaGPozefskyTCharlestonJReynoldsJBDurkinNRubinRRLouisTABrancatiFLComparative effectiveness of weight-loss interventions in clinical practiceN Engl J Med20111124365211959196810.1056/NEJMoa1108660220853172208531737SallisRFranklinBJoyLRossRSabgirDStoneJStrategies for promoting physical activity in clinical practiceProg Cardiovasc Dis201557437538610.1016/j.pcad.2014.10.003254599752545997538WilsonJJO'NeillBCollinsEGBradleyJInterventions to increase physical activity in patients with COPD: a comprehensive reviewCOPD2015612333234310.3109/15412555.2014.948992252219072522190739VerweyRvan der WeegenSSpreeuwenbergMTangeHvan der WeijdenTde WitteLA pilot study of a tool to stimulate physical activity in patients with COPD or type 2 diabetes in primary careJ Telemed Telecare20141201293410.1177/1357633X13519057244143972441439740TabakMBrusse-KeizerMvan der ValkPHermensHVollenbroek-HuttenMA telehealth program for self-management of COPD exacerbations and promotion of an active lifestyle: a pilot randomized controlled trialInt J Chron Obstruct Pulmon Dis2014993594410.2147/COPD.S60179252467812524678141HeathGWParraDCSarmientoOLAndersenLBOwenNGoenkaSMontesFBrownsonRCLancet Physical Activity Series Working GroupEvidence-based intervention in physical activity: lessons from around the worldLancet2012721380983827228110.1016/S0140-6736(12)60816-2228189392281893942SpruitMAPittaFMcAuleyEZuWallackRLNiciLPulmonary rehabilitation and physical activity in patients with chronic obstructive pulmonary diseaseAm J Respir Crit Care Med20151015192892493310.1164/rccm.201505-0929CI261616762616167643RochesterCLVogiatzisIHollandAELareauSCMarciniukDDPuhanMASpruitMAMasefieldSCasaburiRCliniEMCrouchRGarcia-AymerichJGarveyCGoldsteinRSHillKMorganMNiciLPittaFRiesALSinghSJTroostersTWijkstraPJYawnBPZuWallackRLATS/ERS Task Force on Policy in Pulmonary RehabilitationAn official American Thoracic Society/European Respiratory Society policy statement: enhancing implementation, use, and delivery of pulmonary rehabilitationAm J Respir Crit Care Med2015121192111373138610.1164/rccm.201510-1966ST266236862662368644EffingTWVercoulenJHBourbeauJTrappenburgJLenferinkACafarellaPCoultasDMeekPvan der ValkPBischoff ErikEWBucknallCDewanNAEarlyFFanVFrithPJanssenDJMitchellKMorganMNiciLPatelIWaltersHRiceKLSinghSZuwallackRBenzoRGoldsteinRPartridgeMRvan der PalenJDefinition of a COPD self-management intervention: International Expert Group consensusEur Respir J20167481465410.1183/13993003.00025-2016270765952707659545DanilackVAWestonNARichardsonCRMoriDLMoyMLReasons persons with COPD do not walk and relationship with daily step countCOPD2014611329029910.3109/15412555.2013.8416702415221324152213", 'title': 'Long-Term Effects of an Internet-Mediated Pedometer-Based Walking Program for Chronic Obstructive Pulmonary Disease: Randomized Controlled Trial.', 'date': '2016-08-10'}, '26089656': {'article_id': '26089656', 'content': 'Int J Chron Obstruct Pulmon DisInt J Chron Obstruct Pulmon DisInternational Journal of COPDInternational Journal of Chronic Obstructive Pulmonary Disease1176-91061178-2005Dove Medical Press26089656446765210.2147/COPD.S81295copd-10-1061Original ResearchA randomized controlled trial evaluating the effectiveness of a web-based, computer-tailored self-management intervention for people with or at risk for COPDVoncken-BrewsterViola1TangeHuibert1de VriesHein2NagykaldiZsolt3WinkensBjorn4van der WeijdenTrudy11Department of Family Medicine, School for Public Health and Primary Care (CAPHRI), Maastricht University Medical Center, Maastricht, Netherlands2Department of Health Promotion, School for Public Health and Primary Care (CAPHRI), Maastricht University Medical Center, Maastricht, Netherlands3Department of Family and Preventive Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA4Department of Methodology and Statistics, CAPHRI, Maastricht University Medical Center, Maastricht, NetherlandsCorrespondence: Huibert Tange, Maastricht University, PO Box 616, 6200MD, Maastricht, Netherlands, Tel +31 43 388 2230, Fax +31 43 361 9344, Email h.tange@maastrichtuniversity.nl201508620151010611073© 2015 Voncken-Brewster et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2015The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.IntroductionCOPD is a leading cause of morbidity and mortality. Self-management interventions are considered important in order to limit the progression of the disease. Computer-tailored interventions could be an effective tool to facilitate self-management.MethodsThis randomized controlled trial tested the effectiveness of a web-based, computer-tailored COPD self-management intervention on physical activity and smoking behavior. Participants were recruited from an online panel and through primary care practices. Those at risk for or diagnosed with COPD, between 40 and 70 years of age, proficient in Dutch, with access to the Internet, and with basic computer skills (n=1,325), were randomly assigned to either the intervention group (n=662) or control group (n=663). The intervention group received the web-based self-management application, while the control group received no intervention. Participants were not blinded to group assignment. After 6 months, the effect of the intervention was assessed for the primary outcomes, smoking cessation and physical activity, by self-reported 7-day point prevalence abstinence and the International Physical Activity Questionnaire – Short Form.ResultsOf the 1,325 participants, 1,071 (80.8%) completed the 6-month follow-up questionnaire. No significant treatment effect was found on either outcome. The application however, was used by only 36% of the participants in the experimental group.ConclusionA possible explanation for the nonsignificant effect on the primary outcomes, smoking cessation and physical activity, could be the low exposure to the application as engagement with the program has been shown to be crucial for the effectiveness of computer-tailored interventions. (Netherlands Trial Registry number: NTR3421.)Keywordssmoking cessationphysical activityInternet interventiontailoringCOPDBackgroundCOPD is one of the leading causes of morbidity and mortality worldwide.1 COPD patients suffer from airflow limitation that is typically progressive and not reversible.2 Adequate patient self-management and behavior modification, such as smoking cessation and increasing the level of physical activity, are recommended to decelerate disease progression.3,4A relatively small number of studies on the effectiveness of COPD self-management interventions have been conducted, and the evidence on effectiveness remains inconclusive.5 Self-management interventions have mainly focused on educating COPD patients using standardized information, but are now increasingly offering personalized information to patients through counseling with a health care provider.5Another trend in providing health-promoting information is e-Health, which uses information and communication technology.6 Information provided by e-Health interventions has been individualized using computer-tailored technology, often with disease prevention as a main goal.7–9 This intervention method offers computer-generated, personally relevant information by adapting the content of health-promotion messages to users’ characteristics.9 Personalizing and adapting health messages has been found to help attract and keep users’ attention, increase appreciation, and help users process messages more thoroughly.10–12 Computer-tailored interventions have been shown to effectively improve health behaviors, such as smoking cessation and physical activity.13,14 This intervention strategy has also been successful when targeting multiple behaviors11 and has been found to be more cost-effective than usual care.15 To our knowledge, this promising technique has not yet been tested with the purpose of supporting behavior change in COPD patients.In the MasterYourBreath (“AdemDeBaas” in Dutch) project, we developed a web-based, computer-tailored self-management application for COPD patients. We evaluated and improved the usability of the prototype16 and conducted a pilot study.17 In the present paper, we report the effectiveness of this intervention on behavioral (physical activity, smoking cessation, and the intention to be more physically active and to quit smoking) and clinical outcomes (clinical disease control and dyspnea).MethodsStudy designThis randomized controlled trial (RCT) compared an intervention group which received a COPD self-management application to a control group that did not receive the intervention. All participants, whether they were assigned to the control or intervention group, were free to receive usual care or use other resources in order to help them manage their disease or improve their lifestyle.In the Netherlands, a COPD disease-management approach is widely implemented.18 This approach includes a practice nurse who coaches patients to improve their self-management behavior. We originally planned to integrate the intervention in this disease-management approach, but our pilot study had shown that it was not feasible to recruit enough patients to cover the sample size required for our RCT if the practice nurse recruited the patients.17 Instead, to solve the recruitment issues, we invited patients from five general practices by mail and recruited patients from a Dutch online panel. We also broadened our inclusion criteria to include people at risk for COPD as well as people with known COPD.The Dutch online panel was assembled by the company Flycatcher Internet Research BV (www.flycatcher.eu) which is an institute for online research certified by the International Organization for Standardization. In total, the online panel consisted of 16,000 Dutch-speaking members, who had an email address and were at least 12 years old. All age groups, education levels, and provinces of the Netherlands were represented in the panel. Flycatcher’s members are recruited by Flycatcher through newsletters, send-to-a-friend promotions, third parties’ contact lists used for research (with the permission of the owner of the contact list and the person on the list), and word-of-mouth advertising. Members receive seven research questionnaires a year on average.Members from the Dutch online panel and the five general practices were eligible for participation in this study if they were diagnosed with COPD or were at moderate or high risk for COPD, were between 40–70 years of age, were proficient in Dutch, and had access to the Internet and basic computer skills. Dutch proficiency and basic computer literacy were gauged by administration of the first online questionnaire. The Respiratory Health Screening Questionnaire (RHSQ)19 was used to assess the subject’s risk for COPD. This questionnaire contains ten items related to important determinants of COPD for individuals of 40 years and older.19 A scoring system for case-finding20,21 was used to determine if an individual was at low (<16.5 points), moderate (16.5–19.5 points), or high risk (>19.5 points) for COPD (sensitivity =58.7%, specificity =77.0%, for the 16.5 cutoff point).20The five general practices were involved in a parallel project21 in which 40- to 70-year-old patients had already been screened for COPD by their general practitioner using the RHSQ. Potentially eligible members of the online panel were invited for the study by an email from Flycatcher, including a study information letter. Members who decided to participate were screened for eligibility by completing the RHSQ. We implemented a scoring algorithm within the online questionnaire, so eligibility could be determined directly after participants completed the questionnaire. Members received a small incentive equal to €2.55 per completed questionnaire (baseline and follow-up). Figure 1 shows the Consolidated Standards of Reporting Trials (CONSORT) diagram including the two populations.The study was approved by the Medical Ethical Committee of Maastricht University Medical Center (METC 12-4-033) and registered with the Netherlands Trial Registry (NTR3421). All participants received an online study information letter and completed an online informed consent form before entering the study. A more detailed description of the methods can be found in a study protocol published elsewhere.22RandomizationA permuted block design23 with a random block size varying from four to 20 was employed to randomize participants stratified by channel of recruitment (online or through general practice). This approach was chosen in order to achieve balanced and evenly distributed samples for both recruitment strategies. A researcher not involved in data collection or analysis of the results performed the randomization using PROC PLAN in SAS software (v 9.1; SAS Institute, Cary, NC, USA). Due to the study design, it was not feasible to blind participants to group assignments.InterventionMasterYourBreath applicationThe intervention, “MasterYourBreath”,22 was designed to change participants’ health behavior by means of a web-based application providing computer-generated tailored feedback. The intervention was based on earlier studies on computer-tailored feedback for lifestyle changes which have been shown to be effective and cost-effective11,24–26 and adapted to our target groups. The MasterYourBreath application was built using the online application Tailorbuilder (OverNite Software Europe, Sittard, Netherlands).Participants assigned to the experimental group were asked by email to access the application with a personalized account and use the application ad libitum for 6 months. Participants in the online group received the email from Flycatcher and those in the general practice group from the research team. Application use was monitored by the research team and email prompts were sent to encourage application use,27 mostly within a 2-week time interval addressing new content on the website, as this could increase the number of follow-up visits.28 The application had a modular design, including two behavior-change modules, smoking cessation and physical activity. Each module was equally divided into six intervention components: (1) health-risk appraisal: feedback on the behavior (smoking or physical activity) based on Dutch guidelines; (2) motivational beliefs: feedback on perceived positive and negative consequences of the behavior; (3) social influence: feedback on the social influences of participants’ partner, family, friends, and coworkers on the behavior; (4) goal setting and action plans: feedback on achievement of goals and on action plans in order to achieve their goal; (5) self-efficacy: feedback on perceived barriers to change the behavior; and (6) maintenance: feedback in order to maintain the healthy behavior. Participants could switch behavior-change modules and choose to enter one or more intervention components according to their preference.10Feedback was personalized using participants’ names and tailored to participants’ characteristics and key behavior determinants of psychosocial constructs, for which the I-Change model served as theoretical framework.29,30 Examples of the key behavior determinants are: pros and cons of physical activity, perceived social support to quit smoking, action plans to increase physical activity, and self-efficacy to cope with barriers to quit smoking. Participants were asked questions to uncover their personal determinants, using questionnaires that have been tested experimentally among Dutch adults in previous studies in the general public.13,31,32 These questionnaires were adjusted for COPD patients during the usability study.16 The questions were used to generate tailored feedback to the participants about their responses. Participants’ previous responses were also incorporated in the feedback so they could track their own behavior change and goal attainment over the course of the study. The six intervention components per module were available to the participants to be completed over time as they chose. This allowed participants the ability to track their behavior changes by comparing the most current answers with the previous answers.A more detailed description of the intervention and prompt protocol is described elsewhere.22WebsiteThe computer-tailored application was embedded in a website. The website contained general information about the MasterYourBreath project, COPD/being at risk for COPD, smoking, and physical activity. Online self-management resources, such as videos with home exercises (seven exercises focusing on strength and balance) and hyperlinks to other informative websites, were also included. The tailored feedback and prompts referred participants to the home exercises and other resources.Data collectionA web-based questionnaire was administered at baseline between May and November of 2012 with a follow-up questionnaire sent out 6 months later. The frequency of reminders for completing these questionnaires was adapted to the response rate. The online group received one reminder to participate in the study and complete the baseline questionnaire. General practice group participants received two additional reminders if they responded to the invitation but did not complete the baseline questionnaire, since the participation rate in this group was low. The online group received one reminder to complete the follow-up questionnaire, whereas the general practice group received two reminders. Data collection ended in July 2013. All data were captured through these questionnaires, except demographic characteristics in the online group, as these were already documented through an annual update process undertaken by Flycatcher.Outcome measuresTwo primary outcomes were measured, one for each health behavior: smoking cessation and physical activity. Smoking cessation was assessed by one item measuring the 7-day point prevalence abstinence,33,34 and the level of physical activity was assessed by the International Physical Activity Questionnaire – Short Form.35We created a “behavior-change score” by combining the two behaviors (smoking cessation and physical activity). The behavior-change score was only calculated for participants who smoked at baseline or were below the physical activity norm (defined as being physically active for at least 30 minutes a day on 5 days a week at a moderate or vigorous intensity). The efforts of participants were rated as “successful behavior change” if they achieved smoke-free status for 7 consecutive days prior to the follow-up measurement, or if they achieved the norm level of physical activity at follow-up, reflecting a change from their baseline behavior. The actions of participants who smoked or were below the physical activity norm at baseline and achieved neither smoke-free status nor the norm level of physical activity at follow-up were rated as “unsuccessful behavior change”.Secondary outcomes included secondary smoking cessation measures, health status, and intention to change behavior. Secondary smoking cessation measures were: number of quit attempts during the past 6 months, 24-hour point prevalence abstinence, tobacco consumption, and continued and prolonged abstinence.33,34 To assess participants’ health status, participants were asked if they experienced any form of breathlessness, and if so, the Medical Research Council (MRC) dyspnea scale was administered in order to measure the level of disability.36 Clinical disease control was measured using the Clinical COPD Questionnaire. This questionnaire assesses both patient guideline goals (health-related quality of life) and clinical guideline goals such as prevention of disease progression.37 Intention to change behavior was measured by separate questions for physical activity and smoking. Table 1 presents an overview of all outcomes including how and when they were measured.Baseline measurementsThere were several additional baseline measures that were not part of the primary and secondary outcome measures, including demographic characteristics: age, sex, marital status, education level, and current employment status. Several additional questions were asked at baseline to capture smoking behavior. Participants were asked if they had ever smoked and about their number of previous quit attempts. The six-item version of the Fagerström Test for Nicotine Dependence (0= not addicted; 10= highly addicted)38 was included in order to assess the addiction level. Health status was further estimated, measuring COPD status and comorbidities, by asking participants whether they were diagnosed with COPD or any other chronic disease, and which other chronic disease(s).Sample-size calculationSample-size calculations assumed 80% power and a significance level of 0.05 for both behaviors and were completed by PS software version 3.0.43,39 according to Fisher’s exact test. Calculations for smoking indicated that 446 participants per group were necessary at the end of the trial to detect a 10% difference in 7-day point prevalence (20% abstinence in the intervention group, compared to 10% in the control group31). We based this calculation on the assumption that 49.2% of the population with an increased risk for COPD smoked at baseline.40 The number needed for measuring physical activity was smaller and could be obtained following the above sample-size calculation for smoking.22 In another study the standard deviation was 26.63 minutes a day in a Dutch population.41 When including 446 participants per group, a difference of 5 minutes a day, which corresponds to a small standardized effect size (Cohen’s d =0.2), could be detected. In order to allow for a 30% drop-out rate, a baseline total of 1,275 participants was necessary to reach 80% power.AnalysesDifferences at baseline between groups (intervention vs control; and participants who dropped out vs who did not drop out) were compared using chi-square tests for categorical variables and independent-samples t-tests for numerical variables. Data were analyzed according to the intention-to-treat principle. For both primary outcomes, an additional per protocol analysis was conducted. Participants assigned to the experimental group had to have completed at least one of the six intervention components of the specific behavior module to be included in the latter analysis. For the “per protocol” analyses, we conducted two sensitivity analyses with stricter criteria for each primary outcome (smoking cessation and physical activity). For the first analyses, we included only participants who completed at least two intervention components of the specific behavior module. For the second analyses, we included only participants who completed at least three intervention components, since a higher “usage dose” may be necessary to yield a treatment effect.The uncorrected and corrected effects of the intervention on the primary and secondary outcomes were assessed using logistic regression for categorical outcomes and linear regression for numerical outcomes measured at 6 months. Linear mixed models were used for outcomes measured at baseline and at 6 months to account for the correlation between repeated measurements of the same participant and to include all participants, including those with missing data. As for correction, the models included: the stratification variable – that is, recruitment channel (online or general practices); baseline variables if they showed a statistically significant difference between intervention and control group; and baseline variables that were related to drop out, missing data, and/or related to the outcome at 6 months (P value ≤0.20 in univariable regression analysis) to increase the precision of the intervention effect. To assess potential effect modifiers, the interaction of the treatment variable with age, sex, intention to increase level of physical activity, educational level, dyspnea status, and COPD status were added in the corrected mixed-model analyses for level of physical activity. Primary outcomes were analyzed for subgroups based on age (40–50, 50–60, 60–70), sex, intention to change behavior (those who had no intention or were not sure; those who intended to change), education level (low, middle, high), dyspnea (yes, no), COPD status (diagnosed, at risk).The robustness of our results of the primary outcome for smoking cessation was tested by conducting a best- and a worst-case scenario, where respondents lost to follow-up were considered to have quit smoking in the best-case scenario and considered to still be smoking in the worst-case scenario. In addition, as a sensitivity analysis, the intervention effect on the behavior-change score was tested using logistic regression analysis.All statistical analyses were performed using IBM SPSS (v 19). Two-sided P values ≤0.05 were considered statistically significant.ResultsRecruitmentA total of 7,179 individuals were invited for the study of which 3,035 declined to participate, 2,790 did not meet the inclusion criteria, and 29 were excluded because they did not complete the baseline questionnaire (n=24) or provided unreliable responses (n=5). Responses were unreliable if answers were straight lined (ie, the same answer options selected for each set of items) or the questionnaire was completed within 3 minutes (which was considered to be unrealistically fast).A total of 1,325 participants (1,282 in the online group and 43 in the general practice group) completed the baseline questionnaire and were randomly assigned to the experimental (online group: n=641, general practice group: n=21) or control group (online group: n=641, general practice group: n=22). Of the 1,325 participants, 1,071 (80.8%) completed the 6-month follow-up questionnaire, including 1,048 (81.7%) of the online group and 23 (53.5%) of the general practice group. Eighteen participants of the online group were excluded from further analyses, due to a high level of suspicion of interference by someone other than the participant, (eg, a partner with whom they shared an email address). Participants were excluded when at least two of the following variables did not match their Flycatcher profile on the follow-up questionnaire: sex, day of birth, month of birth, year of birth. If only one variable was inconsistent or day and month were reversed, we suspected a typing error and did not exclude those participants.In the group of smokers, 447 participants were included of whom 341 completed the follow-up questionnaire. Figure 1 shows the CONSORT diagram of our RCT.Sample characteristicsTable 2 shows the baseline characteristics of the overall sample and the experimental and control groups separately. The only significant difference between the groups was the employment status of participants (P=0.039). As for the participants who smoked at baseline, we did not find any significant differences in baseline characteristics between the groups.More participants were lost to follow-up in the general practice group (46.5%) than in the online group (18.5%) (P<.001), more in the experimental group (22.8%) than in the control group (16%) (P=.002), more smokers (23.7%) than non-smokers (17.2%) (P=.005), and more female (22.6%) than male participants (15.9%) (P=.002). Participants lost to follow-up were also significantly younger (mean =55.9 years) than completing participants (mean =58.1 years) (P<0.001).Application useThe application was used by 237 (36%) participants of the experimental group (ie, at least one of the six components of a behavior-change module was completed). The average number of components completed by those participants was 2.1 (standard deviation =2.4, range 1–21). For physical activity, 193 (29.3%) of the participants completed at least one intervention component. For smoking cessation, 51 (21.2%) of the smokers at baseline, and seven (1.7%) of the nonsmokers at baseline completed at least one intervention component (although nonsmokers were not included in the effect analyses for smoking cessation). Table 3 shows how many participants completed zero, one, two, or three or more intervention components of both modules.Intervention effectBefore correction for baseline characteristics, no significant treatment effect was found for any primary or secondary outcome, except clinical disease control. After correction, all effects were nonsignificant (Table 4).As for sensitivity analyses, similar results were found for the primary outcomes. More specifically, per protocol analyses yielded nonsignificant results for both primary outcomes (Table 5). Regarding physical activity, all interaction terms were nonsignificant. Also, when evaluating for smoking cessation, neither the uncorrected nor corrected effects on 7-day point prevalence abstinence were significant for best- or worst-case scenarios. All subgroup analyses for both outcomes were nonsignificant. Besides, uncorrected and corrected analyses on the behavior-change score, combining the two behaviors, yielded nonsignificant results.DiscussionThis study examined the effects of a computer-tailored COPD self-management intervention. The intervention had no significant impact on the primary outcome measures (physical activity and smoking), or on the secondary outcome measures (intention to change behavior and dyspnea). The only significant effect found was on clinical disease control, but the improvement was too small to have clinical relevance42 and was not significant after correction for relevant baseline characteristics. Moreover, a borderline significant effect for smoking was found when analyzing the effects among those who completed at least two intervention components. Also, the effect size, for both smoking and physical activity, increased as more intervention components were used. Yet, possibly due to the sample size and thus decreased power of the study, these analyses did not yield a significant effect.Possible explanations for the lack of effect may be: (a) low exposure to the intervention, (b) that the intervention method was not sufficient for our target population, and (c) inadequate content of the intervention itself. Although it was not significant, the trend was for an increased effect size as the participants completed more of the six intervention components. This helps verify the importance of exposure to the application and correlates with other studies which have shown that this is essential for the effectiveness of such interventions.43,44 To enhance exposure to the intervention, we used different strategies to attract participants to the application: sending email prompts every 2 weeks, of which some referred to new content on the website, as this has been shown to effectively increase application use;28 including multiple feedback moments to evaluate participants’ behavior and track their goal achievement;45,46 prompting revisits to the application and evaluate these previously set goals; and embedding a website that provided regular news updates,45–47 such as behavioral journalism stories,48 which were personal stories addressing how other patients overcame potential barriers to use the application and improve their health behavior. Additionally, since the length of the program was of concern in the pilot study,17 we separated the two modules (smoking cessation and physical activity) into six small components, giving participants the opportunity to decide which components they wanted to complete, and consequently, how much time they wanted to spend working with the application. Unfortunately, only one out of three participants completed one or more of the six intervention components. In hindsight, giving participants an option to choose intervention components based on the results of our pilot study was probably not desirable, since it has recently been shown that less freedom of navigation on a website enhances application use.49,50 The intervention did not include ongoing peer or counselor support (eg, by a practice nurse) which could have improved the exposure to the application.47Another potential cause for our study results could be that the intervention method was not sufficient for our target population. Although similar computer-tailoring approaches have found significant effects among the general population,11,14,25,26 several other studies reported a relatively low success rate of disease-management programs for COPD patients51–53 and found that COPD patients are more likely to have characteristics that are associated with a higher resistance to smoking cessation interventions54 than other target populations. Negative results are not uncommon in COPD self-management studies according to a systematic review by Jonsdottir.5 The author describes the need for a paradigm shift in which a prominent health professional-centered approach should make way for a patient-family-centered approach with emphasis on the relationship with the health care professional. As we were aware of this, the MasterYourBreath intervention was patient-centered, and social influence of family members was addressed in the intervention. However, the application did not enable the active participation of family members. An improvement to future versions could be to integrate the MasterYourBreath intervention with a social media platform to facilitate engagement of the family members in the patient’s self-management process. The relationship with the health care professional was indeed emphasized in the original version of the MasterYourBreath intervention, by integration of the application in primary care, but recruiting the number of participants necessary for an RCT from primary care practices was found to be unfeasible in the pilot study,17 so the original study design was changed.Another possible cause for the lack of effect could be related to the web-based intervention content itself. We used key behavioral determinants that were experimentally tested in the Dutch population but not validated for COPD patients. The usability study in which we adjusted these determinants for COPD patients16 is not a replacement for a validation study. Behavioral determinants for this specific group might be different from the general Dutch population. For example, COPD patients are likely to experience different barriers to physical activity due to disease complications. Moreover, the main difference we found comparing our application to programs that were very similar but found positive intervention effects11,14,25,26,43,55 was that participants in our study were free to choose which intervention components they wanted to complete. These other programs contained similar tailored messages, but directed participants through a specified intervention pathway. As described previously, this strategy might increase exposure, as it limits freedom of navigation. Instead of shortening the intervention content by tailoring the use of components to user’s preference,10 it may have been more effective to offer participants only components adapted to their level of motivation to change their behavior; Stanczyk et al55 found this strategy effective. Peels et al56 tested a web-based basic version of their program and a version in which they added additional environmental information with links to other resources to increase physical activity in adults aged 50 and over. They found that only the latter was not effective. The authors suspected that participants might have been distracted from the intervention pathway by visiting other resources. Likewise, the provision of additional information and self-management resources in the MasterYourBreath application, including home exercises and links to other websites might have decreased a potential intervention effect, as these could have distracted participants from the intervention components, which was the core content of the intervention.LimitationsOur study had several limitations. First, despite our relatively large sample of participants, compared to many other COPD self-management studies,5 our study still lacked power concerning the primary outcome for smoking cessation. The number of smokers at the start of the study was lower than expected, and loss to follow-up among smokers was higher than among nonsmokers.Second, we were not able to evaluate selection bias, because we could not collect additional data to differentiate between participants who enrolled versus those who declined participation. The clinical information that would help us address selection bias was not available from the online recruiting company.Third, the inclusion of people at risk for COPD may make it more difficult to compare our results with self-management studies that include only COPD patients. However, we argue that including individuals at risk for COPD is clinically relevant, since early smoking cessation is pivotally important for a greater health benefit in COPD.57 Including both diagnosed patients and individuals at risk for COPD also poses a methodological challenge, since these groups may benefit from different interventions. However, the approach to care in the MasterYourBreath program has been tailored to varying levels of COPD (risk), and thus it was able to address differing patient needs.Fourth, while our intentions were to do so, we were not able to integrate the MasterYourBreath intervention into the Dutch COPD disease-management approach,18 due to recruitment issues.17 We know that it is important that COPD self-management interventions can be incorporated in an existing health care structure.58–60 The recruitment strategy used in this RCT (including an online group and individuals at risk for COPD) was certainly beneficial for the sample size of our RCT, but hampered the integration of our intervention in primary care.ConclusionMasterYourBreath, a web-based COPD self-management intervention with tailored feedback, did not show statistically significant effects on health-related behavioral or clinical outcomes. Given the structurally low exposure to the application in this study, we believe more research is needed to find effective strategies to increase the use of the web-based applications by COPD patients. To further explain this phenomenon and to generate hypotheses for better strategies, we will reevaluate our RCT and explore in depth the characteristics of the intervention and the participants that may have contributed to the use and appreciation of the application.AcknowledgmentsThe authors would like to thank Onno van Schayck, PhD, for his assistance with the study design; Jos Dirven, MD, for his contribution to participant recruitment; and Jean Muris, PhD, for screening feedback messages on content and providing advice as a COPD specialist. The authors also thank the University of Oklahoma, Health Sciences Center, for providing an office; James W Mold, MD, MPH, for providing general support; and E Wickersham, MD, for editing the manuscript. This study was funded by ZonMw, the Netherlands Organization for Health Research and Development.DisclosureHein de Vries is scientific director of Vision2Health, a company that licenses evidence-based innovative computer- tailored health-communication tools. The other authors declare that they have no competing interests in this work.References1ViegiGPistelliFSherrillDLMaioSBaldacciSCarrozziLDefinition, epidemiology and natural history of COPDEur Respir J20073059931013179781572SiafakasNMVermeirePPrideNBOptimal assessment and management of chronic obstructive pulmonary disease (COPD). 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Conceptual framework and item selectionMed Care1992306473483159391466SmitESHovingCSchelleman-OffermansKWestRde VriesHPredictors of successful and unsuccessful quit attempts among smokers motivated to quitAddict Behav20143991318132424837754Figure 1Consolidated Standards of Reporting Trials diagram.Abbreviation: GP, general practice.Table 1Primary and secondary outcomesOutcome(s)MeasurementScaleTimePrimarySmoking cessation: 7-day point prevalence abstinence1 item assessing whether participant smoked during the last 7 daysa0= did not refrain from smoking during the last 7 days; 1= refrained from smoking during the last 7 daysFollow-upLevel of physical activityIPAQ-SFbMET minutes a week (last 7 days): vigorous physical activity =8.0 METs; moderate physical activity =4.0 METs; walking =3.3 METsBaseline and follow-upSecondaryQuit attempts1 item assessing the number of quit attempts during the past 6 monthsaNumber of quit attempts during the past 6 monthsFollow-up24-hour point prevalence abstinence1 item assessing whether participant smoked during the last 24 hoursa0= did not refrain from smoking during the last 24 hours; 1= refrained from smoking during the last 24 hoursFollow-upContinued abstinence1 item assessing when the last serious quit date was, and 1 item assessing smoking behavior since that datea0= smoked since the last quit date; 1= did not smoke at all since the last quit dateFollow-upProlonged abstinence1 item assessing when the last serious quit date was, and 1 item assessing smoking behavior since that date, allowing a grace period of 2 weeks in which smoking behavior was not counted as sucha0= smoked since 2 weeks after the last quit date; 1= did not smoke at all since 2 weeks after the last quit dateFollow-upTobacco consumption4 items assessing what products (cigarettes, rolling tobacco, cigars, or pipe tobacco) are currently smoked, and 4 items assessing how much of each product is currently smokedaNumber of cigarettesfBaseline and follow-upDyspnea status1 item, MRC scalec1–5; higher score means worse dyspneaBaseline and follow-upClinical disease control10-item CCQd0= very good control; 6= extremely poor controlBaseline and follow-upIntention to quit smoking1 item, 7-point Likert scalee1= I certainly plan to quit smoking; 7= I certainly do not plan to quit smokingBaseline and follow-upIntention to increase the level of physical activity1 item, 7-point Likert scalee1= I certainly plan to be more physically active; 7= I certainly do not plan to be more physically activeBaseline and follow-upNotes:aSmoking cessation questions were selected based on the Russel Standard33 and a Dutch guide published by Stivoro that aimed to standardize smoking cessation measures in the Netherlands.34 Self-report has been shown to be reliable in COPD patients: kappa coefficient =0.20 for biochemical validation at 6-month measurement, P=0.003.61bThe reliability and validity of the IPAQ-SF have been tested in the Dutch population: test–retest reliability, ρ=0.85; concurrent validity between long and short IPAQ, from ρ=0.85 to 0.88; criterion validity against accelerometer, ρ=0.32.35cThe MRC scale is a useful measure for disability. Significant associations were found between disability MRC grade and shuttle distance, St George Respiratory Questionnaire,62 Chronic Respiratory Questionnaire63 scores, mood state, and Nottingham Extended Activities of Daily Living64 scores. Forced expiratory volume in one second was not associated with MRC grade.36dThe CCQ is validated in the Dutch population and can be used for COPD patients and individuals at risk for COPD: Cronbach’s alpha =0.91(internal consistency), significantly higher score of people with or at risk for COPD compared to healthy (ex-)smokers (P<0.05) (discriminate validity), significant correlations with 36-Item Short Form Health Survey (ρ=0.48–0.69)65 and St George Respiratory Questionnaire (ρ=0.67–0.72) (internal consistency); correlation with forced expiratory volume in one second % predicted ρ=–0.49 (divergent validity); intra class coefficient =0.94 (test–retest reliability); significant improvement in CCQ found after 2 months’ smoking cessation (responsiveness).37eThe intention questions were based on the I-Change model.29,30 The “intention to quit smoking” question has previously been used successfully in a similar intervention study.66fThe overall score for tobacco consumption was expressed as the number of cigarettes, whereby one hand-rolled cigarette equaled one commercial cigarette, and one cigar equaled four cigarettes.34 We considered one pipe to equal one cigarette, since no concrete guidelines were available on converting the number of pipes to cigarettes.Abbreviations: CCQ, Clinical COPD Questionnaire; IPAQ-SF, International Physical Activity Questionnaire – Short Form; MET, metabolic equivalent task; MRC, Medical Research Council.Table 2Baseline characteristics of study participants – overall, experimental and control groupCharacteristicOverall sample(n=1,307)Experimental group(n=658)Control group(n=649)Age, years (mean [SD])57.6 (7.2)57.7 (7.3)57.6 (7.2)Male (n [%])627 (48.0)326 (49.5)301 (46.4)Education level (n [%])\u2003Primary school/basic vocational school386 (29.5)191 (29.0)195 (30.0)\u2003Secondary vocational school/high school degree427 (32.7)209 (31.8)218 (33.6)\u2003Higher professional degree/university degree494 (37.8)258 (39.2)236 (36.4)Current employment status (n [%])\u2003Employed670 (51.3)356 (54.1)314 (48.4)\u2003Not employed637 (48.7)302 (45.9)335 (51.6)*Marital status (n [%])\u2003Single/divorced/widowed348 (26.6)171 (26.0)177 (27.3)\u2003In a relationship/living together/married959 (73.4)487 (74.0)472 (72.7)COPD status (n [%])\u2003Diagnosed with COPD284 (21.7)146 (22.2)138 (21.3)\u2003Increased risk for COPD per RHSQ191,023 (78.3)512 (77.8)511 (78.7)Comorbidity (n [%])\u2003≥1 chronic condition604 (46.2)292 (44.4)312 (48.1)\u2003Respiratory disease224 (17.1)106 (16.1)118 (18.2)\u2003Cancer53 (4.1)30 (4.6)23 (3.5)\u2003Diabetes120 (9.2)57 (8.7)63 (9.7)\u2003Cardiovascular disease200 (15.3)98 (14.9)102 (15.7)\u2003Musculoskeletal disorder90 (6.9)41 (6.2)49 (7.6)\u2003Other chronic condition124 (9.5)58 (8.8)66 (10.2)MRC dyspnea36 (n=1,305)\u2003No breathlessness359 (27.5)177 (26.9)182 (28.1)\u20031523 (40.1)264 (40.2)259 (40.0)\u20032318 (24.4)167 (25.4)151 (23.3)\u2003375 (5.7)34 (5.2)41 (6.3)\u2003419 (1.5)9 (1.4)10 (1.5)\u2003511 (0.8)6 (0.9)5 (0.8)Smoking status\u2003Currently smoking447 (34.2)241 (36.6)206 (31.7)\u2003Currently not smoking860 (65.8)417 (63.4)443 (68.3)Number of cigarettes smoked/day among smokers, n=447 (mean [SD])19.3 (12.1)19.0 (12.3)19.8 (11.9)FTND score (range 0–10)38 among smokers, n=447 (mean [SD])4.2 (2.3)4.1 (2.3)4.4 (2.3)Number of previous quit attempts among smokers, n=447 (mean [SD])3.8 (8.8)3.1 (4.0)4.8 (12.2)Intention to quit smoking (range 1–7) among smokers, n=447 (mean [SD])3.7 (1.9)3.7 (2.0)3.7 (1.9)Level of physical activity (MET per week), n=1,096 (mean [SD])4,012.6 (3,933.3)4,108.7 (4,034.0)3,914.1 (3,828.4)Intention to be more physically active (range 1–7) (mean [SD])3.2 (1.7)3.2 (1.7)3.1 (1.7)CCQ score (range 0–6)37 (mean [SD])1.0 (0.9)1.0 (0.9)1.0 (0.8)Note:*P<0.05.Abbreviations: CCQ, Clinical COPD Questionnaire; FTND, Fagerström Test for Nicotine Dependence; MET, metabolic equivalent task; MRC, Medical Research Council; RHSQ, Respiratory Health Screening Questionnaire; SD, standard deviation.Table 3Number of participants (%) who completed intervention components of the physical activity and smoking cessation modulesModuleNumber of components completed\n012≥3Physical activity465 (70.7)107 (16.3)48 (7.3)38 (5.8)Smoking cessation, among smokers190 (78.8)29 (12.0)12 (5.0)10 (4.1)Table 4Effects of the web-based COPD self-management intervention on all primary and secondary outcomesPrimary and secondary outcomesUncorrected effectsCorrected effects7-day point prevalence abstinenceaOR=1.12, (0.45; 2.77*), P=0.810OR=1.06, (0.43; 2.66), P=0.895MET minutes a weekbb=−64.70, (−455.39; 326.00), P=0.745b=−84.33, (−476.39; 307.74), P=0.67324-hour point prevalence abstinenceaOR=0.77, (0.36; 1.67), P=0.510OR=0.72, (0.33; 1.59), P=0.420Prolonged abstinenceaOR=0.90, (0.35; 2.34), P=0.834OR=0.86, (0.33; 2.25), P=0.766Continued abstinenceaOR=1.02, (0.39; 2.72), P=0.963OR=0.98, (0.37; 2.63), P=0.969Number of cigarettescb=−0.08, (−1.82; 1.65), P=0.925b=0.11, (−1.61; 1.84), P=0.899Intention to quit smokingdb=−0.01, (−0.31; 0.28), P=0.937b=−0.03, (−0.32; 0.26), P=0.826Number of quit attemptseb=−0.36, (−1.10; 0.37), P=0.334b=−0.38, (−1.11; 0.36), P=0.312Intention to increase physical activityfb=0.00, (−0.17; 0.17), P=0.991b=0.00, (−0.17; 0.17), P=0.987Clinical disease controlgb=−0.06, (−0.11; −0.01), P=0.010b=−0.03, (−0.07; 0.01), P=0.134Dyspnea statushOR=1.16, (0.89; 1.51), P=0.283OR=1.28, (0.92; 1.79), P=0.149Notes:*95% confidence intervals are shown within brackets.aLogistic regression analyses were performed. The corrected analysis only included intention to quit smoking, as including more variables would have overloaded the model. The number of smokers in the general practice group followed up was too small (n=4) to yield reliable results when including recruitment channel in the model.bLinear mixed-model analyses were performed, corrected for age, sex, recruitment channel, smoking status, employment status, comorbidity (yes/no), MRC score, and intention to increase physical activity.cLinear mixed-model analyses were performed, corrected for age, sex, marital status, CCQ score, level of education, MRC score, and FTND score.dLinear mixed-model analyses were performed, corrected for age, sex, level of education, CCQ score, MRC score, number of quit attempts, and employment status.eLinear regression analyses were performed, corrected for age, sex, level of education, CCQ score, MRC score, and FTND score.fLinear mixed-model analyses were performed, corrected for age, sex, recruitment channel, smoking status, employment status, and MRC score.gLinear mixed-model analyses were performed, corrected for age, sex, recruitment channel, smoking status, employment status, COPD status, comorbidity (yes/no), marital status, level of physical activity, MRC score, and level of education.hLogistic regression analyses were performed, corrected for age, sex, recruitment channel, smoking status, employment status, COPD status, comorbidity (yes/no), marital status, level of physical activity, CCQ score, and level of education. Dyspnea status was recoded (0= participants who experienced a form of breathlessness and scored 1–5 on the MRC dyspnea score; 1= participants who indicated to have no breathlessness).Abbreviations: b, estimated mean difference; CCQ, Clinical COPD Questionnaire; FTND, Fagerström Test for Nicotine Dependence; MET, metabolic equivalent task; MRC, Medical Research Council; OR, odds ratio.Table 5Corrected effects of the per protocol analyses for primary outcomesPrimary outcomesAt least 1 component completedAt least 2 components completedAt least 3 components completed7-day point prevalence abstinenceaOR=1.75, (0.51; 6.00), P=0.371OR=3.57, (0.87; 14.73), P=0.078No reliable resultscMET minutes a weekbb=−101.58, (−653.10; 449.94), P=0.718b=120.92, (−683.86; 925.71), P=0.768b=813.44, (−383.29; 2,010.17), P=0.182Notes: 95% confidence interval between brackets.aLogistic regression analyses were performed. This analysis did not include covariates due to the small number of events (successful behavior changes).bLinear mixed-model analyses were performed, corrected for age, sex, recruitment channel, smoking status, employment status, comorbidity (yes/no), MRC score, intention to increase physical activity;cno events (successful behavior change) in the experimental group.Abbreviations: b, estimated mean difference; MET, metabolic equivalent task; OR, odds ratio.', 'title': 'A randomized controlled trial evaluating the effectiveness of a web-based, computer-tailored self-management intervention for people with or at risk for COPD.', 'date': '2015-06-20'}, '24293120': {'article_id': '24293120', 'content': 'First, to investigate the effects of a telerehabilitation intervention on health status and activity level of patients with Chronic Obstructive Pulmonary Disease (COPD), compared to usual care. Second, to investigate how patients comply with the intervention and whether compliance is related to treatment outcomes.\na randomized controlled pilot trial\nThirty-four patients diagnosed with COPD.\nThe telerehabilitation application consists of an activity coach (3D-accelerometer with smartphone) for ambulant activity registration and real-time feedback, complemented by a web portal with a symptom diary for self-treatment of exacerbations. The intervention group used the application for 4 weeks. The control group received usual care.\nActivity level measured by a pedometer (in steps/day), health status by the Clinical COPD Questionnaire at baseline and after intervention. Compliance was expressed as the time the activity coach was worn.\nFourteen intervention and 16 control patients completed the study. Activity level (steps/day) was not significantly affected by the intervention over time. There was a non-significant difference in improvement in health status between the intervention (-0.34±0.55) and control group (0.02±0.57, p=0.10). Health status significantly improved within the intervention group (p=0.05). The activity coach was used more than prescribed (108%) and compliance was related to the increase in activity level for the first two feedback weeks (r=0.62, p=0.03).\nThis pilot study shows the potential of the telerehabilitation intervention: compliance with the activity coach was high, which directly related to an improvement in activity levels.', 'title': 'A telerehabilitation intervention for patients with Chronic Obstructive Pulmonary Disease: a randomized controlled pilot trial.', 'date': '2013-12-03'}}
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Family Medicine & Preventive Care
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Is the risk of adverse events higher, lower, or the same when comparing smart technology for self‐management to face‐to‐face/digital and/or written support for self‐management?
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yes
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['27502583']
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{'27502583': {'article_id': '27502583', 'content': "J Med Internet ResJ. Med. Internet ResJMIRJournal of Medical Internet Research1439-44561438-8871JMIR PublicationsToronto, Canada275025834993862v18i8e21510.2196/jmir.5622Original PaperOriginal PaperLong-Term Effects of an Internet-Mediated Pedometer-Based Walking Program for Chronic Obstructive Pulmonary Disease: Randomized Controlled TrialEysenbachGuntherCobbNathanMullerIngridJeromeGeraldRyanDermotGraingerRebeccaPoderThomasMoyMarilyn LMD12http://orcid.org/0000-0002-2471-9218MartinezCarlos HMD3http://orcid.org/0000-0003-2070-4091KadriReemaMLIS45http://orcid.org/0000-0003-0935-3761RomanPiaMA5http://orcid.org/0000-0002-6190-4666HollemanRobert GMPH5http://orcid.org/0000-0003-2300-1842KimHyungjin MyraScD56http://orcid.org/0000-0002-0604-8027NguyenHuong QPhD7http://orcid.org/0000-0002-3650-3705CohenMiriam DMSN8http://orcid.org/0000-0002-8551-0741GoodrichDavid EEdD5http://orcid.org/0000-0003-3232-2189GiardinoNicholas DPhD9http://orcid.org/0000-0002-5026-3859RichardsonCaroline RMD4Department of Family MedicineUniversity of Michigan1018 Fuller St.Ann Arbor, MI, 48104United States1 734 998 7120 ext 3161 734 998 7335caroli@umich.edu5http://orcid.org/0000-0002-1945-60461Pulmonary and Critical Care Medicine SectionVA Boston Healthcare SystemBoston, MAUnited States2Harvard Medical SchoolBoston, MAUnited States3Pulmonary & Critical Care DivisionUniversity of Michigan Health SystemAnn Arbor, MIUnited States4Department of Family MedicineUniversity of MichiganAnn Arbor, MIUnited States5Center for Clinical Management ResearchVA Ann Arbor Healthcare SystemAnn Arbor, MIUnited States6Department of BiostatisticsSchool of Public HealthUniversity of MichiganAnn Arbor, MIUnited States7Department of Research and EvaluationKaiser Permanente Southern CaliforniaPasadena, CAUnited States8Pulmonary Medicine SectionVA New York HarborBrooklyn, NYUnited States9Department of PsychiatryUniversity of MichiganAnn Arbor, MIUnited StatesCorresponding Author: Caroline R Richardson\ncaroli@umich.edu820160882016188e215922016103201621420162452016©Marilyn L Moy, Carlos H Martinez, Reema Kadri, Pia Roman, Robert G Holleman, Hyungjin Myra Kim, Huong Q Nguyen, Miriam D Cohen, David E Goodrich, Nicholas D Giardino, Caroline R Richardson. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 08.08.2016.2016This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in the Journal of Medical Internet Research, is properly cited. The complete bibliographic information, a link to the original publication on http://www.jmir.org/, as well as this copyright and license information must be included.BackgroundRegular physical activity (PA) is recommended for persons with chronic obstructive pulmonary disease (COPD). Interventions that promote PA and sustain long-term adherence to PA are needed.ObjectiveWe examined the effects of an Internet-mediated, pedometer-based walking intervention, called Taking Healthy Steps, at 12 months.MethodsVeterans with COPD (N=239) were randomized in a 2:1 ratio to the intervention or wait-list control. During the first 4 months, participants in the intervention group were instructed to wear the pedometer every day, upload daily step counts at least once a week, and were provided access to a website with four key components: individualized goal setting, iterative feedback, educational and motivational content, and an online community forum. The subsequent 8-month maintenance phase was the same except that participants no longer received new educational content. Participants randomized to the wait-list control group were instructed to wear the pedometer, but they did not receive step-count goals or instructions to increase PA. The primary outcome was health-related quality of life (HRQL) assessed by the St George’s Respiratory Questionnaire Total Score (SGRQ-TS); the secondary outcome was daily step count. Linear mixed-effect models assessed the effect of intervention over time. One participant was excluded from the analysis because he was an outlier. Within the intervention group, we assessed pedometer adherence and website engagement by examining percent of days with valid step-count data, number of log-ins to the website each month, use of the online community forum, and responses to a structured survey.ResultsParticipants were 93.7% male (223/238) with a mean age of 67 (SD 9) years. At 12 months, there were no significant between-group differences in SGRQ-TS or daily step count. Between-group difference in daily step count was maximal and statistically significant at month 4 (P<.001), but approached zero in months 8-12. Within the intervention group, mean 76.7% (SD 29.5) of 366 days had valid step-count data, which decreased over the months of study (P<.001). Mean number of log-ins to the website each month also significantly decreased over the months of study (P<.001). The online community forum was used at least once during the study by 83.8% (129/154) of participants. Responses to questions assessing participants’ goal commitment and intervention engagement were not significantly different at 12 months compared to 4 months.ConclusionsAn Internet-mediated, pedometer-based PA intervention, although efficacious at 4 months, does not maintain improvements in HRQL and daily step counts at 12 months. Waning pedometer adherence and website engagement by the intervention group were observed. Future efforts should focus on improving features of PA interventions to promote long-term behavior change and sustain engagement in PA.ClinicalTrialClinicaltrials.gov NCT01102777; https://clinicaltrials.gov/ct2/show/NCT01102777 (Archived by WebCite at http://www.webcitation.org/6iyNP9KUC)bronchitis, chronicemphysemapulmonary disease, chronic obstructivequality of lifeexercisemotor activityInternetIntroductionPhysical activity (PA) is significantly reduced in persons with chronic obstructive pulmonary disease (COPD), even at the earliest stages of disease [1-3]. Its clinical course is punctuated with acute exacerbations, during and following which persons suffer further reductions in PA [4,5]. As a disease with systemic consequences, COPD increases vulnerability to frailty, immobility, and loss of functional independence. Despite optimal pharmacological therapy, persons with COPD suffer from a downward spiral of breathlessness, deconditioning, and physical inactivity [6]. Comorbidities of cardiovascular disease, diabetes mellitus, and osteoporosis contribute to further reductions in PA [7,8].Physical activity is a modifiable health behavior that affects COPD-specific outcomes [9-14]. It has been shown that a greater quantity of low-intensity PA reduces risk of COPD hospitalizations, whereas high-intensity PA does not result in risk reduction [15]. In a cohort of persons with COPD, those who walk the least have risks that are 2 and 6 times higher for acute exacerbations and COPD-related hospitalizations, respectively, compared to those who walk the most [12]. In addition, persons with COPD with higher PA levels have a significantly lower risk of dying, independent of forced expiratory volume in 1 second (FEV1) [14]. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend regular PA for all persons with stable COPD as part of standard nonpharmacological treatment [6].Despite the evidence and recommendations, effective long-term PA interventions are lacking in the clinical care of patients with COPD. Most studies of long-term exercise interventions have examined methods to maintain exercise in the subset of persons with COPD who have completed a conventional pulmonary rehabilitation program [16-21]. These interventions have combined weekly- or monthly-supervised exercise classes with unsupervised home exercise, support groups, and/or telephone contact with a health care professional, showing mixed results over the long term [16-21]. Strategies that promote behavior change and long-term adherence to effectively sustain PA in all persons with COPD are needed.We developed an automated, Internet-mediated, pedometer-based walking program called Taking Healthy Steps to promote PA in persons with COPD. Taking Healthy Steps combines the Omron HJ-720 ITC pedometer (Omron Healthcare, Inc, Bannockburn, IL, USA) with a disease-specific website accessed via a URL. Taking Healthy Steps provides iterative step-count feedback, individualized step-count goals, education on disease self-management, motivational support, and an online community of social support [22-27]. We studied the efficacy of Taking Healthy Steps in a randomized controlled trial (trial registration: Clinicaltrials.gov NCT01102777) [27]. The conceptual framework, study design, and results at 4 months have been described previously [26,27]. We have shown that Taking Healthy Steps is safe and engaging, and improves health-related quality of life (HRQL) and increases daily step count at 4 months [25-27]. In this study, our primary aim was to assess the long-term efficacy of Taking Healthy Steps on HRQL and daily step counts, a marker for walking behavior change, at 12 months. Our secondary aim was to assess long-term engagement with the PA intervention.MethodsRecruitmentThe study design and methods have been reported previously [26,27]. Participants were enrolled from national patient care databases of US Veterans, between December 2011 and January 2013, who had received any treatment services in the previous year and had a COPD diagnosis. Zip codes were matched with the Rural Urban Commuting Area Codes to determine whether one’s residence was urban or rural [28]. Of the 21 regional Veteran Integrated Service Networks (VISN) across the 50 United States and Puerto Rico, we excluded Veterans from one VISN (VISN-1) where another COPD research study using the Taking Healthy Steps platform was recruiting participants. The coordinating center was located at the Ann Arbor VA Healthcare System, Ann Arbor, MI, USA. Ethical approval for this study was granted by the VA Ann Arbor Healthcare System Human Studies Subcommittee.A random sample of 28,957 Veterans (half rural, half urban) with a COPD diagnosis was sent a recruitment letter. Inclusion criteria included having access to a computer with an Internet connection, a USB port, and Windows XP, Vista, Windows 7, or Windows 8. Our a priori exclusion criteria excluded those who did not upload baseline step-count data or who did not complete the baseline survey to assess HRQL. Per study protocol, participants had to have baseline values for the primary (HRQL) and secondary outcome (daily step count) to be enrolled and randomized. Ultimately, 239 participants were enrolled and randomized in a 2:1 ratio to either Taking Healthy Steps (Internet-mediated, pedometer-based walking program) or wait-list control (pedometer alone), stratified by Modified Medical Research Council (MMRC) dyspnea score and urban versus rural status (Figure 1). All participants were prompted monthly to report new or worsening medical problems; all self-reported adverse events were recorded. There were no face-to-face encounters with staff; all features were automatically delivered via the website.Figure 1CONSORT diagram at 12 months.OutcomesPrimary OutcomeThe St. George’s Respiratory Questionnaire (SGRQ), a disease-specific instrument with 50 items that has been well validated in COPD [29,30] was used to assess HRQL. It has a summary total score (SGRQ-TS) composed of three domain scores: symptoms (frequency and severity), activities (that cause or are limited by breathlessness), and impact (social functioning and psychological disturbances resulting from airways disease). Scores range from 0 to 100 with lower scores indicating better HRQL. A change of four units is the minimum clinically important difference for the SGRQ-TS [31]. Study participants completed the SGRQ online at study entry, 4 months, and 12 months.Secondary OutcomeDaily step count was assessed by the Omron HJ-720 ITC pedometer. Once participants completed the baseline survey, study staff mailed them a pedometer that had an embedded USB port, an upload cable, and detailed written instructions on how to install the Java software and upload pedometer data. For users who did not have Java already installed on their computers, the software installation was a one-time event. Thereafter, participants uploaded step-count data using the cable that connected the pedometer to their home computer. Research staff were available by telephone to assist with software installation and upload of step counts.A wear day with valid step-count data was defined as one having at least 100 steps and 8 hours of step counts recorded [32]. At baseline, participants wore the pedometer covered with a sticker to blind the participant to device feedback. Baseline daily step count was the mean daily step count calculated using at least 5 days of valid data within a period of seven consecutive days. Follow-up daily step counts were calculated within a window of +/-14 days around day 121 for 4-month values, and +/-14 days around day 366 for 12-month values. Follow-up daily step counts were the means of at least 5 days of valid data within a period of seven consecutive days. We also calculated the mean daily step count each month by examining the data in 30-day increments. We used values from the last valid week (at least 5 days of valid data within a period of seven consecutive days) in each of those months.Intervention GroupParticipants randomized to Taking Healthy Steps completed an intensive 4-month intervention period, followed by a distinct 8-month maintenance phase (Table 1). During the first 4 months, participants were instructed to wear the pedometer every day, reminded to upload at least weekly, and were provided access to the website. The website has four key components [26,27]: individualized goal setting was based on uploaded step counts, iterative feedback allowed self-monitoring of step counts, motivational content provided a new educational tip every other day and a new motivational message each week, and an online community forum enhanced social support [22-27]. During the 8-month maintenance phase, participants continued to wear the pedometer, upload daily step counts, receive weekly step-count goals and feedback, and had access to the online community forum. They could view the initial 4 months of educational content and motivational messages, but no longer received new content. Topics on the online community forum included walking in a variety of weather/seasons, health topics (weight management, COPD disease management), injury prevention, barriers to walking, and technical issues with the pedometer and website.Table 1Features available to the Taking Healthy Steps and control groups during the first 4 months versus last 8 months of the study.Features0-4 Months5-12 MonthsTaking Healthy StepsControlTaking Healthy StepsControlWear pedometerYesYesYesYesUpload step-count dataAt least weeklyAt least monthlyAt least weeklyAt least monthlyGoal settingYesNoYesNoFeedbackYesNoYesNoNew educational and motivational contentYesNoNoNoOnline community forumYesNoYesNoWait-List Control GroupParticipants randomized to the wait-list control group were instructed to wear the pedometer every day, reminded monthly to log in to the website to upload step-count data, and asked to report all adverse events. Veterans in the wait-list control group received neither instruction to increase PA nor step-count goals. They had access to a webpage that showed only a checklist of surveys completed and a count of what week they were in the study. After 12 months, they were given the option to use the Internet-mediated intervention.Participant Characteristics, Device Adherence, and Website EngagementAt baseline, participants answered questions online that assessed comorbidities, oxygen use, smoking status, and demographics. At study entry, 4 months, and 12 months, dyspnea was assessed using the MMRC scale (range 0-4 with 4 indicating the most severe level of dyspnea) [33]. Events self-reported during the study were defined a priori as COPD-related if persons experienced a combination of symptoms and/or required treatment with antibiotics and/or systemic corticosteroids. The COPD-related events included acute exacerbations or pneumonia, ascertained by self-reported events and/or review of health care utilization (hospitalizations and emergency room visits) and pharmacy data. To assure independence of individual acute exacerbations, participants were considered to have experienced a new acute exacerbation only if it were reported 21 or more days after the previous acute exacerbation [34].We examined device adherence, overall and by group, by calculating the percentage of days (of 366 days) that were wear days with valid step-count data. For the participants who uploaded valid step-count data at 12 months and completed the study, we also examined percentage of days (of 42 days) that were wear days during the last 6 weeks of the study.In the intervention group, we objectively examined website engagement by recording the number of log-ins to the website by month of study and assessing the frequency of use of the online community forum. In addition, at 4 and 12 months, participants in the Taking Healthy Steps group answered a structured survey eliciting feedback about their commitment to their step-count goals and various aspects of engagement with the intervention, including participants’ ease of finding time to log in to the website, knowledge of step-count goals, and use of the different components of the website.Statistical AnalysisProportions, means, and standard deviations described baseline participant characteristics. Two-sample t tests and chi-square tests compared baseline characteristics between groups. The occurrence of COPD-related events (acute exacerbations or pneumonia), hospitalizations, emergency room visits, deaths, and adverse events during the study were each compared between groups using a logistic regression model. For the count of hospitalizations, a zero-inflated Poisson regression model was also used to assess the difference in the rate of hospitalizations between groups. These models adjusted for age, gender, treatment group, and oxygen use.The primary analysis used the intention-to-treat approach, and used a linear mixed-effects model with baseline, 4-month, and 12-month outcome values (eg, SGRQ-TS or daily step count) as dependent variables. No baseline variable was predictive of missingness in models adjusting for stratification variables and treatment group. Thus, the longitudinal data model included participants who had the dependent variable for at least one time point and was expected to give unbiased estimates of the intervention effect assuming missingness at random. The model included participants as random intercepts to adjust for within-participant correlations of repeated measures, fixed predictors of treatment group, 4- and 12-month time indicators, and treatment group by time indicator interactions, MMRC dyspnea score (dichotomized to 0-1 vs 2-4), and urban versus rural residence. We also analyzed the data excluding those who died. The proportion of participants who had at least a 4-unit improvement in SGRQ-TS at 12 months was compared between groups using a chi-square test [31]. For the analysis of mean daily step count by month of study, we used a linear mixed-effect model similar to that for the primary outcome except data were assessed in 30-day increments over the 12-month study period. Predictors were treatment group, month of study as indicator variables (coded as 1-12), group-by-month indicator variables interactions, dichotomized MMRC dyspnea score, and urban versus rural residence.We assessed website engagement in the intervention group by characterizing the number of log-ins to the website using the mean, median, and interquartile range, and assessed trends over months of study using a linear mixed-effects regression analysis with monthly number of log-ins for each participant as the outcome and time (month since randomization) as the predictor. Trends for device adherence over month of study were examined with percent of days with valid step-count data using a linear mixed-effects model and for use of the online community forum using a generalized mixed-effects model with logit link. The effect of time on participant responses to the online survey about goal commitment and intervention engagement at 4 and 12 months was estimated for each response variable using a mixed-effects model with 4- and 12-month survey data as the dependent variable and predictors including 12-month indicator, baseline dichotomized MMRC dyspnea score, and urban versus rural status. All models, including the model for the number of log-ins, were checked for model assumptions using residuals.One participant in the Taking Healthy Steps group was considered an outlier given that his change in SGRQ-TS was 4.0 standard deviations greater than the mean for change in SGRQ-TS and his change in daily step count was 8.1 standard deviations greater than the mean for change in daily step count. The extremely high step counts more likely reflected his occupational PA rather than any effects of our intervention. Our main analyses excluded the outlying individual, but we also repeated primary and secondary outcome analyses with this participant included. All analyses were performed with Stata 14.0 (StataCorp LP, College Station, TX, USA).ResultsParticipant CharacteristicsNo information is available on the persons to whom we mailed recruitment materials but who were not screened because they did not go to our website and did not call us (Figure 1). The top three reasons for ineligibility of 459 participants were not sedentary (n=202), could not walk a block (n=120), or no compatible computer access (n=161), with some participants having more than one reason (Figure 1). In all, 68 persons consented but were not enrolled and randomized, including 19 who failed to submit a medical clearance form and did not upload step-count data, one who failed to submit a medical clearance form, four who failed to upload step-count data, and nine who failed to complete the baseline SGRQ (Figure 1).Participants’ (N=238) characteristics include: mean age 67 (SD 9) years, male (93.7%, 223/238), rural residence (45.4%, 108/238), MMRC dyspnea score ≥2 (30.7%, 73/238), current smokers (24.8%, 59/238), and supplemental oxygen use (23.5%, 56/238) (Table 2). There were no significant differences in baseline characteristics between study groups, including current smoking history. Overall, 87.8% (209/238) of participants completed the 12-month online HRQL assessment, and 74.4% (177/238) uploaded 12-month valid step-count data. In the intervention group, 87.7% (135/154) of participants completed the HRQL assessment and 76.6% (118/154) uploaded valid step-count data, compared to 88% (74/84) and 70% (59/84), respectively, in the control group.Table 2Baseline participant characteristics (N=238).CharacteristicIntervention (n=154)Control (n=84)Total (N=238)Age (years), mean (SD)67 (8.6)66.4 (9.2)66.8 (8.8)Gender (male), n(%)146 (94.8)77 (92)223 (93.7)Residence, n(%)Urban83 (53.9)47 (56)130 (54.6)Rural71 (46.1)37 (44)108 (45.4)Hispanic (n=235), n(%)5 (3.3)1 (1)6 (2.6)Race, n(%)Black7 (4.6)3 (4)10 (4.2)White142 (92.2)79 (94)221 (92.9)Other5 (3.3)2 (2)7 (2.9)Current smoker, n(%)41 (26.6)18 (21)59 (24.8)Oxygen use, n(%)35 (22.7)21 (25)56 (23.5)SGRQ,a mean (SD)Symptoms57.2 (19.1)56 (19.9)56.8 (19.3)Activities62.3 (20.2)64.2 (18)62.9 (19.5)Impact32.2 (16.5)34.1 (17.9)32.9 (17)Total45.6 (15.4)46.8 (15.6)46 (15.4)Baseline daily step count, mean (SD)3488 (2316)3521 (2058)3499 (2224)MMRC dyspnea score,b n (%)0-1108 (70.1)57 (68)165 (69.3)2-446 (29.9)27 (32)73 (30.7)aSGRQ: St. George’s Respiratory Questionnaire. Data for symptoms, activities, and impact were available from 236 participants; total from 233 participants.bMMRC: Modified Medical Research Council.At 12 months, 29 of 238 (12.2%) participants did not have sufficient data to calculate the SGRQ-TS: 19 Taking Healthy Steps participants and 10 controls. There was no significant difference in baseline SGRQ-TS (mean 49.8, SD 16.1 vs mean 45.6, SD 15.3; P=.18) or baseline daily step count (mean 3410, SD 2667 vs mean 3512, SD 2163; P=.82) between those for whom SGRQ-TS could not be calculated (n=29) versus those for whom SGRQ-TS was calculated at 12 months (n=209).The percent of participants with COPD-related events (acute exacerbations or pneumonia) during the study did not differ between groups (control: 18%, 15/84; intervention: 22.7%, 35/154; logistic regression OR 1.4, 95% CI 0.7-2.8; P=.33). No between-group difference was found in the percent of participants with hospitalizations (control: 17%, 14/84; intervention: 23.4%, 36/154; logistic regression OR 1.6, 95% CI 0.8-3.2; P=.19) or emergency room visits (control: 24%, 20/84; intervention: 29.9%, 46/154; logistic regression OR 1.4, 95% CI 0.8-2.6; P=.27) during the 12-month study. For the count of hospitalizations, a zero-inflated Poisson regression model also found no between-group difference. The percent of participants who died during the study did not differ between groups (control: 2%, 2/84; intervention: 3.9%, 6/154; P=.53). Finding no between-group differences in the percentage of participants who were hospitalized or died provided assurance that the censoring of the outcome variables (SGRQ-TS or daily step counts) due to these events was not likely to confound the assessment of the between-group outcome differences. However, we repeated the analyses with deaths excluded as well.Health-Related Quality of LifeThere was no significant between-group difference in the primary outcome of SGRQ-TS (mean 1.1 units, 95% CI –2.2 to 4.5; P=.50) at 12 months (Table 3). The proportion of participants who achieved at least a 4-unit improvement in SGRQ-TS at 12 months was 45.2% (61/135) in the intervention versus 32% (23/71) in the control group (P=.08). There was no significant between-group difference in the SGRQ domain scores of symptoms (mean 0.5 unit, 95% CI –4.2 to 5.2; P=.84), activities (mean 0.04 unit, 95% CI –4.2 to 4.2; P=.99), and impact (mean 2.3 units, 95% CI –1.6 to 6.1; P=.25) at 12 months.Table 3Within-group changes and between-group differences in SGRQ scores and daily step counts at 12 months.Outcome and armNDifference from baseline to 12 months, mean (95% CI)PBetween-group difference, mean (95% CI)PaSGRQTotal1.1 (–2.2, 4.5).50Taking Healthy Steps154–2.5 (–4.5, –0.6).01Control84–1.4 (–4.1, 1.3).31Symptoms0.5 (–4.2, 5.2).84Taking Healthy Steps154–3.2 (–6.0, –0.4).02Control84–2.7 (–6.5, 1.1).16Activities0.04 (–4.2, 4.2).99Taking Healthy Steps154–1.2 (–3.7, 1.3).36Control84–1.1 (–4.5, 2.3).51Impact2.3 (–1.6, 6.1).25Taking Healthy Steps154–3.4 (–5.6, –1.1).004Control84–1.1 (–4.2, 2.0).48Daily step count–108 (–720, 505).73Taking Healthy Steps154270 (–86, 626).14Control84163 (–336, 661).52a Based on linear mixed-effect models, adjusting for group, 4- and 12-month indicators, group×time indicator interactions, baseline MMRC dyspnea score (dichotomized to 0-1 vs 2-4), and urban versus rural status.Intervention participants showed an improvement in SGRQ-TS of a mean 2.5 units (95% CI –4.5 to –0.6) at 12 months, compared to baseline (P=.01) (Table 3). For domain scores in the intervention group, symptoms improved by a mean 3.2 units (95% CI –6.0 to –0.4, P=.02), and impact improved by a mean 3.4 units (95% CI –5.6 to –1.1, P=.004) at 12 months. The control group showed no significant changes in the SGRQ-TS and domain scores at 12 months compared to baseline (Table 3). When the analysis was repeated with the outlying individual included, no substantive difference was seen in results, except improvement in symptoms within the Taking Healthy Steps group was marginally significant (P=.05). When the analysis excluded the eight deaths, results remained nearly identical.Daily Step CountThere was no significant difference between groups with respect to the secondary outcome of daily step count at 12 months (P=.73) (Table 3). There was no significant change in daily step count in the intervention participants (P=.14) or in the control group (P=.52) at 12 months, compared to baseline (Table 3). Examination of daily step count by month of intervention showed that differences in daily step counts in the intervention group compared to controls were maximal and statistically significant at month 4, but approached zero in months 8 to 12 (Figure 2). Between-group P values were <.001 at 4 months, .28 at 8 months, and .82 at 12 months. Within the intervention group, although daily step counts peaked at 2 months and then declined over the course of the study, daily step counts continued to be higher than baseline values in all months of the study (Figure 2). Analysis including the outlying individual showed improvement in daily step counts at 12 months to be significant in the Taking Healthy Steps group (P=.048). Analysis excluding the eight deaths did not change results.Figure 2Mean daily step count and 95% confidence intervals by month of study. Note: the Taking Healthy Steps (THS) curve is shifted to the right of the control curve on the x-axis for ease of visual display. Baseline data are included at month zero.Device Adherence and Website EngagementDevice adherence during the 12-month study period was significantly higher in the intervention group than the control group, with mean 76.7% (SD 29.5) of the 366 days having valid step-count data in the intervention group versus mean 63.7% (SD 32.9) of the 366 days having valid step-count data in the control group (P=.002). For the 177 participants in both groups who uploaded valid step-count data at 12 months and completed the study, mean 83.1% (SD 21.9) of days in the last 6 weeks of the study had valid step-count data. In these last 6 weeks, mean 87.5% (SD 16.5) of days had valid step-count data in the intervention group, which was significantly higher than the mean 74.1% (SD 28.1) of days observed in the control group (P<.001). In the intervention group, device adherence decreased significantly over time (P<.001), with mean 92.1% (95% CI 86.6-97.6) of days having valid step-count data at month 1 versus 70.3% (95% CI 64.9-75.8) of days at month 12 (Figure 3).In the intervention group, mean number of log-ins to the website decreased significantly over the months of study (P<.001; Figure 4). The number of monthly log-ins was mean 6.8 (SD 3.7; median 6, IQR 3) at month 1, which declined to mean 4.2 (SD 3.5; median 4, IQR 3) by month 9 and mean 3.0 (SD 3.0; median 3, IQR 5) by month 12 (Figure 4). In the intervention group, 83.8% (129/154) of the participants used the online community forum at some point during the 12-month study; 66.2% (102/154) of participants directly viewed an online community forum thread or entry, and an additional 17.5% (27/154) of participants posted a new topic or a reply at least once. More than half of the participants responded “definitely true” (22/121, 18.2%) or “mostly true” (45/121, 37.2%) to the statement: “I learned helpful information when I used the online community forum.” There was a significant trend for decreasing use of the online community forum by month of study (P<.001).Responses to questions regarding participant’s goal commitment were not significantly different at 12 months compared to 4 months (Table 4). When asked, “Overall, how motivated are you to walk each day?” with responses from 1=not motivated and 10=extremely motivated, the mean response was 6.8 (SD 2.3) at 4 months compared to mean 6.5 (SD 2.5) at 12 months (P=.06). Responses to questions about engagement with the use of Taking Healthy Steps were not significantly different at 12 months compared to 4 months (Table 4).Table 4Goal commitment and engagement with Taking Healthy Steps intervention.Goal commitment and engagementNa4 months mean (95% CI)12 months mean (95% CI)PbGoal commitmentcIt’s hard to take my step-count goal seriously.1472.1 (1.9-2.2)2.0 (1.9-2.2).69Quite frankly, I don’t care if I reach my step goal or not.1471.7 (1.6-1.8)1.7 (1.6-1.8).46I am strongly committed to pursuing my step-count goal.1463.8 (3.6-4.0)3.7 (3.5-3.9).52It wouldn’t take much to make me abandon my step-count goal.1471.9 (1.7-2.1)2.0 (1.8-2.2).27I think my step-count goal is a good goal to shoot for.1464.0 (3.8-4.2)3.9 (3.8-4.1).77Engagement in Taking Healthy StepsdI would recommend the Taking Healthy Steps walking program to another person with COPD.1461.3 (1.2-1.4)1.2 (1.1-1.3).01It was easy for me to find the time to log in to the website once a week.1461.8 (1.6-2.0)1.8 (1.6-2.0).92I had technical difficulty uploading step-count data from the pedometer to my computer.1464.0 (3.7-4.2)3.9 (3.7-4.1).75I knew what my step goal should be every day.1471.5 (1.4-1.6)1.5 (1.4-1.6).48I was able to comfortably increase my daily step count every week.1472.6 (2.5-2.8)2.8 (2.6-3.0).10I looked at the graphs of the step counts that I walked.1471.6 (1.4-1.7)1.6 (1.4-1.7).76The motivational messages and educational tips were easy to understand.1431.9 (1.8-2.0)1.8 (1.7-1.9).21I learned helpful information when I used the online community forum.1372.5 (2.3-2.7)2.4 (2.3-2.6).52The daily step-count goals were too high for me to walk each day.1473.4 (3.2-3.5)3.4 (3.2-3.5).98a Participants with responses at 4 and/or 12 months were included in the models.b Based on linear mixed-effect models with 4 and 12 months as the dependent variable and predictors of 12-month indicator, intervention group indicator and baseline MMRC dyspnea score (dichotomized to 0-1 vs 2-4) and urban versus rural status.c Response scale 1-5 with 1=strongly disagree, 2=disagree, 3=neither agree nor disagree, 4=agree, 5=strongly agree.d Response scale 1-5 with 1=definitely true, 2=mostly true, 3=not sure, 4=mostly false, 5=definitely false.Figure 3Percentage and 95% confidence intervals of days with valid step-count data in the intervention group by month of study.Figure 4Mean log-ins and 95% confidence intervals in the intervention group by month of study.SafetyAdverse events were categorized as pulmonary, cardiac, musculoskeletal, or other. A significantly greater percent of participants in the intervention group (27.9%, 43/154) had minor musculoskeletal adverse events than in the control group (10%, 8/84; P<.001). There were no differences between groups with respect to pulmonary, cardiac, or other adverse events during the 12 months.DiscussionWe show that our Internet-mediated, pedometer-based walking intervention does not maintain benefits in HRQL and daily step counts at 12 months, despite demonstrated improvements at 4 months [27]. Although we report negative findings for the study overall, lessons learned about device adherence and website engagement are highly informative for guiding the development of future PA interventions that can effectively promote long-term behavior change and sustain PA.Overall, we found that a COPD population found the study feasible and were engaged. The percentage of participants who completed the 12-month study, providing HRQL and step-count data, was high. In addition, our objective results assessing device adherence and showing that 83% of days for participants in both groups within the last 6 weeks of the study had valid step-count data support that people were not lost to the study and then showing up for the last evaluation period. Importantly, persons in the intervention group had significantly higher device adherence compared to the control group for the study overall and at the end of the study. This finding supports that the goal setting, feedback, educational and motivational content, and online community forum provided on the website significantly increased intervention engagement beyond that observed with the use of a pedometer alone.For the first time, we rigorously elicited participant survey responses about goal commitment and intervention engagement, and objectively assessed device adherence and website engagement during the 12-month study. In the intervention group, responses to questions about engagement at 12 months were the same compared to those at 4 months, with participants finding time to log in to the intervention, knowing their step-count goal, and using the graphs, tips and messages, and forums. They also reported that they were as committed to their step-count goal at 12 months as they were at 4 months. Although participants reported the same levels of goal commitment and intervention engagement at the end of the study compared to the beginning of the study, sustained behavior change was not observed because there were significant decreases in number of days with valid step-count data, number of log-ins to the website, and use of the online community forum over time. Although we can only speculate as to cause and effect, the decrease in daily step count (a marker of intervention efficacy and walking behavior change) over time mirrors the declines in device adherence and website engagement over time.The reasons for the observed decline in daily step counts over time require further exploration. Participants may not have continued to wear the pedometer, log in to the website, and walk over the 12 months for a variety of possible reasons that we did not assess, such as waning interest with the intervention, progression of underlying COPD, flare-up of comorbidities, or occurrence of intercurrent life events (eg, spouse illness). The effect of the intervention on daily step counts could potentially have been greater if the control group had not received a pedometer and monthly reminders to upload step counts. We are confident that battery life did not affect the results because we mailed a new battery with replacement instructions to each participant every 4 months. We replaced lost or broken devices reported to us.These results are similar to published data examining maintenance exercise programs after conventional pulmonary rehabilitation [16-21]. Typically, the unstable clinical course of a chronic lung disease such as COPD makes it difficult for patients to resume or maintain an exercise program [20]. Although we observed no difference in the number of COPD-related events, such as acute exacerbations, between groups, the occurrence of acute exacerbations and flare-up of comorbidities over a period of 12 months may have modified the response to Taking Healthy Steps within the intervention group.The failure to obtain long-term benefits with our PA interventions parallels the literature studying other behavior changes, such as smoking cessation [35] and weight loss [36]. Our 8-month maintenance phase retained the key components of goal setting, feedback, and social support. The main feature omitted beginning at month 5 was new educational and motivational content. These findings support that ongoing behavioral modification techniques are critical to sustain PA [37,38]. We speculate that additional intervention components, such as face-to-face contact with peers and/or health care providers, would enhance the social support and motivation needed to sustain PA as a routine behavior. Use of evolving technology, such as wireless transmission and mobile connectivity with cell phones, smartphones/mobile phones, or tablets, could potentially provide anytime/anywhere access to the PA intervention and enhance its long-term efficacy [37,39,40]. Intensive counseling and support at the time of acute exacerbations and flare-up of comorbidities would address medical barriers to PA and motivate patients to continue to walk after an illness. Finally, incorporating the health care provider, health care institutions, communities, and society at large into PA interventions could enhance long-term behavior change and adherence to effectively sustain PA in persons with COPD [41,42].The exact role of digital walking programs in starting and maintaining exercise in persons with COPD remains to be determined. Both acute and chronic models of digital walking programs are potentially useful. Acute intervention models are needed to initiate and promote PA in the vast majority of patients with COPD who cannot access a conventional pulmonary rehabilitation program [43]. In addition, maintenance models are appropriate and much needed because long-term maintenance of behavior change is challenging. In addition, digital walking programs can potentially be useful adjuncts after conventional pulmonary rehabilitation to maintain benefits, which start to wane as early as 3 to 6 months after program completion [20,21]. They can also be an important component of COPD self-management programs [44]. An interesting future question to address is whether restarting our intervention every 4 to 8 months would be an efficacious long-term strategy.The potential full impact of our intervention can only be appreciated by performing a future cost-effectiveness analysis. Results from cross-sectional data from our group and others have shown that every step counts. We have not found a “threshold” or “optimal” daily step count to obtain clinical benefits. The benefits appear to be linear such that those with higher step counts have lower risks for acute exacerbations, hospitalizations, hospital admissions and readmissions, and death compared to those with lower step counts [9-14]. Future work is needed to examine whether PA interventions such as ours can decrease health care resource utilization and result in cost savings to our health care system.Major strengths of our study include the randomized controlled trial design with balanced groups at baseline, objective data on device adherence and website engagement, and the long-term follow-up of 12 months. Our intervention is based on a theoretical model, and informed by previous work eliciting patient feedback to optimize user acceptability and develop the motivational and educational content [25,45]. Our Internet-mediated, pedometer-based intervention focuses specifically on walking, a low-intensity PA that most patients can do. It has already been shown that a greater quantity of low-intensity PA reduces risk of COPD hospitalizations, whereas high-intensity PA does not result in risk reduction [15].Our study has several limitations. We studied primarily white male Veterans limiting the generalizability of our results. Spirometric confirmation of the COPD diagnosis was not made at study entry. However, any potential misclassification of asthma as COPD was most likely balanced between groups and would not bias the primary results. The vast majority of the patients had MMRC <2. It is justified to include patients with MMRC <2 because patients with newly diagnosed COPD have reduced PA even at the earliest stages of the disease [3]. It is important to promote PA even when patients are not significantly symptomatic, as recommended by the GOLD guidelines for COPD [6]. We found no difference in benefit of the PA intervention in those with MMRC <2 versus MMRC ≥2. We acknowledge the final response rate was likely biased toward responders who had a particular interest in this type of intervention, and the results may not be generalizable to a wider COPD population. Finally, seasonal variation can influence our secondary outcome of daily step counts. We minimized the impact of season by having a 12-month intervention and enrolling participants over all four seasons.An Internet-mediated, pedometer-based PA intervention for persons with COPD does not maintain improvements in HRQL or daily step count at 12 months, despite demonstrated improvements at 4 months. In addition, waning engagement with the PA intervention support that future efforts should focus on improving features of PA interventions to enhance long-term behavior change and sustain engagement with PA. These findings need to be considered when designing future Internet-mediated PA interventions.We thank the Veterans for their participation in this research study. The study was funded by Department of Veterans Affairs, Health Services Research and Development Service (Grant IIR 09-366, Richardson); Department of Veterans Affairs, Rehabilitation Research and Development Service (Career Development Award, F6847W, Moy); and NIH National Heart, Lung and Blood Institute (Grant T32 HL007749-20, Martinez). None of the funding bodies had any role in the design, collection, analysis or interpretation of the data, in writing the manuscript, or in the decision to submit the manuscript for publication.Authors' Contributions: MLM, RK, HQN, MDC, DEG, NDG, and CRR were involved in the conception and design of all stages of the study. MLM, CHM, RK, PR, HQN, MDC, and CRR were involved in study data collection. CHM, HMK, RK, PR, RGH, and NDG conducted study analyses. All authors read and approved the final manuscript. CRR, the study PI, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.Conflicts of Interest: None declared. This study was initiated by the investigators, who do not receive any financial support from Omron Healthcare. 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Prev2010301475210.1097/HCR.0b013e3181c9c985200684232006842319BeauchampMKEvansRJanaudis-FerreiraTGoldsteinRSBrooksDSystematic review of supervised exercise programs after pulmonary rehabilitation in individuals with COPDChest20131014441124113310.1378/chest.12-2421234299312342993120RiesALKaplanRMMyersRPrewittLMMaintenance after pulmonary rehabilitation in chronic lung disease: a randomized trialAm J Respir Crit Care Med2003315167688088810.1164/rccm.200204-318OC125058591250585921SpencerLMAlisonJAMcKeoughZJMaintaining benefits following pulmonary rehabilitation: a randomised controlled trialEur Respir J2010335357157710.1183/09031936.00073609196439441964394422RichardsonCRBuisLRJanneyAWGoodrichDESenAHessMLMehariKSFortlageLAResnickPJZikmund-FisherBJStrecherVJPietteJDAn online community improves adherence in an internet-mediated walking program. Part 1: results of a randomized controlled trialJ Med Internet Res2010124e7110.2196/jmir.1338211691602116916023RichardsonCRMehariKSMcIntyreLGJanneyAWFortlageLASenAStrecherVJPietteJDA randomized trial comparing structured and lifestyle goals in an internet-mediated walking program for people with type 2 diabetesInt J Behav Nutr Phys Act200745910.1186/1479-5868-4-59180214111802141124MoyMLJanneyAWNguyenHQMatthessKRCohenMGarshickERichardsonCRUse of pedometer and Internet-mediated walking program in patients with chronic obstructive pulmonary diseaseJ Rehabil Res Dev2010475485496208033922080339225MoyMLWestonNAWilsonEJHessMLRichardsonCRA pilot study of an Internet walking program and pedometer in COPDRespir Med2012910691342135010.1016/j.rmed.2012.06.013227959842279598426MartinezCHMoyMLNguyenHQCohenMKadriRRomanPHollemanRGKimHMGoodrichDEGiardinoNDRichardsonCRTaking Healthy Steps: rationale, design and baseline characteristics of a randomized trial of a pedometer-based Internet-mediated walking program in veterans with chronic obstructive pulmonary diseaseBMC Pulm Med2014141210.1186/1471-2466-14-12244911372449113727MoyMLCollinsRJMartinezCHKadriRRomanPHollemanRGKimHMNguyenHQCohenMDGoodrichDEGiardinoNDRichardsonCRAn Internet-mediated pedometer-based program improves health-related quality-of-life domains and daily step counts in COPD: a randomized controlled trialChest20157148112813710.1378/chest.14-1466258113952581139528WeeksWBKazisLEShenYCongZRenXSMillerDLeeAPerlinJBDifferences in health-related quality of life in rural and urban veteransAm J Public Health200410941017621767154517471545174729JonesPWQuirkFHBaveystockCMLittlejohnsPA self-complete measure of health status for chronic airflow limitation. The St. George's Respiratory QuestionnaireAm Rev Respir Dis1992614561321132710.1164/ajrccm/145.6.13211595997159599730KaplanRMRiesALReillyJMohsenifarZNational Emphysema Treatment Trial Research GroupMeasurement of health-related quality of life in the national emphysema treatment trialChest20049126378178910.1378/chest.126.3.781153647571536475731JonesPWSt. George's Respiratory Questionnaire: MCIDCOPD20053217579171369661713696632MatthewsCEHagströmerMPoberDMBowlesHRBest practices for using physical activity monitors in population-based researchMed Sci Sports Exerc20121441 Suppl 1S68S7610.1249/MSS.0b013e3182399e5b221577772215777733MahlerDAWellsCKEvaluation of clinical methods for rating dyspneaChest198839335805863342669334266934AaronSDFergussonDMarksGBSuissaSVandemheenKLDoucetteSMaltaisFBourbeauJFGoldsteinRSBalterMO'DonnellDFitzgeraldMCanadian Thoracic Society/Canadian Respiratory Clinical Research ConsortiumCounting, analysing and reporting exacerbations of COPD in randomised controlled trialsThorax2008263212212810.1136/thx.2007.082636177027901770279035Jiménez-RuizCAAndreasSLewisKETonnesenPvan SchayckCPHajekPTonstadSDautzenbergBFletcherMMasefieldSPowellPHeringTNardiniSToniaTGratziouCStatement on smoking cessation in COPD and other pulmonary diseases and in smokers with comorbidities who find it difficult to quitEur Respir J20157461617910.1183/09031936.00092614258828052588280536AppelLJClarkJMYehHWangNCoughlinJWDaumitGMillerERDalcinAJeromeGJGellerSNoronhaGPozefskyTCharlestonJReynoldsJBDurkinNRubinRRLouisTABrancatiFLComparative effectiveness of weight-loss interventions in clinical practiceN Engl J Med20111124365211959196810.1056/NEJMoa1108660220853172208531737SallisRFranklinBJoyLRossRSabgirDStoneJStrategies for promoting physical activity in clinical practiceProg Cardiovasc Dis201557437538610.1016/j.pcad.2014.10.003254599752545997538WilsonJJO'NeillBCollinsEGBradleyJInterventions to increase physical activity in patients with COPD: a comprehensive reviewCOPD2015612333234310.3109/15412555.2014.948992252219072522190739VerweyRvan der WeegenSSpreeuwenbergMTangeHvan der WeijdenTde WitteLA pilot study of a tool to stimulate physical activity in patients with COPD or type 2 diabetes in primary careJ Telemed Telecare20141201293410.1177/1357633X13519057244143972441439740TabakMBrusse-KeizerMvan der ValkPHermensHVollenbroek-HuttenMA telehealth program for self-management of COPD exacerbations and promotion of an active lifestyle: a pilot randomized controlled trialInt J Chron Obstruct Pulmon Dis2014993594410.2147/COPD.S60179252467812524678141HeathGWParraDCSarmientoOLAndersenLBOwenNGoenkaSMontesFBrownsonRCLancet Physical Activity Series Working GroupEvidence-based intervention in physical activity: lessons from around the worldLancet2012721380983827228110.1016/S0140-6736(12)60816-2228189392281893942SpruitMAPittaFMcAuleyEZuWallackRLNiciLPulmonary rehabilitation and physical activity in patients with chronic obstructive pulmonary diseaseAm J Respir Crit Care Med20151015192892493310.1164/rccm.201505-0929CI261616762616167643RochesterCLVogiatzisIHollandAELareauSCMarciniukDDPuhanMASpruitMAMasefieldSCasaburiRCliniEMCrouchRGarcia-AymerichJGarveyCGoldsteinRSHillKMorganMNiciLPittaFRiesALSinghSJTroostersTWijkstraPJYawnBPZuWallackRLATS/ERS Task Force on Policy in Pulmonary RehabilitationAn official American Thoracic Society/European Respiratory Society policy statement: enhancing implementation, use, and delivery of pulmonary rehabilitationAm J Respir Crit Care Med2015121192111373138610.1164/rccm.201510-1966ST266236862662368644EffingTWVercoulenJHBourbeauJTrappenburgJLenferinkACafarellaPCoultasDMeekPvan der ValkPBischoff ErikEWBucknallCDewanNAEarlyFFanVFrithPJanssenDJMitchellKMorganMNiciLPatelIWaltersHRiceKLSinghSZuwallackRBenzoRGoldsteinRPartridgeMRvan der PalenJDefinition of a COPD self-management intervention: International Expert Group consensusEur Respir J20167481465410.1183/13993003.00025-2016270765952707659545DanilackVAWestonNARichardsonCRMoriDLMoyMLReasons persons with COPD do not walk and relationship with daily step countCOPD2014611329029910.3109/15412555.2013.8416702415221324152213", 'title': 'Long-Term Effects of an Internet-Mediated Pedometer-Based Walking Program for Chronic Obstructive Pulmonary Disease: Randomized Controlled Trial.', 'date': '2016-08-10'}}
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Family Medicine & Preventive Care
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73
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Is activity level up to 6 months higher, lower, or the same when comparing smart technology for self‐management to face‐to‐face/digital and/or written support for self‐management?
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higher
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low
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no
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['25811395', '27502583']
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{'25811395': {'article_id': '25811395', 'content': "Low levels of physical activity (PA) are associated with poor outcomes in people with COPD. Interventions to increase PA could improve outcomes.\nWe tested the efficacy of a novel Internet-mediated, pedometer-based exercise intervention. Veterans with COPD (N = 239) were randomized in a 2:1 ratio to the (1) intervention group (Omron HJ-720 ITC pedometer and Internet-mediated program) or (2) wait-list control group (pedometer). The primary outcome was health-related quality of life (HRQL), assessed by the St. George's Respiratory Questionnaire (SGRQ), at 4 months. We examined the SGRQ total score (SGRQ-TS) and three domain scores: Symptoms, Activities, and Impact. The secondary outcome was daily step counts. Linear regression models assessed the effect of intervention on outcomes.\nParticipants had a mean age of 67 ± 9 years, and 94% were men. There was no significant between-group difference in mean 4-month SGRQ-TS (2.3 units, P = .14). Nevertheless, a significantly greater proportion of intervention participants than control subjects had at least a 4-unit improvement in SGRQ-TS, the minimum clinically important difference (53% vs 39%, respectively, P = .05). For domain scores, the intervention group had a lower (reflecting better HRQL) mean than the control group by 4.6 units for Symptoms (P = .046) and by 3.3 units for Impact (P = .049). There was no significant difference in Activities score between the two groups. Compared with the control subjects, intervention participants walked 779 more steps per day at 4 months (P = .005).\nAn Internet-mediated, pedometer-based walking program can improve domains of HRQL and daily step counts at 4 months in people with COPD.\nClinical Trials.gov; No.: NCT01102777; URL: www.clinicaltrials.gov.", 'title': 'An Internet-Mediated Pedometer-Based Program Improves Health-Related Quality-of-Life Domains and Daily Step Counts in COPD: A Randomized Controlled Trial.', 'date': '2015-03-27'}, '27502583': {'article_id': '27502583', 'content': "J Med Internet ResJ. Med. Internet ResJMIRJournal of Medical Internet Research1439-44561438-8871JMIR PublicationsToronto, Canada275025834993862v18i8e21510.2196/jmir.5622Original PaperOriginal PaperLong-Term Effects of an Internet-Mediated Pedometer-Based Walking Program for Chronic Obstructive Pulmonary Disease: Randomized Controlled TrialEysenbachGuntherCobbNathanMullerIngridJeromeGeraldRyanDermotGraingerRebeccaPoderThomasMoyMarilyn LMD12http://orcid.org/0000-0002-2471-9218MartinezCarlos HMD3http://orcid.org/0000-0003-2070-4091KadriReemaMLIS45http://orcid.org/0000-0003-0935-3761RomanPiaMA5http://orcid.org/0000-0002-6190-4666HollemanRobert GMPH5http://orcid.org/0000-0003-2300-1842KimHyungjin MyraScD56http://orcid.org/0000-0002-0604-8027NguyenHuong QPhD7http://orcid.org/0000-0002-3650-3705CohenMiriam DMSN8http://orcid.org/0000-0002-8551-0741GoodrichDavid EEdD5http://orcid.org/0000-0003-3232-2189GiardinoNicholas DPhD9http://orcid.org/0000-0002-5026-3859RichardsonCaroline RMD4Department of Family MedicineUniversity of Michigan1018 Fuller St.Ann Arbor, MI, 48104United States1 734 998 7120 ext 3161 734 998 7335caroli@umich.edu5http://orcid.org/0000-0002-1945-60461Pulmonary and Critical Care Medicine SectionVA Boston Healthcare SystemBoston, MAUnited States2Harvard Medical SchoolBoston, MAUnited States3Pulmonary & Critical Care DivisionUniversity of Michigan Health SystemAnn Arbor, MIUnited States4Department of Family MedicineUniversity of MichiganAnn Arbor, MIUnited States5Center for Clinical Management ResearchVA Ann Arbor Healthcare SystemAnn Arbor, MIUnited States6Department of BiostatisticsSchool of Public HealthUniversity of MichiganAnn Arbor, MIUnited States7Department of Research and EvaluationKaiser Permanente Southern CaliforniaPasadena, CAUnited States8Pulmonary Medicine SectionVA New York HarborBrooklyn, NYUnited States9Department of PsychiatryUniversity of MichiganAnn Arbor, MIUnited StatesCorresponding Author: Caroline R Richardson\ncaroli@umich.edu820160882016188e215922016103201621420162452016©Marilyn L Moy, Carlos H Martinez, Reema Kadri, Pia Roman, Robert G Holleman, Hyungjin Myra Kim, Huong Q Nguyen, Miriam D Cohen, David E Goodrich, Nicholas D Giardino, Caroline R Richardson. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 08.08.2016.2016This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in the Journal of Medical Internet Research, is properly cited. The complete bibliographic information, a link to the original publication on http://www.jmir.org/, as well as this copyright and license information must be included.BackgroundRegular physical activity (PA) is recommended for persons with chronic obstructive pulmonary disease (COPD). Interventions that promote PA and sustain long-term adherence to PA are needed.ObjectiveWe examined the effects of an Internet-mediated, pedometer-based walking intervention, called Taking Healthy Steps, at 12 months.MethodsVeterans with COPD (N=239) were randomized in a 2:1 ratio to the intervention or wait-list control. During the first 4 months, participants in the intervention group were instructed to wear the pedometer every day, upload daily step counts at least once a week, and were provided access to a website with four key components: individualized goal setting, iterative feedback, educational and motivational content, and an online community forum. The subsequent 8-month maintenance phase was the same except that participants no longer received new educational content. Participants randomized to the wait-list control group were instructed to wear the pedometer, but they did not receive step-count goals or instructions to increase PA. The primary outcome was health-related quality of life (HRQL) assessed by the St George’s Respiratory Questionnaire Total Score (SGRQ-TS); the secondary outcome was daily step count. Linear mixed-effect models assessed the effect of intervention over time. One participant was excluded from the analysis because he was an outlier. Within the intervention group, we assessed pedometer adherence and website engagement by examining percent of days with valid step-count data, number of log-ins to the website each month, use of the online community forum, and responses to a structured survey.ResultsParticipants were 93.7% male (223/238) with a mean age of 67 (SD 9) years. At 12 months, there were no significant between-group differences in SGRQ-TS or daily step count. Between-group difference in daily step count was maximal and statistically significant at month 4 (P<.001), but approached zero in months 8-12. Within the intervention group, mean 76.7% (SD 29.5) of 366 days had valid step-count data, which decreased over the months of study (P<.001). Mean number of log-ins to the website each month also significantly decreased over the months of study (P<.001). The online community forum was used at least once during the study by 83.8% (129/154) of participants. Responses to questions assessing participants’ goal commitment and intervention engagement were not significantly different at 12 months compared to 4 months.ConclusionsAn Internet-mediated, pedometer-based PA intervention, although efficacious at 4 months, does not maintain improvements in HRQL and daily step counts at 12 months. Waning pedometer adherence and website engagement by the intervention group were observed. Future efforts should focus on improving features of PA interventions to promote long-term behavior change and sustain engagement in PA.ClinicalTrialClinicaltrials.gov NCT01102777; https://clinicaltrials.gov/ct2/show/NCT01102777 (Archived by WebCite at http://www.webcitation.org/6iyNP9KUC)bronchitis, chronicemphysemapulmonary disease, chronic obstructivequality of lifeexercisemotor activityInternetIntroductionPhysical activity (PA) is significantly reduced in persons with chronic obstructive pulmonary disease (COPD), even at the earliest stages of disease [1-3]. Its clinical course is punctuated with acute exacerbations, during and following which persons suffer further reductions in PA [4,5]. As a disease with systemic consequences, COPD increases vulnerability to frailty, immobility, and loss of functional independence. Despite optimal pharmacological therapy, persons with COPD suffer from a downward spiral of breathlessness, deconditioning, and physical inactivity [6]. Comorbidities of cardiovascular disease, diabetes mellitus, and osteoporosis contribute to further reductions in PA [7,8].Physical activity is a modifiable health behavior that affects COPD-specific outcomes [9-14]. It has been shown that a greater quantity of low-intensity PA reduces risk of COPD hospitalizations, whereas high-intensity PA does not result in risk reduction [15]. In a cohort of persons with COPD, those who walk the least have risks that are 2 and 6 times higher for acute exacerbations and COPD-related hospitalizations, respectively, compared to those who walk the most [12]. In addition, persons with COPD with higher PA levels have a significantly lower risk of dying, independent of forced expiratory volume in 1 second (FEV1) [14]. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend regular PA for all persons with stable COPD as part of standard nonpharmacological treatment [6].Despite the evidence and recommendations, effective long-term PA interventions are lacking in the clinical care of patients with COPD. Most studies of long-term exercise interventions have examined methods to maintain exercise in the subset of persons with COPD who have completed a conventional pulmonary rehabilitation program [16-21]. These interventions have combined weekly- or monthly-supervised exercise classes with unsupervised home exercise, support groups, and/or telephone contact with a health care professional, showing mixed results over the long term [16-21]. Strategies that promote behavior change and long-term adherence to effectively sustain PA in all persons with COPD are needed.We developed an automated, Internet-mediated, pedometer-based walking program called Taking Healthy Steps to promote PA in persons with COPD. Taking Healthy Steps combines the Omron HJ-720 ITC pedometer (Omron Healthcare, Inc, Bannockburn, IL, USA) with a disease-specific website accessed via a URL. Taking Healthy Steps provides iterative step-count feedback, individualized step-count goals, education on disease self-management, motivational support, and an online community of social support [22-27]. We studied the efficacy of Taking Healthy Steps in a randomized controlled trial (trial registration: Clinicaltrials.gov NCT01102777) [27]. The conceptual framework, study design, and results at 4 months have been described previously [26,27]. We have shown that Taking Healthy Steps is safe and engaging, and improves health-related quality of life (HRQL) and increases daily step count at 4 months [25-27]. In this study, our primary aim was to assess the long-term efficacy of Taking Healthy Steps on HRQL and daily step counts, a marker for walking behavior change, at 12 months. Our secondary aim was to assess long-term engagement with the PA intervention.MethodsRecruitmentThe study design and methods have been reported previously [26,27]. Participants were enrolled from national patient care databases of US Veterans, between December 2011 and January 2013, who had received any treatment services in the previous year and had a COPD diagnosis. Zip codes were matched with the Rural Urban Commuting Area Codes to determine whether one’s residence was urban or rural [28]. Of the 21 regional Veteran Integrated Service Networks (VISN) across the 50 United States and Puerto Rico, we excluded Veterans from one VISN (VISN-1) where another COPD research study using the Taking Healthy Steps platform was recruiting participants. The coordinating center was located at the Ann Arbor VA Healthcare System, Ann Arbor, MI, USA. Ethical approval for this study was granted by the VA Ann Arbor Healthcare System Human Studies Subcommittee.A random sample of 28,957 Veterans (half rural, half urban) with a COPD diagnosis was sent a recruitment letter. Inclusion criteria included having access to a computer with an Internet connection, a USB port, and Windows XP, Vista, Windows 7, or Windows 8. Our a priori exclusion criteria excluded those who did not upload baseline step-count data or who did not complete the baseline survey to assess HRQL. Per study protocol, participants had to have baseline values for the primary (HRQL) and secondary outcome (daily step count) to be enrolled and randomized. Ultimately, 239 participants were enrolled and randomized in a 2:1 ratio to either Taking Healthy Steps (Internet-mediated, pedometer-based walking program) or wait-list control (pedometer alone), stratified by Modified Medical Research Council (MMRC) dyspnea score and urban versus rural status (Figure 1). All participants were prompted monthly to report new or worsening medical problems; all self-reported adverse events were recorded. There were no face-to-face encounters with staff; all features were automatically delivered via the website.Figure 1CONSORT diagram at 12 months.OutcomesPrimary OutcomeThe St. George’s Respiratory Questionnaire (SGRQ), a disease-specific instrument with 50 items that has been well validated in COPD [29,30] was used to assess HRQL. It has a summary total score (SGRQ-TS) composed of three domain scores: symptoms (frequency and severity), activities (that cause or are limited by breathlessness), and impact (social functioning and psychological disturbances resulting from airways disease). Scores range from 0 to 100 with lower scores indicating better HRQL. A change of four units is the minimum clinically important difference for the SGRQ-TS [31]. Study participants completed the SGRQ online at study entry, 4 months, and 12 months.Secondary OutcomeDaily step count was assessed by the Omron HJ-720 ITC pedometer. Once participants completed the baseline survey, study staff mailed them a pedometer that had an embedded USB port, an upload cable, and detailed written instructions on how to install the Java software and upload pedometer data. For users who did not have Java already installed on their computers, the software installation was a one-time event. Thereafter, participants uploaded step-count data using the cable that connected the pedometer to their home computer. Research staff were available by telephone to assist with software installation and upload of step counts.A wear day with valid step-count data was defined as one having at least 100 steps and 8 hours of step counts recorded [32]. At baseline, participants wore the pedometer covered with a sticker to blind the participant to device feedback. Baseline daily step count was the mean daily step count calculated using at least 5 days of valid data within a period of seven consecutive days. Follow-up daily step counts were calculated within a window of +/-14 days around day 121 for 4-month values, and +/-14 days around day 366 for 12-month values. Follow-up daily step counts were the means of at least 5 days of valid data within a period of seven consecutive days. We also calculated the mean daily step count each month by examining the data in 30-day increments. We used values from the last valid week (at least 5 days of valid data within a period of seven consecutive days) in each of those months.Intervention GroupParticipants randomized to Taking Healthy Steps completed an intensive 4-month intervention period, followed by a distinct 8-month maintenance phase (Table 1). During the first 4 months, participants were instructed to wear the pedometer every day, reminded to upload at least weekly, and were provided access to the website. The website has four key components [26,27]: individualized goal setting was based on uploaded step counts, iterative feedback allowed self-monitoring of step counts, motivational content provided a new educational tip every other day and a new motivational message each week, and an online community forum enhanced social support [22-27]. During the 8-month maintenance phase, participants continued to wear the pedometer, upload daily step counts, receive weekly step-count goals and feedback, and had access to the online community forum. They could view the initial 4 months of educational content and motivational messages, but no longer received new content. Topics on the online community forum included walking in a variety of weather/seasons, health topics (weight management, COPD disease management), injury prevention, barriers to walking, and technical issues with the pedometer and website.Table 1Features available to the Taking Healthy Steps and control groups during the first 4 months versus last 8 months of the study.Features0-4 Months5-12 MonthsTaking Healthy StepsControlTaking Healthy StepsControlWear pedometerYesYesYesYesUpload step-count dataAt least weeklyAt least monthlyAt least weeklyAt least monthlyGoal settingYesNoYesNoFeedbackYesNoYesNoNew educational and motivational contentYesNoNoNoOnline community forumYesNoYesNoWait-List Control GroupParticipants randomized to the wait-list control group were instructed to wear the pedometer every day, reminded monthly to log in to the website to upload step-count data, and asked to report all adverse events. Veterans in the wait-list control group received neither instruction to increase PA nor step-count goals. They had access to a webpage that showed only a checklist of surveys completed and a count of what week they were in the study. After 12 months, they were given the option to use the Internet-mediated intervention.Participant Characteristics, Device Adherence, and Website EngagementAt baseline, participants answered questions online that assessed comorbidities, oxygen use, smoking status, and demographics. At study entry, 4 months, and 12 months, dyspnea was assessed using the MMRC scale (range 0-4 with 4 indicating the most severe level of dyspnea) [33]. Events self-reported during the study were defined a priori as COPD-related if persons experienced a combination of symptoms and/or required treatment with antibiotics and/or systemic corticosteroids. The COPD-related events included acute exacerbations or pneumonia, ascertained by self-reported events and/or review of health care utilization (hospitalizations and emergency room visits) and pharmacy data. To assure independence of individual acute exacerbations, participants were considered to have experienced a new acute exacerbation only if it were reported 21 or more days after the previous acute exacerbation [34].We examined device adherence, overall and by group, by calculating the percentage of days (of 366 days) that were wear days with valid step-count data. For the participants who uploaded valid step-count data at 12 months and completed the study, we also examined percentage of days (of 42 days) that were wear days during the last 6 weeks of the study.In the intervention group, we objectively examined website engagement by recording the number of log-ins to the website by month of study and assessing the frequency of use of the online community forum. In addition, at 4 and 12 months, participants in the Taking Healthy Steps group answered a structured survey eliciting feedback about their commitment to their step-count goals and various aspects of engagement with the intervention, including participants’ ease of finding time to log in to the website, knowledge of step-count goals, and use of the different components of the website.Statistical AnalysisProportions, means, and standard deviations described baseline participant characteristics. Two-sample t tests and chi-square tests compared baseline characteristics between groups. The occurrence of COPD-related events (acute exacerbations or pneumonia), hospitalizations, emergency room visits, deaths, and adverse events during the study were each compared between groups using a logistic regression model. For the count of hospitalizations, a zero-inflated Poisson regression model was also used to assess the difference in the rate of hospitalizations between groups. These models adjusted for age, gender, treatment group, and oxygen use.The primary analysis used the intention-to-treat approach, and used a linear mixed-effects model with baseline, 4-month, and 12-month outcome values (eg, SGRQ-TS or daily step count) as dependent variables. No baseline variable was predictive of missingness in models adjusting for stratification variables and treatment group. Thus, the longitudinal data model included participants who had the dependent variable for at least one time point and was expected to give unbiased estimates of the intervention effect assuming missingness at random. The model included participants as random intercepts to adjust for within-participant correlations of repeated measures, fixed predictors of treatment group, 4- and 12-month time indicators, and treatment group by time indicator interactions, MMRC dyspnea score (dichotomized to 0-1 vs 2-4), and urban versus rural residence. We also analyzed the data excluding those who died. The proportion of participants who had at least a 4-unit improvement in SGRQ-TS at 12 months was compared between groups using a chi-square test [31]. For the analysis of mean daily step count by month of study, we used a linear mixed-effect model similar to that for the primary outcome except data were assessed in 30-day increments over the 12-month study period. Predictors were treatment group, month of study as indicator variables (coded as 1-12), group-by-month indicator variables interactions, dichotomized MMRC dyspnea score, and urban versus rural residence.We assessed website engagement in the intervention group by characterizing the number of log-ins to the website using the mean, median, and interquartile range, and assessed trends over months of study using a linear mixed-effects regression analysis with monthly number of log-ins for each participant as the outcome and time (month since randomization) as the predictor. Trends for device adherence over month of study were examined with percent of days with valid step-count data using a linear mixed-effects model and for use of the online community forum using a generalized mixed-effects model with logit link. The effect of time on participant responses to the online survey about goal commitment and intervention engagement at 4 and 12 months was estimated for each response variable using a mixed-effects model with 4- and 12-month survey data as the dependent variable and predictors including 12-month indicator, baseline dichotomized MMRC dyspnea score, and urban versus rural status. All models, including the model for the number of log-ins, were checked for model assumptions using residuals.One participant in the Taking Healthy Steps group was considered an outlier given that his change in SGRQ-TS was 4.0 standard deviations greater than the mean for change in SGRQ-TS and his change in daily step count was 8.1 standard deviations greater than the mean for change in daily step count. The extremely high step counts more likely reflected his occupational PA rather than any effects of our intervention. Our main analyses excluded the outlying individual, but we also repeated primary and secondary outcome analyses with this participant included. All analyses were performed with Stata 14.0 (StataCorp LP, College Station, TX, USA).ResultsParticipant CharacteristicsNo information is available on the persons to whom we mailed recruitment materials but who were not screened because they did not go to our website and did not call us (Figure 1). The top three reasons for ineligibility of 459 participants were not sedentary (n=202), could not walk a block (n=120), or no compatible computer access (n=161), with some participants having more than one reason (Figure 1). In all, 68 persons consented but were not enrolled and randomized, including 19 who failed to submit a medical clearance form and did not upload step-count data, one who failed to submit a medical clearance form, four who failed to upload step-count data, and nine who failed to complete the baseline SGRQ (Figure 1).Participants’ (N=238) characteristics include: mean age 67 (SD 9) years, male (93.7%, 223/238), rural residence (45.4%, 108/238), MMRC dyspnea score ≥2 (30.7%, 73/238), current smokers (24.8%, 59/238), and supplemental oxygen use (23.5%, 56/238) (Table 2). There were no significant differences in baseline characteristics between study groups, including current smoking history. Overall, 87.8% (209/238) of participants completed the 12-month online HRQL assessment, and 74.4% (177/238) uploaded 12-month valid step-count data. In the intervention group, 87.7% (135/154) of participants completed the HRQL assessment and 76.6% (118/154) uploaded valid step-count data, compared to 88% (74/84) and 70% (59/84), respectively, in the control group.Table 2Baseline participant characteristics (N=238).CharacteristicIntervention (n=154)Control (n=84)Total (N=238)Age (years), mean (SD)67 (8.6)66.4 (9.2)66.8 (8.8)Gender (male), n(%)146 (94.8)77 (92)223 (93.7)Residence, n(%)Urban83 (53.9)47 (56)130 (54.6)Rural71 (46.1)37 (44)108 (45.4)Hispanic (n=235), n(%)5 (3.3)1 (1)6 (2.6)Race, n(%)Black7 (4.6)3 (4)10 (4.2)White142 (92.2)79 (94)221 (92.9)Other5 (3.3)2 (2)7 (2.9)Current smoker, n(%)41 (26.6)18 (21)59 (24.8)Oxygen use, n(%)35 (22.7)21 (25)56 (23.5)SGRQ,a mean (SD)Symptoms57.2 (19.1)56 (19.9)56.8 (19.3)Activities62.3 (20.2)64.2 (18)62.9 (19.5)Impact32.2 (16.5)34.1 (17.9)32.9 (17)Total45.6 (15.4)46.8 (15.6)46 (15.4)Baseline daily step count, mean (SD)3488 (2316)3521 (2058)3499 (2224)MMRC dyspnea score,b n (%)0-1108 (70.1)57 (68)165 (69.3)2-446 (29.9)27 (32)73 (30.7)aSGRQ: St. George’s Respiratory Questionnaire. Data for symptoms, activities, and impact were available from 236 participants; total from 233 participants.bMMRC: Modified Medical Research Council.At 12 months, 29 of 238 (12.2%) participants did not have sufficient data to calculate the SGRQ-TS: 19 Taking Healthy Steps participants and 10 controls. There was no significant difference in baseline SGRQ-TS (mean 49.8, SD 16.1 vs mean 45.6, SD 15.3; P=.18) or baseline daily step count (mean 3410, SD 2667 vs mean 3512, SD 2163; P=.82) between those for whom SGRQ-TS could not be calculated (n=29) versus those for whom SGRQ-TS was calculated at 12 months (n=209).The percent of participants with COPD-related events (acute exacerbations or pneumonia) during the study did not differ between groups (control: 18%, 15/84; intervention: 22.7%, 35/154; logistic regression OR 1.4, 95% CI 0.7-2.8; P=.33). No between-group difference was found in the percent of participants with hospitalizations (control: 17%, 14/84; intervention: 23.4%, 36/154; logistic regression OR 1.6, 95% CI 0.8-3.2; P=.19) or emergency room visits (control: 24%, 20/84; intervention: 29.9%, 46/154; logistic regression OR 1.4, 95% CI 0.8-2.6; P=.27) during the 12-month study. For the count of hospitalizations, a zero-inflated Poisson regression model also found no between-group difference. The percent of participants who died during the study did not differ between groups (control: 2%, 2/84; intervention: 3.9%, 6/154; P=.53). Finding no between-group differences in the percentage of participants who were hospitalized or died provided assurance that the censoring of the outcome variables (SGRQ-TS or daily step counts) due to these events was not likely to confound the assessment of the between-group outcome differences. However, we repeated the analyses with deaths excluded as well.Health-Related Quality of LifeThere was no significant between-group difference in the primary outcome of SGRQ-TS (mean 1.1 units, 95% CI –2.2 to 4.5; P=.50) at 12 months (Table 3). The proportion of participants who achieved at least a 4-unit improvement in SGRQ-TS at 12 months was 45.2% (61/135) in the intervention versus 32% (23/71) in the control group (P=.08). There was no significant between-group difference in the SGRQ domain scores of symptoms (mean 0.5 unit, 95% CI –4.2 to 5.2; P=.84), activities (mean 0.04 unit, 95% CI –4.2 to 4.2; P=.99), and impact (mean 2.3 units, 95% CI –1.6 to 6.1; P=.25) at 12 months.Table 3Within-group changes and between-group differences in SGRQ scores and daily step counts at 12 months.Outcome and armNDifference from baseline to 12 months, mean (95% CI)PBetween-group difference, mean (95% CI)PaSGRQTotal1.1 (–2.2, 4.5).50Taking Healthy Steps154–2.5 (–4.5, –0.6).01Control84–1.4 (–4.1, 1.3).31Symptoms0.5 (–4.2, 5.2).84Taking Healthy Steps154–3.2 (–6.0, –0.4).02Control84–2.7 (–6.5, 1.1).16Activities0.04 (–4.2, 4.2).99Taking Healthy Steps154–1.2 (–3.7, 1.3).36Control84–1.1 (–4.5, 2.3).51Impact2.3 (–1.6, 6.1).25Taking Healthy Steps154–3.4 (–5.6, –1.1).004Control84–1.1 (–4.2, 2.0).48Daily step count–108 (–720, 505).73Taking Healthy Steps154270 (–86, 626).14Control84163 (–336, 661).52a Based on linear mixed-effect models, adjusting for group, 4- and 12-month indicators, group×time indicator interactions, baseline MMRC dyspnea score (dichotomized to 0-1 vs 2-4), and urban versus rural status.Intervention participants showed an improvement in SGRQ-TS of a mean 2.5 units (95% CI –4.5 to –0.6) at 12 months, compared to baseline (P=.01) (Table 3). For domain scores in the intervention group, symptoms improved by a mean 3.2 units (95% CI –6.0 to –0.4, P=.02), and impact improved by a mean 3.4 units (95% CI –5.6 to –1.1, P=.004) at 12 months. The control group showed no significant changes in the SGRQ-TS and domain scores at 12 months compared to baseline (Table 3). When the analysis was repeated with the outlying individual included, no substantive difference was seen in results, except improvement in symptoms within the Taking Healthy Steps group was marginally significant (P=.05). When the analysis excluded the eight deaths, results remained nearly identical.Daily Step CountThere was no significant difference between groups with respect to the secondary outcome of daily step count at 12 months (P=.73) (Table 3). There was no significant change in daily step count in the intervention participants (P=.14) or in the control group (P=.52) at 12 months, compared to baseline (Table 3). Examination of daily step count by month of intervention showed that differences in daily step counts in the intervention group compared to controls were maximal and statistically significant at month 4, but approached zero in months 8 to 12 (Figure 2). Between-group P values were <.001 at 4 months, .28 at 8 months, and .82 at 12 months. Within the intervention group, although daily step counts peaked at 2 months and then declined over the course of the study, daily step counts continued to be higher than baseline values in all months of the study (Figure 2). Analysis including the outlying individual showed improvement in daily step counts at 12 months to be significant in the Taking Healthy Steps group (P=.048). Analysis excluding the eight deaths did not change results.Figure 2Mean daily step count and 95% confidence intervals by month of study. Note: the Taking Healthy Steps (THS) curve is shifted to the right of the control curve on the x-axis for ease of visual display. Baseline data are included at month zero.Device Adherence and Website EngagementDevice adherence during the 12-month study period was significantly higher in the intervention group than the control group, with mean 76.7% (SD 29.5) of the 366 days having valid step-count data in the intervention group versus mean 63.7% (SD 32.9) of the 366 days having valid step-count data in the control group (P=.002). For the 177 participants in both groups who uploaded valid step-count data at 12 months and completed the study, mean 83.1% (SD 21.9) of days in the last 6 weeks of the study had valid step-count data. In these last 6 weeks, mean 87.5% (SD 16.5) of days had valid step-count data in the intervention group, which was significantly higher than the mean 74.1% (SD 28.1) of days observed in the control group (P<.001). In the intervention group, device adherence decreased significantly over time (P<.001), with mean 92.1% (95% CI 86.6-97.6) of days having valid step-count data at month 1 versus 70.3% (95% CI 64.9-75.8) of days at month 12 (Figure 3).In the intervention group, mean number of log-ins to the website decreased significantly over the months of study (P<.001; Figure 4). The number of monthly log-ins was mean 6.8 (SD 3.7; median 6, IQR 3) at month 1, which declined to mean 4.2 (SD 3.5; median 4, IQR 3) by month 9 and mean 3.0 (SD 3.0; median 3, IQR 5) by month 12 (Figure 4). In the intervention group, 83.8% (129/154) of the participants used the online community forum at some point during the 12-month study; 66.2% (102/154) of participants directly viewed an online community forum thread or entry, and an additional 17.5% (27/154) of participants posted a new topic or a reply at least once. More than half of the participants responded “definitely true” (22/121, 18.2%) or “mostly true” (45/121, 37.2%) to the statement: “I learned helpful information when I used the online community forum.” There was a significant trend for decreasing use of the online community forum by month of study (P<.001).Responses to questions regarding participant’s goal commitment were not significantly different at 12 months compared to 4 months (Table 4). When asked, “Overall, how motivated are you to walk each day?” with responses from 1=not motivated and 10=extremely motivated, the mean response was 6.8 (SD 2.3) at 4 months compared to mean 6.5 (SD 2.5) at 12 months (P=.06). Responses to questions about engagement with the use of Taking Healthy Steps were not significantly different at 12 months compared to 4 months (Table 4).Table 4Goal commitment and engagement with Taking Healthy Steps intervention.Goal commitment and engagementNa4 months mean (95% CI)12 months mean (95% CI)PbGoal commitmentcIt’s hard to take my step-count goal seriously.1472.1 (1.9-2.2)2.0 (1.9-2.2).69Quite frankly, I don’t care if I reach my step goal or not.1471.7 (1.6-1.8)1.7 (1.6-1.8).46I am strongly committed to pursuing my step-count goal.1463.8 (3.6-4.0)3.7 (3.5-3.9).52It wouldn’t take much to make me abandon my step-count goal.1471.9 (1.7-2.1)2.0 (1.8-2.2).27I think my step-count goal is a good goal to shoot for.1464.0 (3.8-4.2)3.9 (3.8-4.1).77Engagement in Taking Healthy StepsdI would recommend the Taking Healthy Steps walking program to another person with COPD.1461.3 (1.2-1.4)1.2 (1.1-1.3).01It was easy for me to find the time to log in to the website once a week.1461.8 (1.6-2.0)1.8 (1.6-2.0).92I had technical difficulty uploading step-count data from the pedometer to my computer.1464.0 (3.7-4.2)3.9 (3.7-4.1).75I knew what my step goal should be every day.1471.5 (1.4-1.6)1.5 (1.4-1.6).48I was able to comfortably increase my daily step count every week.1472.6 (2.5-2.8)2.8 (2.6-3.0).10I looked at the graphs of the step counts that I walked.1471.6 (1.4-1.7)1.6 (1.4-1.7).76The motivational messages and educational tips were easy to understand.1431.9 (1.8-2.0)1.8 (1.7-1.9).21I learned helpful information when I used the online community forum.1372.5 (2.3-2.7)2.4 (2.3-2.6).52The daily step-count goals were too high for me to walk each day.1473.4 (3.2-3.5)3.4 (3.2-3.5).98a Participants with responses at 4 and/or 12 months were included in the models.b Based on linear mixed-effect models with 4 and 12 months as the dependent variable and predictors of 12-month indicator, intervention group indicator and baseline MMRC dyspnea score (dichotomized to 0-1 vs 2-4) and urban versus rural status.c Response scale 1-5 with 1=strongly disagree, 2=disagree, 3=neither agree nor disagree, 4=agree, 5=strongly agree.d Response scale 1-5 with 1=definitely true, 2=mostly true, 3=not sure, 4=mostly false, 5=definitely false.Figure 3Percentage and 95% confidence intervals of days with valid step-count data in the intervention group by month of study.Figure 4Mean log-ins and 95% confidence intervals in the intervention group by month of study.SafetyAdverse events were categorized as pulmonary, cardiac, musculoskeletal, or other. A significantly greater percent of participants in the intervention group (27.9%, 43/154) had minor musculoskeletal adverse events than in the control group (10%, 8/84; P<.001). There were no differences between groups with respect to pulmonary, cardiac, or other adverse events during the 12 months.DiscussionWe show that our Internet-mediated, pedometer-based walking intervention does not maintain benefits in HRQL and daily step counts at 12 months, despite demonstrated improvements at 4 months [27]. Although we report negative findings for the study overall, lessons learned about device adherence and website engagement are highly informative for guiding the development of future PA interventions that can effectively promote long-term behavior change and sustain PA.Overall, we found that a COPD population found the study feasible and were engaged. The percentage of participants who completed the 12-month study, providing HRQL and step-count data, was high. In addition, our objective results assessing device adherence and showing that 83% of days for participants in both groups within the last 6 weeks of the study had valid step-count data support that people were not lost to the study and then showing up for the last evaluation period. Importantly, persons in the intervention group had significantly higher device adherence compared to the control group for the study overall and at the end of the study. This finding supports that the goal setting, feedback, educational and motivational content, and online community forum provided on the website significantly increased intervention engagement beyond that observed with the use of a pedometer alone.For the first time, we rigorously elicited participant survey responses about goal commitment and intervention engagement, and objectively assessed device adherence and website engagement during the 12-month study. In the intervention group, responses to questions about engagement at 12 months were the same compared to those at 4 months, with participants finding time to log in to the intervention, knowing their step-count goal, and using the graphs, tips and messages, and forums. They also reported that they were as committed to their step-count goal at 12 months as they were at 4 months. Although participants reported the same levels of goal commitment and intervention engagement at the end of the study compared to the beginning of the study, sustained behavior change was not observed because there were significant decreases in number of days with valid step-count data, number of log-ins to the website, and use of the online community forum over time. Although we can only speculate as to cause and effect, the decrease in daily step count (a marker of intervention efficacy and walking behavior change) over time mirrors the declines in device adherence and website engagement over time.The reasons for the observed decline in daily step counts over time require further exploration. Participants may not have continued to wear the pedometer, log in to the website, and walk over the 12 months for a variety of possible reasons that we did not assess, such as waning interest with the intervention, progression of underlying COPD, flare-up of comorbidities, or occurrence of intercurrent life events (eg, spouse illness). The effect of the intervention on daily step counts could potentially have been greater if the control group had not received a pedometer and monthly reminders to upload step counts. We are confident that battery life did not affect the results because we mailed a new battery with replacement instructions to each participant every 4 months. We replaced lost or broken devices reported to us.These results are similar to published data examining maintenance exercise programs after conventional pulmonary rehabilitation [16-21]. Typically, the unstable clinical course of a chronic lung disease such as COPD makes it difficult for patients to resume or maintain an exercise program [20]. Although we observed no difference in the number of COPD-related events, such as acute exacerbations, between groups, the occurrence of acute exacerbations and flare-up of comorbidities over a period of 12 months may have modified the response to Taking Healthy Steps within the intervention group.The failure to obtain long-term benefits with our PA interventions parallels the literature studying other behavior changes, such as smoking cessation [35] and weight loss [36]. Our 8-month maintenance phase retained the key components of goal setting, feedback, and social support. The main feature omitted beginning at month 5 was new educational and motivational content. These findings support that ongoing behavioral modification techniques are critical to sustain PA [37,38]. We speculate that additional intervention components, such as face-to-face contact with peers and/or health care providers, would enhance the social support and motivation needed to sustain PA as a routine behavior. Use of evolving technology, such as wireless transmission and mobile connectivity with cell phones, smartphones/mobile phones, or tablets, could potentially provide anytime/anywhere access to the PA intervention and enhance its long-term efficacy [37,39,40]. Intensive counseling and support at the time of acute exacerbations and flare-up of comorbidities would address medical barriers to PA and motivate patients to continue to walk after an illness. Finally, incorporating the health care provider, health care institutions, communities, and society at large into PA interventions could enhance long-term behavior change and adherence to effectively sustain PA in persons with COPD [41,42].The exact role of digital walking programs in starting and maintaining exercise in persons with COPD remains to be determined. Both acute and chronic models of digital walking programs are potentially useful. Acute intervention models are needed to initiate and promote PA in the vast majority of patients with COPD who cannot access a conventional pulmonary rehabilitation program [43]. In addition, maintenance models are appropriate and much needed because long-term maintenance of behavior change is challenging. In addition, digital walking programs can potentially be useful adjuncts after conventional pulmonary rehabilitation to maintain benefits, which start to wane as early as 3 to 6 months after program completion [20,21]. They can also be an important component of COPD self-management programs [44]. An interesting future question to address is whether restarting our intervention every 4 to 8 months would be an efficacious long-term strategy.The potential full impact of our intervention can only be appreciated by performing a future cost-effectiveness analysis. Results from cross-sectional data from our group and others have shown that every step counts. We have not found a “threshold” or “optimal” daily step count to obtain clinical benefits. The benefits appear to be linear such that those with higher step counts have lower risks for acute exacerbations, hospitalizations, hospital admissions and readmissions, and death compared to those with lower step counts [9-14]. Future work is needed to examine whether PA interventions such as ours can decrease health care resource utilization and result in cost savings to our health care system.Major strengths of our study include the randomized controlled trial design with balanced groups at baseline, objective data on device adherence and website engagement, and the long-term follow-up of 12 months. Our intervention is based on a theoretical model, and informed by previous work eliciting patient feedback to optimize user acceptability and develop the motivational and educational content [25,45]. Our Internet-mediated, pedometer-based intervention focuses specifically on walking, a low-intensity PA that most patients can do. It has already been shown that a greater quantity of low-intensity PA reduces risk of COPD hospitalizations, whereas high-intensity PA does not result in risk reduction [15].Our study has several limitations. We studied primarily white male Veterans limiting the generalizability of our results. Spirometric confirmation of the COPD diagnosis was not made at study entry. However, any potential misclassification of asthma as COPD was most likely balanced between groups and would not bias the primary results. The vast majority of the patients had MMRC <2. It is justified to include patients with MMRC <2 because patients with newly diagnosed COPD have reduced PA even at the earliest stages of the disease [3]. It is important to promote PA even when patients are not significantly symptomatic, as recommended by the GOLD guidelines for COPD [6]. We found no difference in benefit of the PA intervention in those with MMRC <2 versus MMRC ≥2. We acknowledge the final response rate was likely biased toward responders who had a particular interest in this type of intervention, and the results may not be generalizable to a wider COPD population. Finally, seasonal variation can influence our secondary outcome of daily step counts. We minimized the impact of season by having a 12-month intervention and enrolling participants over all four seasons.An Internet-mediated, pedometer-based PA intervention for persons with COPD does not maintain improvements in HRQL or daily step count at 12 months, despite demonstrated improvements at 4 months. In addition, waning engagement with the PA intervention support that future efforts should focus on improving features of PA interventions to enhance long-term behavior change and sustain engagement with PA. These findings need to be considered when designing future Internet-mediated PA interventions.We thank the Veterans for their participation in this research study. The study was funded by Department of Veterans Affairs, Health Services Research and Development Service (Grant IIR 09-366, Richardson); Department of Veterans Affairs, Rehabilitation Research and Development Service (Career Development Award, F6847W, Moy); and NIH National Heart, Lung and Blood Institute (Grant T32 HL007749-20, Martinez). None of the funding bodies had any role in the design, collection, analysis or interpretation of the data, in writing the manuscript, or in the decision to submit the manuscript for publication.Authors' Contributions: MLM, RK, HQN, MDC, DEG, NDG, and CRR were involved in the conception and design of all stages of the study. MLM, CHM, RK, PR, HQN, MDC, and CRR were involved in study data collection. CHM, HMK, RK, PR, RGH, and NDG conducted study analyses. All authors read and approved the final manuscript. CRR, the study PI, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.Conflicts of Interest: None declared. This study was initiated by the investigators, who do not receive any financial support from Omron Healthcare. 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Prev2010301475210.1097/HCR.0b013e3181c9c985200684232006842319BeauchampMKEvansRJanaudis-FerreiraTGoldsteinRSBrooksDSystematic review of supervised exercise programs after pulmonary rehabilitation in individuals with COPDChest20131014441124113310.1378/chest.12-2421234299312342993120RiesALKaplanRMMyersRPrewittLMMaintenance after pulmonary rehabilitation in chronic lung disease: a randomized trialAm J Respir Crit Care Med2003315167688088810.1164/rccm.200204-318OC125058591250585921SpencerLMAlisonJAMcKeoughZJMaintaining benefits following pulmonary rehabilitation: a randomised controlled trialEur Respir J2010335357157710.1183/09031936.00073609196439441964394422RichardsonCRBuisLRJanneyAWGoodrichDESenAHessMLMehariKSFortlageLAResnickPJZikmund-FisherBJStrecherVJPietteJDAn online community improves adherence in an internet-mediated walking program. Part 1: results of a randomized controlled trialJ Med Internet Res2010124e7110.2196/jmir.1338211691602116916023RichardsonCRMehariKSMcIntyreLGJanneyAWFortlageLASenAStrecherVJPietteJDA randomized trial comparing structured and lifestyle goals in an internet-mediated walking program for people with type 2 diabetesInt J Behav Nutr Phys Act200745910.1186/1479-5868-4-59180214111802141124MoyMLJanneyAWNguyenHQMatthessKRCohenMGarshickERichardsonCRUse of pedometer and Internet-mediated walking program in patients with chronic obstructive pulmonary diseaseJ Rehabil Res Dev2010475485496208033922080339225MoyMLWestonNAWilsonEJHessMLRichardsonCRA pilot study of an Internet walking program and pedometer in COPDRespir Med2012910691342135010.1016/j.rmed.2012.06.013227959842279598426MartinezCHMoyMLNguyenHQCohenMKadriRRomanPHollemanRGKimHMGoodrichDEGiardinoNDRichardsonCRTaking Healthy Steps: rationale, design and baseline characteristics of a randomized trial of a pedometer-based Internet-mediated walking program in veterans with chronic obstructive pulmonary diseaseBMC Pulm Med2014141210.1186/1471-2466-14-12244911372449113727MoyMLCollinsRJMartinezCHKadriRRomanPHollemanRGKimHMNguyenHQCohenMDGoodrichDEGiardinoNDRichardsonCRAn Internet-mediated pedometer-based program improves health-related quality-of-life domains and daily step counts in COPD: a randomized controlled trialChest20157148112813710.1378/chest.14-1466258113952581139528WeeksWBKazisLEShenYCongZRenXSMillerDLeeAPerlinJBDifferences in health-related quality of life in rural and urban veteransAm J Public Health200410941017621767154517471545174729JonesPWQuirkFHBaveystockCMLittlejohnsPA self-complete measure of health status for chronic airflow limitation. The St. George's Respiratory QuestionnaireAm Rev Respir Dis1992614561321132710.1164/ajrccm/145.6.13211595997159599730KaplanRMRiesALReillyJMohsenifarZNational Emphysema Treatment Trial Research GroupMeasurement of health-related quality of life in the national emphysema treatment trialChest20049126378178910.1378/chest.126.3.781153647571536475731JonesPWSt. George's Respiratory Questionnaire: MCIDCOPD20053217579171369661713696632MatthewsCEHagströmerMPoberDMBowlesHRBest practices for using physical activity monitors in population-based researchMed Sci Sports Exerc20121441 Suppl 1S68S7610.1249/MSS.0b013e3182399e5b221577772215777733MahlerDAWellsCKEvaluation of clinical methods for rating dyspneaChest198839335805863342669334266934AaronSDFergussonDMarksGBSuissaSVandemheenKLDoucetteSMaltaisFBourbeauJFGoldsteinRSBalterMO'DonnellDFitzgeraldMCanadian Thoracic Society/Canadian Respiratory Clinical Research ConsortiumCounting, analysing and reporting exacerbations of COPD in randomised controlled trialsThorax2008263212212810.1136/thx.2007.082636177027901770279035Jiménez-RuizCAAndreasSLewisKETonnesenPvan SchayckCPHajekPTonstadSDautzenbergBFletcherMMasefieldSPowellPHeringTNardiniSToniaTGratziouCStatement on smoking cessation in COPD and other pulmonary diseases and in smokers with comorbidities who find it difficult to quitEur Respir J20157461617910.1183/09031936.00092614258828052588280536AppelLJClarkJMYehHWangNCoughlinJWDaumitGMillerERDalcinAJeromeGJGellerSNoronhaGPozefskyTCharlestonJReynoldsJBDurkinNRubinRRLouisTABrancatiFLComparative effectiveness of weight-loss interventions in clinical practiceN Engl J Med20111124365211959196810.1056/NEJMoa1108660220853172208531737SallisRFranklinBJoyLRossRSabgirDStoneJStrategies for promoting physical activity in clinical practiceProg Cardiovasc Dis201557437538610.1016/j.pcad.2014.10.003254599752545997538WilsonJJO'NeillBCollinsEGBradleyJInterventions to increase physical activity in patients with COPD: a comprehensive reviewCOPD2015612333234310.3109/15412555.2014.948992252219072522190739VerweyRvan der WeegenSSpreeuwenbergMTangeHvan der WeijdenTde WitteLA pilot study of a tool to stimulate physical activity in patients with COPD or type 2 diabetes in primary careJ Telemed Telecare20141201293410.1177/1357633X13519057244143972441439740TabakMBrusse-KeizerMvan der ValkPHermensHVollenbroek-HuttenMA telehealth program for self-management of COPD exacerbations and promotion of an active lifestyle: a pilot randomized controlled trialInt J Chron Obstruct Pulmon Dis2014993594410.2147/COPD.S60179252467812524678141HeathGWParraDCSarmientoOLAndersenLBOwenNGoenkaSMontesFBrownsonRCLancet Physical Activity Series Working GroupEvidence-based intervention in physical activity: lessons from around the worldLancet2012721380983827228110.1016/S0140-6736(12)60816-2228189392281893942SpruitMAPittaFMcAuleyEZuWallackRLNiciLPulmonary rehabilitation and physical activity in patients with chronic obstructive pulmonary diseaseAm J Respir Crit Care Med20151015192892493310.1164/rccm.201505-0929CI261616762616167643RochesterCLVogiatzisIHollandAELareauSCMarciniukDDPuhanMASpruitMAMasefieldSCasaburiRCliniEMCrouchRGarcia-AymerichJGarveyCGoldsteinRSHillKMorganMNiciLPittaFRiesALSinghSJTroostersTWijkstraPJYawnBPZuWallackRLATS/ERS Task Force on Policy in Pulmonary RehabilitationAn official American Thoracic Society/European Respiratory Society policy statement: enhancing implementation, use, and delivery of pulmonary rehabilitationAm J Respir Crit Care Med2015121192111373138610.1164/rccm.201510-1966ST266236862662368644EffingTWVercoulenJHBourbeauJTrappenburgJLenferinkACafarellaPCoultasDMeekPvan der ValkPBischoff ErikEWBucknallCDewanNAEarlyFFanVFrithPJanssenDJMitchellKMorganMNiciLPatelIWaltersHRiceKLSinghSZuwallackRBenzoRGoldsteinRPartridgeMRvan der PalenJDefinition of a COPD self-management intervention: International Expert Group consensusEur Respir J20167481465410.1183/13993003.00025-2016270765952707659545DanilackVAWestonNARichardsonCRMoriDLMoyMLReasons persons with COPD do not walk and relationship with daily step countCOPD2014611329029910.3109/15412555.2013.8416702415221324152213", 'title': 'Long-Term Effects of an Internet-Mediated Pedometer-Based Walking Program for Chronic Obstructive Pulmonary Disease: Randomized Controlled Trial.', 'date': '2016-08-10'}}
| 0
|
Family Medicine & Preventive Care
|
74
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Is activity level at 12 months higher, lower, or the same when comparing smart technology for self‐management to face‐to‐face/digital and/or written support for self‐management?
|
no difference
| null |
no
|
['25811395']
| 28,535,331
| 2,017
|
{'25811395': {'article_id': '25811395', 'content': "Low levels of physical activity (PA) are associated with poor outcomes in people with COPD. Interventions to increase PA could improve outcomes.\nWe tested the efficacy of a novel Internet-mediated, pedometer-based exercise intervention. Veterans with COPD (N = 239) were randomized in a 2:1 ratio to the (1) intervention group (Omron HJ-720 ITC pedometer and Internet-mediated program) or (2) wait-list control group (pedometer). The primary outcome was health-related quality of life (HRQL), assessed by the St. George's Respiratory Questionnaire (SGRQ), at 4 months. We examined the SGRQ total score (SGRQ-TS) and three domain scores: Symptoms, Activities, and Impact. The secondary outcome was daily step counts. Linear regression models assessed the effect of intervention on outcomes.\nParticipants had a mean age of 67 ± 9 years, and 94% were men. There was no significant between-group difference in mean 4-month SGRQ-TS (2.3 units, P = .14). Nevertheless, a significantly greater proportion of intervention participants than control subjects had at least a 4-unit improvement in SGRQ-TS, the minimum clinically important difference (53% vs 39%, respectively, P = .05). For domain scores, the intervention group had a lower (reflecting better HRQL) mean than the control group by 4.6 units for Symptoms (P = .046) and by 3.3 units for Impact (P = .049). There was no significant difference in Activities score between the two groups. Compared with the control subjects, intervention participants walked 779 more steps per day at 4 months (P = .005).\nAn Internet-mediated, pedometer-based walking program can improve domains of HRQL and daily step counts at 4 months in people with COPD.\nClinical Trials.gov; No.: NCT01102777; URL: www.clinicaltrials.gov.", 'title': 'An Internet-Mediated Pedometer-Based Program Improves Health-Related Quality-of-Life Domains and Daily Step Counts in COPD: A Randomized Controlled Trial.', 'date': '2015-03-27'}}
| 0
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Public Health, Epidemiology & Health Systems
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75
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Is the risk of hospital admission by 12 months higher, lower, or the same when comparing smart technology for self‐management to face‐to‐face/digital and/or written support for self‐management?
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no difference
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low
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yes
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['27502583']
| 28,535,331
| 2,017
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{'27502583': {'article_id': '27502583', 'content': "J Med Internet ResJ. Med. Internet ResJMIRJournal of Medical Internet Research1439-44561438-8871JMIR PublicationsToronto, Canada275025834993862v18i8e21510.2196/jmir.5622Original PaperOriginal PaperLong-Term Effects of an Internet-Mediated Pedometer-Based Walking Program for Chronic Obstructive Pulmonary Disease: Randomized Controlled TrialEysenbachGuntherCobbNathanMullerIngridJeromeGeraldRyanDermotGraingerRebeccaPoderThomasMoyMarilyn LMD12http://orcid.org/0000-0002-2471-9218MartinezCarlos HMD3http://orcid.org/0000-0003-2070-4091KadriReemaMLIS45http://orcid.org/0000-0003-0935-3761RomanPiaMA5http://orcid.org/0000-0002-6190-4666HollemanRobert GMPH5http://orcid.org/0000-0003-2300-1842KimHyungjin MyraScD56http://orcid.org/0000-0002-0604-8027NguyenHuong QPhD7http://orcid.org/0000-0002-3650-3705CohenMiriam DMSN8http://orcid.org/0000-0002-8551-0741GoodrichDavid EEdD5http://orcid.org/0000-0003-3232-2189GiardinoNicholas DPhD9http://orcid.org/0000-0002-5026-3859RichardsonCaroline RMD4Department of Family MedicineUniversity of Michigan1018 Fuller St.Ann Arbor, MI, 48104United States1 734 998 7120 ext 3161 734 998 7335caroli@umich.edu5http://orcid.org/0000-0002-1945-60461Pulmonary and Critical Care Medicine SectionVA Boston Healthcare SystemBoston, MAUnited States2Harvard Medical SchoolBoston, MAUnited States3Pulmonary & Critical Care DivisionUniversity of Michigan Health SystemAnn Arbor, MIUnited States4Department of Family MedicineUniversity of MichiganAnn Arbor, MIUnited States5Center for Clinical Management ResearchVA Ann Arbor Healthcare SystemAnn Arbor, MIUnited States6Department of BiostatisticsSchool of Public HealthUniversity of MichiganAnn Arbor, MIUnited States7Department of Research and EvaluationKaiser Permanente Southern CaliforniaPasadena, CAUnited States8Pulmonary Medicine SectionVA New York HarborBrooklyn, NYUnited States9Department of PsychiatryUniversity of MichiganAnn Arbor, MIUnited StatesCorresponding Author: Caroline R Richardson\ncaroli@umich.edu820160882016188e215922016103201621420162452016©Marilyn L Moy, Carlos H Martinez, Reema Kadri, Pia Roman, Robert G Holleman, Hyungjin Myra Kim, Huong Q Nguyen, Miriam D Cohen, David E Goodrich, Nicholas D Giardino, Caroline R Richardson. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 08.08.2016.2016This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in the Journal of Medical Internet Research, is properly cited. The complete bibliographic information, a link to the original publication on http://www.jmir.org/, as well as this copyright and license information must be included.BackgroundRegular physical activity (PA) is recommended for persons with chronic obstructive pulmonary disease (COPD). Interventions that promote PA and sustain long-term adherence to PA are needed.ObjectiveWe examined the effects of an Internet-mediated, pedometer-based walking intervention, called Taking Healthy Steps, at 12 months.MethodsVeterans with COPD (N=239) were randomized in a 2:1 ratio to the intervention or wait-list control. During the first 4 months, participants in the intervention group were instructed to wear the pedometer every day, upload daily step counts at least once a week, and were provided access to a website with four key components: individualized goal setting, iterative feedback, educational and motivational content, and an online community forum. The subsequent 8-month maintenance phase was the same except that participants no longer received new educational content. Participants randomized to the wait-list control group were instructed to wear the pedometer, but they did not receive step-count goals or instructions to increase PA. The primary outcome was health-related quality of life (HRQL) assessed by the St George’s Respiratory Questionnaire Total Score (SGRQ-TS); the secondary outcome was daily step count. Linear mixed-effect models assessed the effect of intervention over time. One participant was excluded from the analysis because he was an outlier. Within the intervention group, we assessed pedometer adherence and website engagement by examining percent of days with valid step-count data, number of log-ins to the website each month, use of the online community forum, and responses to a structured survey.ResultsParticipants were 93.7% male (223/238) with a mean age of 67 (SD 9) years. At 12 months, there were no significant between-group differences in SGRQ-TS or daily step count. Between-group difference in daily step count was maximal and statistically significant at month 4 (P<.001), but approached zero in months 8-12. Within the intervention group, mean 76.7% (SD 29.5) of 366 days had valid step-count data, which decreased over the months of study (P<.001). Mean number of log-ins to the website each month also significantly decreased over the months of study (P<.001). The online community forum was used at least once during the study by 83.8% (129/154) of participants. Responses to questions assessing participants’ goal commitment and intervention engagement were not significantly different at 12 months compared to 4 months.ConclusionsAn Internet-mediated, pedometer-based PA intervention, although efficacious at 4 months, does not maintain improvements in HRQL and daily step counts at 12 months. Waning pedometer adherence and website engagement by the intervention group were observed. Future efforts should focus on improving features of PA interventions to promote long-term behavior change and sustain engagement in PA.ClinicalTrialClinicaltrials.gov NCT01102777; https://clinicaltrials.gov/ct2/show/NCT01102777 (Archived by WebCite at http://www.webcitation.org/6iyNP9KUC)bronchitis, chronicemphysemapulmonary disease, chronic obstructivequality of lifeexercisemotor activityInternetIntroductionPhysical activity (PA) is significantly reduced in persons with chronic obstructive pulmonary disease (COPD), even at the earliest stages of disease [1-3]. Its clinical course is punctuated with acute exacerbations, during and following which persons suffer further reductions in PA [4,5]. As a disease with systemic consequences, COPD increases vulnerability to frailty, immobility, and loss of functional independence. Despite optimal pharmacological therapy, persons with COPD suffer from a downward spiral of breathlessness, deconditioning, and physical inactivity [6]. Comorbidities of cardiovascular disease, diabetes mellitus, and osteoporosis contribute to further reductions in PA [7,8].Physical activity is a modifiable health behavior that affects COPD-specific outcomes [9-14]. It has been shown that a greater quantity of low-intensity PA reduces risk of COPD hospitalizations, whereas high-intensity PA does not result in risk reduction [15]. In a cohort of persons with COPD, those who walk the least have risks that are 2 and 6 times higher for acute exacerbations and COPD-related hospitalizations, respectively, compared to those who walk the most [12]. In addition, persons with COPD with higher PA levels have a significantly lower risk of dying, independent of forced expiratory volume in 1 second (FEV1) [14]. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend regular PA for all persons with stable COPD as part of standard nonpharmacological treatment [6].Despite the evidence and recommendations, effective long-term PA interventions are lacking in the clinical care of patients with COPD. Most studies of long-term exercise interventions have examined methods to maintain exercise in the subset of persons with COPD who have completed a conventional pulmonary rehabilitation program [16-21]. These interventions have combined weekly- or monthly-supervised exercise classes with unsupervised home exercise, support groups, and/or telephone contact with a health care professional, showing mixed results over the long term [16-21]. Strategies that promote behavior change and long-term adherence to effectively sustain PA in all persons with COPD are needed.We developed an automated, Internet-mediated, pedometer-based walking program called Taking Healthy Steps to promote PA in persons with COPD. Taking Healthy Steps combines the Omron HJ-720 ITC pedometer (Omron Healthcare, Inc, Bannockburn, IL, USA) with a disease-specific website accessed via a URL. Taking Healthy Steps provides iterative step-count feedback, individualized step-count goals, education on disease self-management, motivational support, and an online community of social support [22-27]. We studied the efficacy of Taking Healthy Steps in a randomized controlled trial (trial registration: Clinicaltrials.gov NCT01102777) [27]. The conceptual framework, study design, and results at 4 months have been described previously [26,27]. We have shown that Taking Healthy Steps is safe and engaging, and improves health-related quality of life (HRQL) and increases daily step count at 4 months [25-27]. In this study, our primary aim was to assess the long-term efficacy of Taking Healthy Steps on HRQL and daily step counts, a marker for walking behavior change, at 12 months. Our secondary aim was to assess long-term engagement with the PA intervention.MethodsRecruitmentThe study design and methods have been reported previously [26,27]. Participants were enrolled from national patient care databases of US Veterans, between December 2011 and January 2013, who had received any treatment services in the previous year and had a COPD diagnosis. Zip codes were matched with the Rural Urban Commuting Area Codes to determine whether one’s residence was urban or rural [28]. Of the 21 regional Veteran Integrated Service Networks (VISN) across the 50 United States and Puerto Rico, we excluded Veterans from one VISN (VISN-1) where another COPD research study using the Taking Healthy Steps platform was recruiting participants. The coordinating center was located at the Ann Arbor VA Healthcare System, Ann Arbor, MI, USA. Ethical approval for this study was granted by the VA Ann Arbor Healthcare System Human Studies Subcommittee.A random sample of 28,957 Veterans (half rural, half urban) with a COPD diagnosis was sent a recruitment letter. Inclusion criteria included having access to a computer with an Internet connection, a USB port, and Windows XP, Vista, Windows 7, or Windows 8. Our a priori exclusion criteria excluded those who did not upload baseline step-count data or who did not complete the baseline survey to assess HRQL. Per study protocol, participants had to have baseline values for the primary (HRQL) and secondary outcome (daily step count) to be enrolled and randomized. Ultimately, 239 participants were enrolled and randomized in a 2:1 ratio to either Taking Healthy Steps (Internet-mediated, pedometer-based walking program) or wait-list control (pedometer alone), stratified by Modified Medical Research Council (MMRC) dyspnea score and urban versus rural status (Figure 1). All participants were prompted monthly to report new or worsening medical problems; all self-reported adverse events were recorded. There were no face-to-face encounters with staff; all features were automatically delivered via the website.Figure 1CONSORT diagram at 12 months.OutcomesPrimary OutcomeThe St. George’s Respiratory Questionnaire (SGRQ), a disease-specific instrument with 50 items that has been well validated in COPD [29,30] was used to assess HRQL. It has a summary total score (SGRQ-TS) composed of three domain scores: symptoms (frequency and severity), activities (that cause or are limited by breathlessness), and impact (social functioning and psychological disturbances resulting from airways disease). Scores range from 0 to 100 with lower scores indicating better HRQL. A change of four units is the minimum clinically important difference for the SGRQ-TS [31]. Study participants completed the SGRQ online at study entry, 4 months, and 12 months.Secondary OutcomeDaily step count was assessed by the Omron HJ-720 ITC pedometer. Once participants completed the baseline survey, study staff mailed them a pedometer that had an embedded USB port, an upload cable, and detailed written instructions on how to install the Java software and upload pedometer data. For users who did not have Java already installed on their computers, the software installation was a one-time event. Thereafter, participants uploaded step-count data using the cable that connected the pedometer to their home computer. Research staff were available by telephone to assist with software installation and upload of step counts.A wear day with valid step-count data was defined as one having at least 100 steps and 8 hours of step counts recorded [32]. At baseline, participants wore the pedometer covered with a sticker to blind the participant to device feedback. Baseline daily step count was the mean daily step count calculated using at least 5 days of valid data within a period of seven consecutive days. Follow-up daily step counts were calculated within a window of +/-14 days around day 121 for 4-month values, and +/-14 days around day 366 for 12-month values. Follow-up daily step counts were the means of at least 5 days of valid data within a period of seven consecutive days. We also calculated the mean daily step count each month by examining the data in 30-day increments. We used values from the last valid week (at least 5 days of valid data within a period of seven consecutive days) in each of those months.Intervention GroupParticipants randomized to Taking Healthy Steps completed an intensive 4-month intervention period, followed by a distinct 8-month maintenance phase (Table 1). During the first 4 months, participants were instructed to wear the pedometer every day, reminded to upload at least weekly, and were provided access to the website. The website has four key components [26,27]: individualized goal setting was based on uploaded step counts, iterative feedback allowed self-monitoring of step counts, motivational content provided a new educational tip every other day and a new motivational message each week, and an online community forum enhanced social support [22-27]. During the 8-month maintenance phase, participants continued to wear the pedometer, upload daily step counts, receive weekly step-count goals and feedback, and had access to the online community forum. They could view the initial 4 months of educational content and motivational messages, but no longer received new content. Topics on the online community forum included walking in a variety of weather/seasons, health topics (weight management, COPD disease management), injury prevention, barriers to walking, and technical issues with the pedometer and website.Table 1Features available to the Taking Healthy Steps and control groups during the first 4 months versus last 8 months of the study.Features0-4 Months5-12 MonthsTaking Healthy StepsControlTaking Healthy StepsControlWear pedometerYesYesYesYesUpload step-count dataAt least weeklyAt least monthlyAt least weeklyAt least monthlyGoal settingYesNoYesNoFeedbackYesNoYesNoNew educational and motivational contentYesNoNoNoOnline community forumYesNoYesNoWait-List Control GroupParticipants randomized to the wait-list control group were instructed to wear the pedometer every day, reminded monthly to log in to the website to upload step-count data, and asked to report all adverse events. Veterans in the wait-list control group received neither instruction to increase PA nor step-count goals. They had access to a webpage that showed only a checklist of surveys completed and a count of what week they were in the study. After 12 months, they were given the option to use the Internet-mediated intervention.Participant Characteristics, Device Adherence, and Website EngagementAt baseline, participants answered questions online that assessed comorbidities, oxygen use, smoking status, and demographics. At study entry, 4 months, and 12 months, dyspnea was assessed using the MMRC scale (range 0-4 with 4 indicating the most severe level of dyspnea) [33]. Events self-reported during the study were defined a priori as COPD-related if persons experienced a combination of symptoms and/or required treatment with antibiotics and/or systemic corticosteroids. The COPD-related events included acute exacerbations or pneumonia, ascertained by self-reported events and/or review of health care utilization (hospitalizations and emergency room visits) and pharmacy data. To assure independence of individual acute exacerbations, participants were considered to have experienced a new acute exacerbation only if it were reported 21 or more days after the previous acute exacerbation [34].We examined device adherence, overall and by group, by calculating the percentage of days (of 366 days) that were wear days with valid step-count data. For the participants who uploaded valid step-count data at 12 months and completed the study, we also examined percentage of days (of 42 days) that were wear days during the last 6 weeks of the study.In the intervention group, we objectively examined website engagement by recording the number of log-ins to the website by month of study and assessing the frequency of use of the online community forum. In addition, at 4 and 12 months, participants in the Taking Healthy Steps group answered a structured survey eliciting feedback about their commitment to their step-count goals and various aspects of engagement with the intervention, including participants’ ease of finding time to log in to the website, knowledge of step-count goals, and use of the different components of the website.Statistical AnalysisProportions, means, and standard deviations described baseline participant characteristics. Two-sample t tests and chi-square tests compared baseline characteristics between groups. The occurrence of COPD-related events (acute exacerbations or pneumonia), hospitalizations, emergency room visits, deaths, and adverse events during the study were each compared between groups using a logistic regression model. For the count of hospitalizations, a zero-inflated Poisson regression model was also used to assess the difference in the rate of hospitalizations between groups. These models adjusted for age, gender, treatment group, and oxygen use.The primary analysis used the intention-to-treat approach, and used a linear mixed-effects model with baseline, 4-month, and 12-month outcome values (eg, SGRQ-TS or daily step count) as dependent variables. No baseline variable was predictive of missingness in models adjusting for stratification variables and treatment group. Thus, the longitudinal data model included participants who had the dependent variable for at least one time point and was expected to give unbiased estimates of the intervention effect assuming missingness at random. The model included participants as random intercepts to adjust for within-participant correlations of repeated measures, fixed predictors of treatment group, 4- and 12-month time indicators, and treatment group by time indicator interactions, MMRC dyspnea score (dichotomized to 0-1 vs 2-4), and urban versus rural residence. We also analyzed the data excluding those who died. The proportion of participants who had at least a 4-unit improvement in SGRQ-TS at 12 months was compared between groups using a chi-square test [31]. For the analysis of mean daily step count by month of study, we used a linear mixed-effect model similar to that for the primary outcome except data were assessed in 30-day increments over the 12-month study period. Predictors were treatment group, month of study as indicator variables (coded as 1-12), group-by-month indicator variables interactions, dichotomized MMRC dyspnea score, and urban versus rural residence.We assessed website engagement in the intervention group by characterizing the number of log-ins to the website using the mean, median, and interquartile range, and assessed trends over months of study using a linear mixed-effects regression analysis with monthly number of log-ins for each participant as the outcome and time (month since randomization) as the predictor. Trends for device adherence over month of study were examined with percent of days with valid step-count data using a linear mixed-effects model and for use of the online community forum using a generalized mixed-effects model with logit link. The effect of time on participant responses to the online survey about goal commitment and intervention engagement at 4 and 12 months was estimated for each response variable using a mixed-effects model with 4- and 12-month survey data as the dependent variable and predictors including 12-month indicator, baseline dichotomized MMRC dyspnea score, and urban versus rural status. All models, including the model for the number of log-ins, were checked for model assumptions using residuals.One participant in the Taking Healthy Steps group was considered an outlier given that his change in SGRQ-TS was 4.0 standard deviations greater than the mean for change in SGRQ-TS and his change in daily step count was 8.1 standard deviations greater than the mean for change in daily step count. The extremely high step counts more likely reflected his occupational PA rather than any effects of our intervention. Our main analyses excluded the outlying individual, but we also repeated primary and secondary outcome analyses with this participant included. All analyses were performed with Stata 14.0 (StataCorp LP, College Station, TX, USA).ResultsParticipant CharacteristicsNo information is available on the persons to whom we mailed recruitment materials but who were not screened because they did not go to our website and did not call us (Figure 1). The top three reasons for ineligibility of 459 participants were not sedentary (n=202), could not walk a block (n=120), or no compatible computer access (n=161), with some participants having more than one reason (Figure 1). In all, 68 persons consented but were not enrolled and randomized, including 19 who failed to submit a medical clearance form and did not upload step-count data, one who failed to submit a medical clearance form, four who failed to upload step-count data, and nine who failed to complete the baseline SGRQ (Figure 1).Participants’ (N=238) characteristics include: mean age 67 (SD 9) years, male (93.7%, 223/238), rural residence (45.4%, 108/238), MMRC dyspnea score ≥2 (30.7%, 73/238), current smokers (24.8%, 59/238), and supplemental oxygen use (23.5%, 56/238) (Table 2). There were no significant differences in baseline characteristics between study groups, including current smoking history. Overall, 87.8% (209/238) of participants completed the 12-month online HRQL assessment, and 74.4% (177/238) uploaded 12-month valid step-count data. In the intervention group, 87.7% (135/154) of participants completed the HRQL assessment and 76.6% (118/154) uploaded valid step-count data, compared to 88% (74/84) and 70% (59/84), respectively, in the control group.Table 2Baseline participant characteristics (N=238).CharacteristicIntervention (n=154)Control (n=84)Total (N=238)Age (years), mean (SD)67 (8.6)66.4 (9.2)66.8 (8.8)Gender (male), n(%)146 (94.8)77 (92)223 (93.7)Residence, n(%)Urban83 (53.9)47 (56)130 (54.6)Rural71 (46.1)37 (44)108 (45.4)Hispanic (n=235), n(%)5 (3.3)1 (1)6 (2.6)Race, n(%)Black7 (4.6)3 (4)10 (4.2)White142 (92.2)79 (94)221 (92.9)Other5 (3.3)2 (2)7 (2.9)Current smoker, n(%)41 (26.6)18 (21)59 (24.8)Oxygen use, n(%)35 (22.7)21 (25)56 (23.5)SGRQ,a mean (SD)Symptoms57.2 (19.1)56 (19.9)56.8 (19.3)Activities62.3 (20.2)64.2 (18)62.9 (19.5)Impact32.2 (16.5)34.1 (17.9)32.9 (17)Total45.6 (15.4)46.8 (15.6)46 (15.4)Baseline daily step count, mean (SD)3488 (2316)3521 (2058)3499 (2224)MMRC dyspnea score,b n (%)0-1108 (70.1)57 (68)165 (69.3)2-446 (29.9)27 (32)73 (30.7)aSGRQ: St. George’s Respiratory Questionnaire. Data for symptoms, activities, and impact were available from 236 participants; total from 233 participants.bMMRC: Modified Medical Research Council.At 12 months, 29 of 238 (12.2%) participants did not have sufficient data to calculate the SGRQ-TS: 19 Taking Healthy Steps participants and 10 controls. There was no significant difference in baseline SGRQ-TS (mean 49.8, SD 16.1 vs mean 45.6, SD 15.3; P=.18) or baseline daily step count (mean 3410, SD 2667 vs mean 3512, SD 2163; P=.82) between those for whom SGRQ-TS could not be calculated (n=29) versus those for whom SGRQ-TS was calculated at 12 months (n=209).The percent of participants with COPD-related events (acute exacerbations or pneumonia) during the study did not differ between groups (control: 18%, 15/84; intervention: 22.7%, 35/154; logistic regression OR 1.4, 95% CI 0.7-2.8; P=.33). No between-group difference was found in the percent of participants with hospitalizations (control: 17%, 14/84; intervention: 23.4%, 36/154; logistic regression OR 1.6, 95% CI 0.8-3.2; P=.19) or emergency room visits (control: 24%, 20/84; intervention: 29.9%, 46/154; logistic regression OR 1.4, 95% CI 0.8-2.6; P=.27) during the 12-month study. For the count of hospitalizations, a zero-inflated Poisson regression model also found no between-group difference. The percent of participants who died during the study did not differ between groups (control: 2%, 2/84; intervention: 3.9%, 6/154; P=.53). Finding no between-group differences in the percentage of participants who were hospitalized or died provided assurance that the censoring of the outcome variables (SGRQ-TS or daily step counts) due to these events was not likely to confound the assessment of the between-group outcome differences. However, we repeated the analyses with deaths excluded as well.Health-Related Quality of LifeThere was no significant between-group difference in the primary outcome of SGRQ-TS (mean 1.1 units, 95% CI –2.2 to 4.5; P=.50) at 12 months (Table 3). The proportion of participants who achieved at least a 4-unit improvement in SGRQ-TS at 12 months was 45.2% (61/135) in the intervention versus 32% (23/71) in the control group (P=.08). There was no significant between-group difference in the SGRQ domain scores of symptoms (mean 0.5 unit, 95% CI –4.2 to 5.2; P=.84), activities (mean 0.04 unit, 95% CI –4.2 to 4.2; P=.99), and impact (mean 2.3 units, 95% CI –1.6 to 6.1; P=.25) at 12 months.Table 3Within-group changes and between-group differences in SGRQ scores and daily step counts at 12 months.Outcome and armNDifference from baseline to 12 months, mean (95% CI)PBetween-group difference, mean (95% CI)PaSGRQTotal1.1 (–2.2, 4.5).50Taking Healthy Steps154–2.5 (–4.5, –0.6).01Control84–1.4 (–4.1, 1.3).31Symptoms0.5 (–4.2, 5.2).84Taking Healthy Steps154–3.2 (–6.0, –0.4).02Control84–2.7 (–6.5, 1.1).16Activities0.04 (–4.2, 4.2).99Taking Healthy Steps154–1.2 (–3.7, 1.3).36Control84–1.1 (–4.5, 2.3).51Impact2.3 (–1.6, 6.1).25Taking Healthy Steps154–3.4 (–5.6, –1.1).004Control84–1.1 (–4.2, 2.0).48Daily step count–108 (–720, 505).73Taking Healthy Steps154270 (–86, 626).14Control84163 (–336, 661).52a Based on linear mixed-effect models, adjusting for group, 4- and 12-month indicators, group×time indicator interactions, baseline MMRC dyspnea score (dichotomized to 0-1 vs 2-4), and urban versus rural status.Intervention participants showed an improvement in SGRQ-TS of a mean 2.5 units (95% CI –4.5 to –0.6) at 12 months, compared to baseline (P=.01) (Table 3). For domain scores in the intervention group, symptoms improved by a mean 3.2 units (95% CI –6.0 to –0.4, P=.02), and impact improved by a mean 3.4 units (95% CI –5.6 to –1.1, P=.004) at 12 months. The control group showed no significant changes in the SGRQ-TS and domain scores at 12 months compared to baseline (Table 3). When the analysis was repeated with the outlying individual included, no substantive difference was seen in results, except improvement in symptoms within the Taking Healthy Steps group was marginally significant (P=.05). When the analysis excluded the eight deaths, results remained nearly identical.Daily Step CountThere was no significant difference between groups with respect to the secondary outcome of daily step count at 12 months (P=.73) (Table 3). There was no significant change in daily step count in the intervention participants (P=.14) or in the control group (P=.52) at 12 months, compared to baseline (Table 3). Examination of daily step count by month of intervention showed that differences in daily step counts in the intervention group compared to controls were maximal and statistically significant at month 4, but approached zero in months 8 to 12 (Figure 2). Between-group P values were <.001 at 4 months, .28 at 8 months, and .82 at 12 months. Within the intervention group, although daily step counts peaked at 2 months and then declined over the course of the study, daily step counts continued to be higher than baseline values in all months of the study (Figure 2). Analysis including the outlying individual showed improvement in daily step counts at 12 months to be significant in the Taking Healthy Steps group (P=.048). Analysis excluding the eight deaths did not change results.Figure 2Mean daily step count and 95% confidence intervals by month of study. Note: the Taking Healthy Steps (THS) curve is shifted to the right of the control curve on the x-axis for ease of visual display. Baseline data are included at month zero.Device Adherence and Website EngagementDevice adherence during the 12-month study period was significantly higher in the intervention group than the control group, with mean 76.7% (SD 29.5) of the 366 days having valid step-count data in the intervention group versus mean 63.7% (SD 32.9) of the 366 days having valid step-count data in the control group (P=.002). For the 177 participants in both groups who uploaded valid step-count data at 12 months and completed the study, mean 83.1% (SD 21.9) of days in the last 6 weeks of the study had valid step-count data. In these last 6 weeks, mean 87.5% (SD 16.5) of days had valid step-count data in the intervention group, which was significantly higher than the mean 74.1% (SD 28.1) of days observed in the control group (P<.001). In the intervention group, device adherence decreased significantly over time (P<.001), with mean 92.1% (95% CI 86.6-97.6) of days having valid step-count data at month 1 versus 70.3% (95% CI 64.9-75.8) of days at month 12 (Figure 3).In the intervention group, mean number of log-ins to the website decreased significantly over the months of study (P<.001; Figure 4). The number of monthly log-ins was mean 6.8 (SD 3.7; median 6, IQR 3) at month 1, which declined to mean 4.2 (SD 3.5; median 4, IQR 3) by month 9 and mean 3.0 (SD 3.0; median 3, IQR 5) by month 12 (Figure 4). In the intervention group, 83.8% (129/154) of the participants used the online community forum at some point during the 12-month study; 66.2% (102/154) of participants directly viewed an online community forum thread or entry, and an additional 17.5% (27/154) of participants posted a new topic or a reply at least once. More than half of the participants responded “definitely true” (22/121, 18.2%) or “mostly true” (45/121, 37.2%) to the statement: “I learned helpful information when I used the online community forum.” There was a significant trend for decreasing use of the online community forum by month of study (P<.001).Responses to questions regarding participant’s goal commitment were not significantly different at 12 months compared to 4 months (Table 4). When asked, “Overall, how motivated are you to walk each day?” with responses from 1=not motivated and 10=extremely motivated, the mean response was 6.8 (SD 2.3) at 4 months compared to mean 6.5 (SD 2.5) at 12 months (P=.06). Responses to questions about engagement with the use of Taking Healthy Steps were not significantly different at 12 months compared to 4 months (Table 4).Table 4Goal commitment and engagement with Taking Healthy Steps intervention.Goal commitment and engagementNa4 months mean (95% CI)12 months mean (95% CI)PbGoal commitmentcIt’s hard to take my step-count goal seriously.1472.1 (1.9-2.2)2.0 (1.9-2.2).69Quite frankly, I don’t care if I reach my step goal or not.1471.7 (1.6-1.8)1.7 (1.6-1.8).46I am strongly committed to pursuing my step-count goal.1463.8 (3.6-4.0)3.7 (3.5-3.9).52It wouldn’t take much to make me abandon my step-count goal.1471.9 (1.7-2.1)2.0 (1.8-2.2).27I think my step-count goal is a good goal to shoot for.1464.0 (3.8-4.2)3.9 (3.8-4.1).77Engagement in Taking Healthy StepsdI would recommend the Taking Healthy Steps walking program to another person with COPD.1461.3 (1.2-1.4)1.2 (1.1-1.3).01It was easy for me to find the time to log in to the website once a week.1461.8 (1.6-2.0)1.8 (1.6-2.0).92I had technical difficulty uploading step-count data from the pedometer to my computer.1464.0 (3.7-4.2)3.9 (3.7-4.1).75I knew what my step goal should be every day.1471.5 (1.4-1.6)1.5 (1.4-1.6).48I was able to comfortably increase my daily step count every week.1472.6 (2.5-2.8)2.8 (2.6-3.0).10I looked at the graphs of the step counts that I walked.1471.6 (1.4-1.7)1.6 (1.4-1.7).76The motivational messages and educational tips were easy to understand.1431.9 (1.8-2.0)1.8 (1.7-1.9).21I learned helpful information when I used the online community forum.1372.5 (2.3-2.7)2.4 (2.3-2.6).52The daily step-count goals were too high for me to walk each day.1473.4 (3.2-3.5)3.4 (3.2-3.5).98a Participants with responses at 4 and/or 12 months were included in the models.b Based on linear mixed-effect models with 4 and 12 months as the dependent variable and predictors of 12-month indicator, intervention group indicator and baseline MMRC dyspnea score (dichotomized to 0-1 vs 2-4) and urban versus rural status.c Response scale 1-5 with 1=strongly disagree, 2=disagree, 3=neither agree nor disagree, 4=agree, 5=strongly agree.d Response scale 1-5 with 1=definitely true, 2=mostly true, 3=not sure, 4=mostly false, 5=definitely false.Figure 3Percentage and 95% confidence intervals of days with valid step-count data in the intervention group by month of study.Figure 4Mean log-ins and 95% confidence intervals in the intervention group by month of study.SafetyAdverse events were categorized as pulmonary, cardiac, musculoskeletal, or other. A significantly greater percent of participants in the intervention group (27.9%, 43/154) had minor musculoskeletal adverse events than in the control group (10%, 8/84; P<.001). There were no differences between groups with respect to pulmonary, cardiac, or other adverse events during the 12 months.DiscussionWe show that our Internet-mediated, pedometer-based walking intervention does not maintain benefits in HRQL and daily step counts at 12 months, despite demonstrated improvements at 4 months [27]. Although we report negative findings for the study overall, lessons learned about device adherence and website engagement are highly informative for guiding the development of future PA interventions that can effectively promote long-term behavior change and sustain PA.Overall, we found that a COPD population found the study feasible and were engaged. The percentage of participants who completed the 12-month study, providing HRQL and step-count data, was high. In addition, our objective results assessing device adherence and showing that 83% of days for participants in both groups within the last 6 weeks of the study had valid step-count data support that people were not lost to the study and then showing up for the last evaluation period. Importantly, persons in the intervention group had significantly higher device adherence compared to the control group for the study overall and at the end of the study. This finding supports that the goal setting, feedback, educational and motivational content, and online community forum provided on the website significantly increased intervention engagement beyond that observed with the use of a pedometer alone.For the first time, we rigorously elicited participant survey responses about goal commitment and intervention engagement, and objectively assessed device adherence and website engagement during the 12-month study. In the intervention group, responses to questions about engagement at 12 months were the same compared to those at 4 months, with participants finding time to log in to the intervention, knowing their step-count goal, and using the graphs, tips and messages, and forums. They also reported that they were as committed to their step-count goal at 12 months as they were at 4 months. Although participants reported the same levels of goal commitment and intervention engagement at the end of the study compared to the beginning of the study, sustained behavior change was not observed because there were significant decreases in number of days with valid step-count data, number of log-ins to the website, and use of the online community forum over time. Although we can only speculate as to cause and effect, the decrease in daily step count (a marker of intervention efficacy and walking behavior change) over time mirrors the declines in device adherence and website engagement over time.The reasons for the observed decline in daily step counts over time require further exploration. Participants may not have continued to wear the pedometer, log in to the website, and walk over the 12 months for a variety of possible reasons that we did not assess, such as waning interest with the intervention, progression of underlying COPD, flare-up of comorbidities, or occurrence of intercurrent life events (eg, spouse illness). The effect of the intervention on daily step counts could potentially have been greater if the control group had not received a pedometer and monthly reminders to upload step counts. We are confident that battery life did not affect the results because we mailed a new battery with replacement instructions to each participant every 4 months. We replaced lost or broken devices reported to us.These results are similar to published data examining maintenance exercise programs after conventional pulmonary rehabilitation [16-21]. Typically, the unstable clinical course of a chronic lung disease such as COPD makes it difficult for patients to resume or maintain an exercise program [20]. Although we observed no difference in the number of COPD-related events, such as acute exacerbations, between groups, the occurrence of acute exacerbations and flare-up of comorbidities over a period of 12 months may have modified the response to Taking Healthy Steps within the intervention group.The failure to obtain long-term benefits with our PA interventions parallels the literature studying other behavior changes, such as smoking cessation [35] and weight loss [36]. Our 8-month maintenance phase retained the key components of goal setting, feedback, and social support. The main feature omitted beginning at month 5 was new educational and motivational content. These findings support that ongoing behavioral modification techniques are critical to sustain PA [37,38]. We speculate that additional intervention components, such as face-to-face contact with peers and/or health care providers, would enhance the social support and motivation needed to sustain PA as a routine behavior. Use of evolving technology, such as wireless transmission and mobile connectivity with cell phones, smartphones/mobile phones, or tablets, could potentially provide anytime/anywhere access to the PA intervention and enhance its long-term efficacy [37,39,40]. Intensive counseling and support at the time of acute exacerbations and flare-up of comorbidities would address medical barriers to PA and motivate patients to continue to walk after an illness. Finally, incorporating the health care provider, health care institutions, communities, and society at large into PA interventions could enhance long-term behavior change and adherence to effectively sustain PA in persons with COPD [41,42].The exact role of digital walking programs in starting and maintaining exercise in persons with COPD remains to be determined. Both acute and chronic models of digital walking programs are potentially useful. Acute intervention models are needed to initiate and promote PA in the vast majority of patients with COPD who cannot access a conventional pulmonary rehabilitation program [43]. In addition, maintenance models are appropriate and much needed because long-term maintenance of behavior change is challenging. In addition, digital walking programs can potentially be useful adjuncts after conventional pulmonary rehabilitation to maintain benefits, which start to wane as early as 3 to 6 months after program completion [20,21]. They can also be an important component of COPD self-management programs [44]. An interesting future question to address is whether restarting our intervention every 4 to 8 months would be an efficacious long-term strategy.The potential full impact of our intervention can only be appreciated by performing a future cost-effectiveness analysis. Results from cross-sectional data from our group and others have shown that every step counts. We have not found a “threshold” or “optimal” daily step count to obtain clinical benefits. The benefits appear to be linear such that those with higher step counts have lower risks for acute exacerbations, hospitalizations, hospital admissions and readmissions, and death compared to those with lower step counts [9-14]. Future work is needed to examine whether PA interventions such as ours can decrease health care resource utilization and result in cost savings to our health care system.Major strengths of our study include the randomized controlled trial design with balanced groups at baseline, objective data on device adherence and website engagement, and the long-term follow-up of 12 months. Our intervention is based on a theoretical model, and informed by previous work eliciting patient feedback to optimize user acceptability and develop the motivational and educational content [25,45]. Our Internet-mediated, pedometer-based intervention focuses specifically on walking, a low-intensity PA that most patients can do. It has already been shown that a greater quantity of low-intensity PA reduces risk of COPD hospitalizations, whereas high-intensity PA does not result in risk reduction [15].Our study has several limitations. We studied primarily white male Veterans limiting the generalizability of our results. Spirometric confirmation of the COPD diagnosis was not made at study entry. However, any potential misclassification of asthma as COPD was most likely balanced between groups and would not bias the primary results. The vast majority of the patients had MMRC <2. It is justified to include patients with MMRC <2 because patients with newly diagnosed COPD have reduced PA even at the earliest stages of the disease [3]. It is important to promote PA even when patients are not significantly symptomatic, as recommended by the GOLD guidelines for COPD [6]. We found no difference in benefit of the PA intervention in those with MMRC <2 versus MMRC ≥2. We acknowledge the final response rate was likely biased toward responders who had a particular interest in this type of intervention, and the results may not be generalizable to a wider COPD population. Finally, seasonal variation can influence our secondary outcome of daily step counts. We minimized the impact of season by having a 12-month intervention and enrolling participants over all four seasons.An Internet-mediated, pedometer-based PA intervention for persons with COPD does not maintain improvements in HRQL or daily step count at 12 months, despite demonstrated improvements at 4 months. In addition, waning engagement with the PA intervention support that future efforts should focus on improving features of PA interventions to enhance long-term behavior change and sustain engagement with PA. These findings need to be considered when designing future Internet-mediated PA interventions.We thank the Veterans for their participation in this research study. The study was funded by Department of Veterans Affairs, Health Services Research and Development Service (Grant IIR 09-366, Richardson); Department of Veterans Affairs, Rehabilitation Research and Development Service (Career Development Award, F6847W, Moy); and NIH National Heart, Lung and Blood Institute (Grant T32 HL007749-20, Martinez). None of the funding bodies had any role in the design, collection, analysis or interpretation of the data, in writing the manuscript, or in the decision to submit the manuscript for publication.Authors' Contributions: MLM, RK, HQN, MDC, DEG, NDG, and CRR were involved in the conception and design of all stages of the study. MLM, CHM, RK, PR, HQN, MDC, and CRR were involved in study data collection. CHM, HMK, RK, PR, RGH, and NDG conducted study analyses. All authors read and approved the final manuscript. CRR, the study PI, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.Conflicts of Interest: None declared. This study was initiated by the investigators, who do not receive any financial support from Omron Healthcare. 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Prev2010301475210.1097/HCR.0b013e3181c9c985200684232006842319BeauchampMKEvansRJanaudis-FerreiraTGoldsteinRSBrooksDSystematic review of supervised exercise programs after pulmonary rehabilitation in individuals with COPDChest20131014441124113310.1378/chest.12-2421234299312342993120RiesALKaplanRMMyersRPrewittLMMaintenance after pulmonary rehabilitation in chronic lung disease: a randomized trialAm J Respir Crit Care Med2003315167688088810.1164/rccm.200204-318OC125058591250585921SpencerLMAlisonJAMcKeoughZJMaintaining benefits following pulmonary rehabilitation: a randomised controlled trialEur Respir J2010335357157710.1183/09031936.00073609196439441964394422RichardsonCRBuisLRJanneyAWGoodrichDESenAHessMLMehariKSFortlageLAResnickPJZikmund-FisherBJStrecherVJPietteJDAn online community improves adherence in an internet-mediated walking program. Part 1: results of a randomized controlled trialJ Med Internet Res2010124e7110.2196/jmir.1338211691602116916023RichardsonCRMehariKSMcIntyreLGJanneyAWFortlageLASenAStrecherVJPietteJDA randomized trial comparing structured and lifestyle goals in an internet-mediated walking program for people with type 2 diabetesInt J Behav Nutr Phys Act200745910.1186/1479-5868-4-59180214111802141124MoyMLJanneyAWNguyenHQMatthessKRCohenMGarshickERichardsonCRUse of pedometer and Internet-mediated walking program in patients with chronic obstructive pulmonary diseaseJ Rehabil Res Dev2010475485496208033922080339225MoyMLWestonNAWilsonEJHessMLRichardsonCRA pilot study of an Internet walking program and pedometer in COPDRespir Med2012910691342135010.1016/j.rmed.2012.06.013227959842279598426MartinezCHMoyMLNguyenHQCohenMKadriRRomanPHollemanRGKimHMGoodrichDEGiardinoNDRichardsonCRTaking Healthy Steps: rationale, design and baseline characteristics of a randomized trial of a pedometer-based Internet-mediated walking program in veterans with chronic obstructive pulmonary diseaseBMC Pulm Med2014141210.1186/1471-2466-14-12244911372449113727MoyMLCollinsRJMartinezCHKadriRRomanPHollemanRGKimHMNguyenHQCohenMDGoodrichDEGiardinoNDRichardsonCRAn Internet-mediated pedometer-based program improves health-related quality-of-life domains and daily step counts in COPD: a randomized controlled trialChest20157148112813710.1378/chest.14-1466258113952581139528WeeksWBKazisLEShenYCongZRenXSMillerDLeeAPerlinJBDifferences in health-related quality of life in rural and urban veteransAm J Public Health200410941017621767154517471545174729JonesPWQuirkFHBaveystockCMLittlejohnsPA self-complete measure of health status for chronic airflow limitation. The St. George's Respiratory QuestionnaireAm Rev Respir Dis1992614561321132710.1164/ajrccm/145.6.13211595997159599730KaplanRMRiesALReillyJMohsenifarZNational Emphysema Treatment Trial Research GroupMeasurement of health-related quality of life in the national emphysema treatment trialChest20049126378178910.1378/chest.126.3.781153647571536475731JonesPWSt. George's Respiratory Questionnaire: MCIDCOPD20053217579171369661713696632MatthewsCEHagströmerMPoberDMBowlesHRBest practices for using physical activity monitors in population-based researchMed Sci Sports Exerc20121441 Suppl 1S68S7610.1249/MSS.0b013e3182399e5b221577772215777733MahlerDAWellsCKEvaluation of clinical methods for rating dyspneaChest198839335805863342669334266934AaronSDFergussonDMarksGBSuissaSVandemheenKLDoucetteSMaltaisFBourbeauJFGoldsteinRSBalterMO'DonnellDFitzgeraldMCanadian Thoracic Society/Canadian Respiratory Clinical Research ConsortiumCounting, analysing and reporting exacerbations of COPD in randomised controlled trialsThorax2008263212212810.1136/thx.2007.082636177027901770279035Jiménez-RuizCAAndreasSLewisKETonnesenPvan SchayckCPHajekPTonstadSDautzenbergBFletcherMMasefieldSPowellPHeringTNardiniSToniaTGratziouCStatement on smoking cessation in COPD and other pulmonary diseases and in smokers with comorbidities who find it difficult to quitEur Respir J20157461617910.1183/09031936.00092614258828052588280536AppelLJClarkJMYehHWangNCoughlinJWDaumitGMillerERDalcinAJeromeGJGellerSNoronhaGPozefskyTCharlestonJReynoldsJBDurkinNRubinRRLouisTABrancatiFLComparative effectiveness of weight-loss interventions in clinical practiceN Engl J Med20111124365211959196810.1056/NEJMoa1108660220853172208531737SallisRFranklinBJoyLRossRSabgirDStoneJStrategies for promoting physical activity in clinical practiceProg Cardiovasc Dis201557437538610.1016/j.pcad.2014.10.003254599752545997538WilsonJJO'NeillBCollinsEGBradleyJInterventions to increase physical activity in patients with COPD: a comprehensive reviewCOPD2015612333234310.3109/15412555.2014.948992252219072522190739VerweyRvan der WeegenSSpreeuwenbergMTangeHvan der WeijdenTde WitteLA pilot study of a tool to stimulate physical activity in patients with COPD or type 2 diabetes in primary careJ Telemed Telecare20141201293410.1177/1357633X13519057244143972441439740TabakMBrusse-KeizerMvan der ValkPHermensHVollenbroek-HuttenMA telehealth program for self-management of COPD exacerbations and promotion of an active lifestyle: a pilot randomized controlled trialInt J Chron Obstruct Pulmon Dis2014993594410.2147/COPD.S60179252467812524678141HeathGWParraDCSarmientoOLAndersenLBOwenNGoenkaSMontesFBrownsonRCLancet Physical Activity Series Working GroupEvidence-based intervention in physical activity: lessons from around the worldLancet2012721380983827228110.1016/S0140-6736(12)60816-2228189392281893942SpruitMAPittaFMcAuleyEZuWallackRLNiciLPulmonary rehabilitation and physical activity in patients with chronic obstructive pulmonary diseaseAm J Respir Crit Care Med20151015192892493310.1164/rccm.201505-0929CI261616762616167643RochesterCLVogiatzisIHollandAELareauSCMarciniukDDPuhanMASpruitMAMasefieldSCasaburiRCliniEMCrouchRGarcia-AymerichJGarveyCGoldsteinRSHillKMorganMNiciLPittaFRiesALSinghSJTroostersTWijkstraPJYawnBPZuWallackRLATS/ERS Task Force on Policy in Pulmonary RehabilitationAn official American Thoracic Society/European Respiratory Society policy statement: enhancing implementation, use, and delivery of pulmonary rehabilitationAm J Respir Crit Care Med2015121192111373138610.1164/rccm.201510-1966ST266236862662368644EffingTWVercoulenJHBourbeauJTrappenburgJLenferinkACafarellaPCoultasDMeekPvan der ValkPBischoff ErikEWBucknallCDewanNAEarlyFFanVFrithPJanssenDJMitchellKMorganMNiciLPatelIWaltersHRiceKLSinghSZuwallackRBenzoRGoldsteinRPartridgeMRvan der PalenJDefinition of a COPD self-management intervention: International Expert Group consensusEur Respir J20167481465410.1183/13993003.00025-2016270765952707659545DanilackVAWestonNARichardsonCRMoriDLMoyMLReasons persons with COPD do not walk and relationship with daily step countCOPD2014611329029910.3109/15412555.2013.8416702415221324152213", 'title': 'Long-Term Effects of an Internet-Mediated Pedometer-Based Walking Program for Chronic Obstructive Pulmonary Disease: Randomized Controlled Trial.', 'date': '2016-08-10'}}
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Public Health, Epidemiology & Health Systems
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76
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Is smoking cessation higher, lower, or the same when comparing smart technology for self‐management to face‐to‐face/digital and/or written support for self‐management?
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no difference
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moderate
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no
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['26089656']
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{'26089656': {'article_id': '26089656', 'content': 'Int J Chron Obstruct Pulmon DisInt J Chron Obstruct Pulmon DisInternational Journal of COPDInternational Journal of Chronic Obstructive Pulmonary Disease1176-91061178-2005Dove Medical Press26089656446765210.2147/COPD.S81295copd-10-1061Original ResearchA randomized controlled trial evaluating the effectiveness of a web-based, computer-tailored self-management intervention for people with or at risk for COPDVoncken-BrewsterViola1TangeHuibert1de VriesHein2NagykaldiZsolt3WinkensBjorn4van der WeijdenTrudy11Department of Family Medicine, School for Public Health and Primary Care (CAPHRI), Maastricht University Medical Center, Maastricht, Netherlands2Department of Health Promotion, School for Public Health and Primary Care (CAPHRI), Maastricht University Medical Center, Maastricht, Netherlands3Department of Family and Preventive Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA4Department of Methodology and Statistics, CAPHRI, Maastricht University Medical Center, Maastricht, NetherlandsCorrespondence: Huibert Tange, Maastricht University, PO Box 616, 6200MD, Maastricht, Netherlands, Tel +31 43 388 2230, Fax +31 43 361 9344, Email h.tange@maastrichtuniversity.nl201508620151010611073© 2015 Voncken-Brewster et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2015The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.IntroductionCOPD is a leading cause of morbidity and mortality. Self-management interventions are considered important in order to limit the progression of the disease. Computer-tailored interventions could be an effective tool to facilitate self-management.MethodsThis randomized controlled trial tested the effectiveness of a web-based, computer-tailored COPD self-management intervention on physical activity and smoking behavior. Participants were recruited from an online panel and through primary care practices. Those at risk for or diagnosed with COPD, between 40 and 70 years of age, proficient in Dutch, with access to the Internet, and with basic computer skills (n=1,325), were randomly assigned to either the intervention group (n=662) or control group (n=663). The intervention group received the web-based self-management application, while the control group received no intervention. Participants were not blinded to group assignment. After 6 months, the effect of the intervention was assessed for the primary outcomes, smoking cessation and physical activity, by self-reported 7-day point prevalence abstinence and the International Physical Activity Questionnaire – Short Form.ResultsOf the 1,325 participants, 1,071 (80.8%) completed the 6-month follow-up questionnaire. No significant treatment effect was found on either outcome. The application however, was used by only 36% of the participants in the experimental group.ConclusionA possible explanation for the nonsignificant effect on the primary outcomes, smoking cessation and physical activity, could be the low exposure to the application as engagement with the program has been shown to be crucial for the effectiveness of computer-tailored interventions. (Netherlands Trial Registry number: NTR3421.)Keywordssmoking cessationphysical activityInternet interventiontailoringCOPDBackgroundCOPD is one of the leading causes of morbidity and mortality worldwide.1 COPD patients suffer from airflow limitation that is typically progressive and not reversible.2 Adequate patient self-management and behavior modification, such as smoking cessation and increasing the level of physical activity, are recommended to decelerate disease progression.3,4A relatively small number of studies on the effectiveness of COPD self-management interventions have been conducted, and the evidence on effectiveness remains inconclusive.5 Self-management interventions have mainly focused on educating COPD patients using standardized information, but are now increasingly offering personalized information to patients through counseling with a health care provider.5Another trend in providing health-promoting information is e-Health, which uses information and communication technology.6 Information provided by e-Health interventions has been individualized using computer-tailored technology, often with disease prevention as a main goal.7–9 This intervention method offers computer-generated, personally relevant information by adapting the content of health-promotion messages to users’ characteristics.9 Personalizing and adapting health messages has been found to help attract and keep users’ attention, increase appreciation, and help users process messages more thoroughly.10–12 Computer-tailored interventions have been shown to effectively improve health behaviors, such as smoking cessation and physical activity.13,14 This intervention strategy has also been successful when targeting multiple behaviors11 and has been found to be more cost-effective than usual care.15 To our knowledge, this promising technique has not yet been tested with the purpose of supporting behavior change in COPD patients.In the MasterYourBreath (“AdemDeBaas” in Dutch) project, we developed a web-based, computer-tailored self-management application for COPD patients. We evaluated and improved the usability of the prototype16 and conducted a pilot study.17 In the present paper, we report the effectiveness of this intervention on behavioral (physical activity, smoking cessation, and the intention to be more physically active and to quit smoking) and clinical outcomes (clinical disease control and dyspnea).MethodsStudy designThis randomized controlled trial (RCT) compared an intervention group which received a COPD self-management application to a control group that did not receive the intervention. All participants, whether they were assigned to the control or intervention group, were free to receive usual care or use other resources in order to help them manage their disease or improve their lifestyle.In the Netherlands, a COPD disease-management approach is widely implemented.18 This approach includes a practice nurse who coaches patients to improve their self-management behavior. We originally planned to integrate the intervention in this disease-management approach, but our pilot study had shown that it was not feasible to recruit enough patients to cover the sample size required for our RCT if the practice nurse recruited the patients.17 Instead, to solve the recruitment issues, we invited patients from five general practices by mail and recruited patients from a Dutch online panel. We also broadened our inclusion criteria to include people at risk for COPD as well as people with known COPD.The Dutch online panel was assembled by the company Flycatcher Internet Research BV (www.flycatcher.eu) which is an institute for online research certified by the International Organization for Standardization. In total, the online panel consisted of 16,000 Dutch-speaking members, who had an email address and were at least 12 years old. All age groups, education levels, and provinces of the Netherlands were represented in the panel. Flycatcher’s members are recruited by Flycatcher through newsletters, send-to-a-friend promotions, third parties’ contact lists used for research (with the permission of the owner of the contact list and the person on the list), and word-of-mouth advertising. Members receive seven research questionnaires a year on average.Members from the Dutch online panel and the five general practices were eligible for participation in this study if they were diagnosed with COPD or were at moderate or high risk for COPD, were between 40–70 years of age, were proficient in Dutch, and had access to the Internet and basic computer skills. Dutch proficiency and basic computer literacy were gauged by administration of the first online questionnaire. The Respiratory Health Screening Questionnaire (RHSQ)19 was used to assess the subject’s risk for COPD. This questionnaire contains ten items related to important determinants of COPD for individuals of 40 years and older.19 A scoring system for case-finding20,21 was used to determine if an individual was at low (<16.5 points), moderate (16.5–19.5 points), or high risk (>19.5 points) for COPD (sensitivity =58.7%, specificity =77.0%, for the 16.5 cutoff point).20The five general practices were involved in a parallel project21 in which 40- to 70-year-old patients had already been screened for COPD by their general practitioner using the RHSQ. Potentially eligible members of the online panel were invited for the study by an email from Flycatcher, including a study information letter. Members who decided to participate were screened for eligibility by completing the RHSQ. We implemented a scoring algorithm within the online questionnaire, so eligibility could be determined directly after participants completed the questionnaire. Members received a small incentive equal to €2.55 per completed questionnaire (baseline and follow-up). Figure 1 shows the Consolidated Standards of Reporting Trials (CONSORT) diagram including the two populations.The study was approved by the Medical Ethical Committee of Maastricht University Medical Center (METC 12-4-033) and registered with the Netherlands Trial Registry (NTR3421). All participants received an online study information letter and completed an online informed consent form before entering the study. A more detailed description of the methods can be found in a study protocol published elsewhere.22RandomizationA permuted block design23 with a random block size varying from four to 20 was employed to randomize participants stratified by channel of recruitment (online or through general practice). This approach was chosen in order to achieve balanced and evenly distributed samples for both recruitment strategies. A researcher not involved in data collection or analysis of the results performed the randomization using PROC PLAN in SAS software (v 9.1; SAS Institute, Cary, NC, USA). Due to the study design, it was not feasible to blind participants to group assignments.InterventionMasterYourBreath applicationThe intervention, “MasterYourBreath”,22 was designed to change participants’ health behavior by means of a web-based application providing computer-generated tailored feedback. The intervention was based on earlier studies on computer-tailored feedback for lifestyle changes which have been shown to be effective and cost-effective11,24–26 and adapted to our target groups. The MasterYourBreath application was built using the online application Tailorbuilder (OverNite Software Europe, Sittard, Netherlands).Participants assigned to the experimental group were asked by email to access the application with a personalized account and use the application ad libitum for 6 months. Participants in the online group received the email from Flycatcher and those in the general practice group from the research team. Application use was monitored by the research team and email prompts were sent to encourage application use,27 mostly within a 2-week time interval addressing new content on the website, as this could increase the number of follow-up visits.28 The application had a modular design, including two behavior-change modules, smoking cessation and physical activity. Each module was equally divided into six intervention components: (1) health-risk appraisal: feedback on the behavior (smoking or physical activity) based on Dutch guidelines; (2) motivational beliefs: feedback on perceived positive and negative consequences of the behavior; (3) social influence: feedback on the social influences of participants’ partner, family, friends, and coworkers on the behavior; (4) goal setting and action plans: feedback on achievement of goals and on action plans in order to achieve their goal; (5) self-efficacy: feedback on perceived barriers to change the behavior; and (6) maintenance: feedback in order to maintain the healthy behavior. Participants could switch behavior-change modules and choose to enter one or more intervention components according to their preference.10Feedback was personalized using participants’ names and tailored to participants’ characteristics and key behavior determinants of psychosocial constructs, for which the I-Change model served as theoretical framework.29,30 Examples of the key behavior determinants are: pros and cons of physical activity, perceived social support to quit smoking, action plans to increase physical activity, and self-efficacy to cope with barriers to quit smoking. Participants were asked questions to uncover their personal determinants, using questionnaires that have been tested experimentally among Dutch adults in previous studies in the general public.13,31,32 These questionnaires were adjusted for COPD patients during the usability study.16 The questions were used to generate tailored feedback to the participants about their responses. Participants’ previous responses were also incorporated in the feedback so they could track their own behavior change and goal attainment over the course of the study. The six intervention components per module were available to the participants to be completed over time as they chose. This allowed participants the ability to track their behavior changes by comparing the most current answers with the previous answers.A more detailed description of the intervention and prompt protocol is described elsewhere.22WebsiteThe computer-tailored application was embedded in a website. The website contained general information about the MasterYourBreath project, COPD/being at risk for COPD, smoking, and physical activity. Online self-management resources, such as videos with home exercises (seven exercises focusing on strength and balance) and hyperlinks to other informative websites, were also included. The tailored feedback and prompts referred participants to the home exercises and other resources.Data collectionA web-based questionnaire was administered at baseline between May and November of 2012 with a follow-up questionnaire sent out 6 months later. The frequency of reminders for completing these questionnaires was adapted to the response rate. The online group received one reminder to participate in the study and complete the baseline questionnaire. General practice group participants received two additional reminders if they responded to the invitation but did not complete the baseline questionnaire, since the participation rate in this group was low. The online group received one reminder to complete the follow-up questionnaire, whereas the general practice group received two reminders. Data collection ended in July 2013. All data were captured through these questionnaires, except demographic characteristics in the online group, as these were already documented through an annual update process undertaken by Flycatcher.Outcome measuresTwo primary outcomes were measured, one for each health behavior: smoking cessation and physical activity. Smoking cessation was assessed by one item measuring the 7-day point prevalence abstinence,33,34 and the level of physical activity was assessed by the International Physical Activity Questionnaire – Short Form.35We created a “behavior-change score” by combining the two behaviors (smoking cessation and physical activity). The behavior-change score was only calculated for participants who smoked at baseline or were below the physical activity norm (defined as being physically active for at least 30 minutes a day on 5 days a week at a moderate or vigorous intensity). The efforts of participants were rated as “successful behavior change” if they achieved smoke-free status for 7 consecutive days prior to the follow-up measurement, or if they achieved the norm level of physical activity at follow-up, reflecting a change from their baseline behavior. The actions of participants who smoked or were below the physical activity norm at baseline and achieved neither smoke-free status nor the norm level of physical activity at follow-up were rated as “unsuccessful behavior change”.Secondary outcomes included secondary smoking cessation measures, health status, and intention to change behavior. Secondary smoking cessation measures were: number of quit attempts during the past 6 months, 24-hour point prevalence abstinence, tobacco consumption, and continued and prolonged abstinence.33,34 To assess participants’ health status, participants were asked if they experienced any form of breathlessness, and if so, the Medical Research Council (MRC) dyspnea scale was administered in order to measure the level of disability.36 Clinical disease control was measured using the Clinical COPD Questionnaire. This questionnaire assesses both patient guideline goals (health-related quality of life) and clinical guideline goals such as prevention of disease progression.37 Intention to change behavior was measured by separate questions for physical activity and smoking. Table 1 presents an overview of all outcomes including how and when they were measured.Baseline measurementsThere were several additional baseline measures that were not part of the primary and secondary outcome measures, including demographic characteristics: age, sex, marital status, education level, and current employment status. Several additional questions were asked at baseline to capture smoking behavior. Participants were asked if they had ever smoked and about their number of previous quit attempts. The six-item version of the Fagerström Test for Nicotine Dependence (0= not addicted; 10= highly addicted)38 was included in order to assess the addiction level. Health status was further estimated, measuring COPD status and comorbidities, by asking participants whether they were diagnosed with COPD or any other chronic disease, and which other chronic disease(s).Sample-size calculationSample-size calculations assumed 80% power and a significance level of 0.05 for both behaviors and were completed by PS software version 3.0.43,39 according to Fisher’s exact test. Calculations for smoking indicated that 446 participants per group were necessary at the end of the trial to detect a 10% difference in 7-day point prevalence (20% abstinence in the intervention group, compared to 10% in the control group31). We based this calculation on the assumption that 49.2% of the population with an increased risk for COPD smoked at baseline.40 The number needed for measuring physical activity was smaller and could be obtained following the above sample-size calculation for smoking.22 In another study the standard deviation was 26.63 minutes a day in a Dutch population.41 When including 446 participants per group, a difference of 5 minutes a day, which corresponds to a small standardized effect size (Cohen’s d =0.2), could be detected. In order to allow for a 30% drop-out rate, a baseline total of 1,275 participants was necessary to reach 80% power.AnalysesDifferences at baseline between groups (intervention vs control; and participants who dropped out vs who did not drop out) were compared using chi-square tests for categorical variables and independent-samples t-tests for numerical variables. Data were analyzed according to the intention-to-treat principle. For both primary outcomes, an additional per protocol analysis was conducted. Participants assigned to the experimental group had to have completed at least one of the six intervention components of the specific behavior module to be included in the latter analysis. For the “per protocol” analyses, we conducted two sensitivity analyses with stricter criteria for each primary outcome (smoking cessation and physical activity). For the first analyses, we included only participants who completed at least two intervention components of the specific behavior module. For the second analyses, we included only participants who completed at least three intervention components, since a higher “usage dose” may be necessary to yield a treatment effect.The uncorrected and corrected effects of the intervention on the primary and secondary outcomes were assessed using logistic regression for categorical outcomes and linear regression for numerical outcomes measured at 6 months. Linear mixed models were used for outcomes measured at baseline and at 6 months to account for the correlation between repeated measurements of the same participant and to include all participants, including those with missing data. As for correction, the models included: the stratification variable – that is, recruitment channel (online or general practices); baseline variables if they showed a statistically significant difference between intervention and control group; and baseline variables that were related to drop out, missing data, and/or related to the outcome at 6 months (P value ≤0.20 in univariable regression analysis) to increase the precision of the intervention effect. To assess potential effect modifiers, the interaction of the treatment variable with age, sex, intention to increase level of physical activity, educational level, dyspnea status, and COPD status were added in the corrected mixed-model analyses for level of physical activity. Primary outcomes were analyzed for subgroups based on age (40–50, 50–60, 60–70), sex, intention to change behavior (those who had no intention or were not sure; those who intended to change), education level (low, middle, high), dyspnea (yes, no), COPD status (diagnosed, at risk).The robustness of our results of the primary outcome for smoking cessation was tested by conducting a best- and a worst-case scenario, where respondents lost to follow-up were considered to have quit smoking in the best-case scenario and considered to still be smoking in the worst-case scenario. In addition, as a sensitivity analysis, the intervention effect on the behavior-change score was tested using logistic regression analysis.All statistical analyses were performed using IBM SPSS (v 19). Two-sided P values ≤0.05 were considered statistically significant.ResultsRecruitmentA total of 7,179 individuals were invited for the study of which 3,035 declined to participate, 2,790 did not meet the inclusion criteria, and 29 were excluded because they did not complete the baseline questionnaire (n=24) or provided unreliable responses (n=5). Responses were unreliable if answers were straight lined (ie, the same answer options selected for each set of items) or the questionnaire was completed within 3 minutes (which was considered to be unrealistically fast).A total of 1,325 participants (1,282 in the online group and 43 in the general practice group) completed the baseline questionnaire and were randomly assigned to the experimental (online group: n=641, general practice group: n=21) or control group (online group: n=641, general practice group: n=22). Of the 1,325 participants, 1,071 (80.8%) completed the 6-month follow-up questionnaire, including 1,048 (81.7%) of the online group and 23 (53.5%) of the general practice group. Eighteen participants of the online group were excluded from further analyses, due to a high level of suspicion of interference by someone other than the participant, (eg, a partner with whom they shared an email address). Participants were excluded when at least two of the following variables did not match their Flycatcher profile on the follow-up questionnaire: sex, day of birth, month of birth, year of birth. If only one variable was inconsistent or day and month were reversed, we suspected a typing error and did not exclude those participants.In the group of smokers, 447 participants were included of whom 341 completed the follow-up questionnaire. Figure 1 shows the CONSORT diagram of our RCT.Sample characteristicsTable 2 shows the baseline characteristics of the overall sample and the experimental and control groups separately. The only significant difference between the groups was the employment status of participants (P=0.039). As for the participants who smoked at baseline, we did not find any significant differences in baseline characteristics between the groups.More participants were lost to follow-up in the general practice group (46.5%) than in the online group (18.5%) (P<.001), more in the experimental group (22.8%) than in the control group (16%) (P=.002), more smokers (23.7%) than non-smokers (17.2%) (P=.005), and more female (22.6%) than male participants (15.9%) (P=.002). Participants lost to follow-up were also significantly younger (mean =55.9 years) than completing participants (mean =58.1 years) (P<0.001).Application useThe application was used by 237 (36%) participants of the experimental group (ie, at least one of the six components of a behavior-change module was completed). The average number of components completed by those participants was 2.1 (standard deviation =2.4, range 1–21). For physical activity, 193 (29.3%) of the participants completed at least one intervention component. For smoking cessation, 51 (21.2%) of the smokers at baseline, and seven (1.7%) of the nonsmokers at baseline completed at least one intervention component (although nonsmokers were not included in the effect analyses for smoking cessation). Table 3 shows how many participants completed zero, one, two, or three or more intervention components of both modules.Intervention effectBefore correction for baseline characteristics, no significant treatment effect was found for any primary or secondary outcome, except clinical disease control. After correction, all effects were nonsignificant (Table 4).As for sensitivity analyses, similar results were found for the primary outcomes. More specifically, per protocol analyses yielded nonsignificant results for both primary outcomes (Table 5). Regarding physical activity, all interaction terms were nonsignificant. Also, when evaluating for smoking cessation, neither the uncorrected nor corrected effects on 7-day point prevalence abstinence were significant for best- or worst-case scenarios. All subgroup analyses for both outcomes were nonsignificant. Besides, uncorrected and corrected analyses on the behavior-change score, combining the two behaviors, yielded nonsignificant results.DiscussionThis study examined the effects of a computer-tailored COPD self-management intervention. The intervention had no significant impact on the primary outcome measures (physical activity and smoking), or on the secondary outcome measures (intention to change behavior and dyspnea). The only significant effect found was on clinical disease control, but the improvement was too small to have clinical relevance42 and was not significant after correction for relevant baseline characteristics. Moreover, a borderline significant effect for smoking was found when analyzing the effects among those who completed at least two intervention components. Also, the effect size, for both smoking and physical activity, increased as more intervention components were used. Yet, possibly due to the sample size and thus decreased power of the study, these analyses did not yield a significant effect.Possible explanations for the lack of effect may be: (a) low exposure to the intervention, (b) that the intervention method was not sufficient for our target population, and (c) inadequate content of the intervention itself. Although it was not significant, the trend was for an increased effect size as the participants completed more of the six intervention components. This helps verify the importance of exposure to the application and correlates with other studies which have shown that this is essential for the effectiveness of such interventions.43,44 To enhance exposure to the intervention, we used different strategies to attract participants to the application: sending email prompts every 2 weeks, of which some referred to new content on the website, as this has been shown to effectively increase application use;28 including multiple feedback moments to evaluate participants’ behavior and track their goal achievement;45,46 prompting revisits to the application and evaluate these previously set goals; and embedding a website that provided regular news updates,45–47 such as behavioral journalism stories,48 which were personal stories addressing how other patients overcame potential barriers to use the application and improve their health behavior. Additionally, since the length of the program was of concern in the pilot study,17 we separated the two modules (smoking cessation and physical activity) into six small components, giving participants the opportunity to decide which components they wanted to complete, and consequently, how much time they wanted to spend working with the application. Unfortunately, only one out of three participants completed one or more of the six intervention components. In hindsight, giving participants an option to choose intervention components based on the results of our pilot study was probably not desirable, since it has recently been shown that less freedom of navigation on a website enhances application use.49,50 The intervention did not include ongoing peer or counselor support (eg, by a practice nurse) which could have improved the exposure to the application.47Another potential cause for our study results could be that the intervention method was not sufficient for our target population. Although similar computer-tailoring approaches have found significant effects among the general population,11,14,25,26 several other studies reported a relatively low success rate of disease-management programs for COPD patients51–53 and found that COPD patients are more likely to have characteristics that are associated with a higher resistance to smoking cessation interventions54 than other target populations. Negative results are not uncommon in COPD self-management studies according to a systematic review by Jonsdottir.5 The author describes the need for a paradigm shift in which a prominent health professional-centered approach should make way for a patient-family-centered approach with emphasis on the relationship with the health care professional. As we were aware of this, the MasterYourBreath intervention was patient-centered, and social influence of family members was addressed in the intervention. However, the application did not enable the active participation of family members. An improvement to future versions could be to integrate the MasterYourBreath intervention with a social media platform to facilitate engagement of the family members in the patient’s self-management process. The relationship with the health care professional was indeed emphasized in the original version of the MasterYourBreath intervention, by integration of the application in primary care, but recruiting the number of participants necessary for an RCT from primary care practices was found to be unfeasible in the pilot study,17 so the original study design was changed.Another possible cause for the lack of effect could be related to the web-based intervention content itself. We used key behavioral determinants that were experimentally tested in the Dutch population but not validated for COPD patients. The usability study in which we adjusted these determinants for COPD patients16 is not a replacement for a validation study. Behavioral determinants for this specific group might be different from the general Dutch population. For example, COPD patients are likely to experience different barriers to physical activity due to disease complications. Moreover, the main difference we found comparing our application to programs that were very similar but found positive intervention effects11,14,25,26,43,55 was that participants in our study were free to choose which intervention components they wanted to complete. These other programs contained similar tailored messages, but directed participants through a specified intervention pathway. As described previously, this strategy might increase exposure, as it limits freedom of navigation. Instead of shortening the intervention content by tailoring the use of components to user’s preference,10 it may have been more effective to offer participants only components adapted to their level of motivation to change their behavior; Stanczyk et al55 found this strategy effective. Peels et al56 tested a web-based basic version of their program and a version in which they added additional environmental information with links to other resources to increase physical activity in adults aged 50 and over. They found that only the latter was not effective. The authors suspected that participants might have been distracted from the intervention pathway by visiting other resources. Likewise, the provision of additional information and self-management resources in the MasterYourBreath application, including home exercises and links to other websites might have decreased a potential intervention effect, as these could have distracted participants from the intervention components, which was the core content of the intervention.LimitationsOur study had several limitations. First, despite our relatively large sample of participants, compared to many other COPD self-management studies,5 our study still lacked power concerning the primary outcome for smoking cessation. The number of smokers at the start of the study was lower than expected, and loss to follow-up among smokers was higher than among nonsmokers.Second, we were not able to evaluate selection bias, because we could not collect additional data to differentiate between participants who enrolled versus those who declined participation. The clinical information that would help us address selection bias was not available from the online recruiting company.Third, the inclusion of people at risk for COPD may make it more difficult to compare our results with self-management studies that include only COPD patients. However, we argue that including individuals at risk for COPD is clinically relevant, since early smoking cessation is pivotally important for a greater health benefit in COPD.57 Including both diagnosed patients and individuals at risk for COPD also poses a methodological challenge, since these groups may benefit from different interventions. However, the approach to care in the MasterYourBreath program has been tailored to varying levels of COPD (risk), and thus it was able to address differing patient needs.Fourth, while our intentions were to do so, we were not able to integrate the MasterYourBreath intervention into the Dutch COPD disease-management approach,18 due to recruitment issues.17 We know that it is important that COPD self-management interventions can be incorporated in an existing health care structure.58–60 The recruitment strategy used in this RCT (including an online group and individuals at risk for COPD) was certainly beneficial for the sample size of our RCT, but hampered the integration of our intervention in primary care.ConclusionMasterYourBreath, a web-based COPD self-management intervention with tailored feedback, did not show statistically significant effects on health-related behavioral or clinical outcomes. Given the structurally low exposure to the application in this study, we believe more research is needed to find effective strategies to increase the use of the web-based applications by COPD patients. To further explain this phenomenon and to generate hypotheses for better strategies, we will reevaluate our RCT and explore in depth the characteristics of the intervention and the participants that may have contributed to the use and appreciation of the application.AcknowledgmentsThe authors would like to thank Onno van Schayck, PhD, for his assistance with the study design; Jos Dirven, MD, for his contribution to participant recruitment; and Jean Muris, PhD, for screening feedback messages on content and providing advice as a COPD specialist. The authors also thank the University of Oklahoma, Health Sciences Center, for providing an office; James W Mold, MD, MPH, for providing general support; and E Wickersham, MD, for editing the manuscript. This study was funded by ZonMw, the Netherlands Organization for Health Research and Development.DisclosureHein de Vries is scientific director of Vision2Health, a company that licenses evidence-based innovative computer- tailored health-communication tools. The other authors declare that they have no competing interests in this work.References1ViegiGPistelliFSherrillDLMaioSBaldacciSCarrozziLDefinition, epidemiology and natural history of COPDEur Respir J20073059931013179781572SiafakasNMVermeirePPrideNBOptimal assessment and management of chronic obstructive pulmonary disease (COPD). 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A systematic reviewAm J Med200411731821921530096653MattkeSSeidMMaSEvidence for the effect of disease management: is $1 billion a year a good investment?Am J Manag Care200713126706761806991054Jiménez-RuizCAMasaFMiravitllesMSmoking characteristics: differences in attitudes and dependence between healthy smokers and smokers with COPDChest20011195136513701134894055StanczykNBolmanCvan AdrichemMCandelMMurisJde VriesHComparison of text and video computer-tailored interventions for smoking cessation: randomized controlled trialJ Med Internet Res2014163e692458993856PeelsDAvan StralenMMBolmanCThe differentiated effectiveness of a printed versus a Web-based tailored physical activity intervention among adults aged over 50Health Educ Res20142958708822498002357FletcherCPetoRThe natural history of chronic airflow obstructionBr Med J1977160771645164887170458EffingTvan der PalenJFrithPEducation in COPD self-management: only part of the gameRespirology20141921511522437292959EffingTWBourbeauJVercoulenJSelf-management programmes for COPD: moving forwardChron Respir Dis20129127352230855160AdamsSGSmithPKAllanPFAnzuetoAPughJACornellJESystematic review of the chronic care model in chronic obstructive pulmonary disease prevention and managementArch Intern Med200716765515611738928661WilsonJSElbornJSFitzsimonsDMcCrum-GardnerEDo smokers with chronic obstructive pulmonary disease report their smoking status reliably? A comparison of self-report and bio-chemical validationInt J Nurs Stud20114878568622128852062JonesPWQuirkFHBaveystockCMLittlejohnsPA self-complete measure of health status for chronic airflow limitation. The St George’s Respiratory QuestionnaireAm Rev Respir Dis1992145613211327159599763GuyattGHBermanLBTownsendMPugsleySOChambersLWA measure of quality of life for clinical trials in chronic lung diseaseThorax19874210773778332153764LincolnNBGladmanJRThe Extended Activities of Daily Living scale: a further validationDisabil Rehabil19921414143158676065WareJEJrSherbourneCDThe MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selectionMed Care1992306473483159391466SmitESHovingCSchelleman-OffermansKWestRde VriesHPredictors of successful and unsuccessful quit attempts among smokers motivated to quitAddict Behav20143991318132424837754Figure 1Consolidated Standards of Reporting Trials diagram.Abbreviation: GP, general practice.Table 1Primary and secondary outcomesOutcome(s)MeasurementScaleTimePrimarySmoking cessation: 7-day point prevalence abstinence1 item assessing whether participant smoked during the last 7 daysa0= did not refrain from smoking during the last 7 days; 1= refrained from smoking during the last 7 daysFollow-upLevel of physical activityIPAQ-SFbMET minutes a week (last 7 days): vigorous physical activity =8.0 METs; moderate physical activity =4.0 METs; walking =3.3 METsBaseline and follow-upSecondaryQuit attempts1 item assessing the number of quit attempts during the past 6 monthsaNumber of quit attempts during the past 6 monthsFollow-up24-hour point prevalence abstinence1 item assessing whether participant smoked during the last 24 hoursa0= did not refrain from smoking during the last 24 hours; 1= refrained from smoking during the last 24 hoursFollow-upContinued abstinence1 item assessing when the last serious quit date was, and 1 item assessing smoking behavior since that datea0= smoked since the last quit date; 1= did not smoke at all since the last quit dateFollow-upProlonged abstinence1 item assessing when the last serious quit date was, and 1 item assessing smoking behavior since that date, allowing a grace period of 2 weeks in which smoking behavior was not counted as sucha0= smoked since 2 weeks after the last quit date; 1= did not smoke at all since 2 weeks after the last quit dateFollow-upTobacco consumption4 items assessing what products (cigarettes, rolling tobacco, cigars, or pipe tobacco) are currently smoked, and 4 items assessing how much of each product is currently smokedaNumber of cigarettesfBaseline and follow-upDyspnea status1 item, MRC scalec1–5; higher score means worse dyspneaBaseline and follow-upClinical disease control10-item CCQd0= very good control; 6= extremely poor controlBaseline and follow-upIntention to quit smoking1 item, 7-point Likert scalee1= I certainly plan to quit smoking; 7= I certainly do not plan to quit smokingBaseline and follow-upIntention to increase the level of physical activity1 item, 7-point Likert scalee1= I certainly plan to be more physically active; 7= I certainly do not plan to be more physically activeBaseline and follow-upNotes:aSmoking cessation questions were selected based on the Russel Standard33 and a Dutch guide published by Stivoro that aimed to standardize smoking cessation measures in the Netherlands.34 Self-report has been shown to be reliable in COPD patients: kappa coefficient =0.20 for biochemical validation at 6-month measurement, P=0.003.61bThe reliability and validity of the IPAQ-SF have been tested in the Dutch population: test–retest reliability, ρ=0.85; concurrent validity between long and short IPAQ, from ρ=0.85 to 0.88; criterion validity against accelerometer, ρ=0.32.35cThe MRC scale is a useful measure for disability. Significant associations were found between disability MRC grade and shuttle distance, St George Respiratory Questionnaire,62 Chronic Respiratory Questionnaire63 scores, mood state, and Nottingham Extended Activities of Daily Living64 scores. Forced expiratory volume in one second was not associated with MRC grade.36dThe CCQ is validated in the Dutch population and can be used for COPD patients and individuals at risk for COPD: Cronbach’s alpha =0.91(internal consistency), significantly higher score of people with or at risk for COPD compared to healthy (ex-)smokers (P<0.05) (discriminate validity), significant correlations with 36-Item Short Form Health Survey (ρ=0.48–0.69)65 and St George Respiratory Questionnaire (ρ=0.67–0.72) (internal consistency); correlation with forced expiratory volume in one second % predicted ρ=–0.49 (divergent validity); intra class coefficient =0.94 (test–retest reliability); significant improvement in CCQ found after 2 months’ smoking cessation (responsiveness).37eThe intention questions were based on the I-Change model.29,30 The “intention to quit smoking” question has previously been used successfully in a similar intervention study.66fThe overall score for tobacco consumption was expressed as the number of cigarettes, whereby one hand-rolled cigarette equaled one commercial cigarette, and one cigar equaled four cigarettes.34 We considered one pipe to equal one cigarette, since no concrete guidelines were available on converting the number of pipes to cigarettes.Abbreviations: CCQ, Clinical COPD Questionnaire; IPAQ-SF, International Physical Activity Questionnaire – Short Form; MET, metabolic equivalent task; MRC, Medical Research Council.Table 2Baseline characteristics of study participants – overall, experimental and control groupCharacteristicOverall sample(n=1,307)Experimental group(n=658)Control group(n=649)Age, years (mean [SD])57.6 (7.2)57.7 (7.3)57.6 (7.2)Male (n [%])627 (48.0)326 (49.5)301 (46.4)Education level (n [%])\u2003Primary school/basic vocational school386 (29.5)191 (29.0)195 (30.0)\u2003Secondary vocational school/high school degree427 (32.7)209 (31.8)218 (33.6)\u2003Higher professional degree/university degree494 (37.8)258 (39.2)236 (36.4)Current employment status (n [%])\u2003Employed670 (51.3)356 (54.1)314 (48.4)\u2003Not employed637 (48.7)302 (45.9)335 (51.6)*Marital status (n [%])\u2003Single/divorced/widowed348 (26.6)171 (26.0)177 (27.3)\u2003In a relationship/living together/married959 (73.4)487 (74.0)472 (72.7)COPD status (n [%])\u2003Diagnosed with COPD284 (21.7)146 (22.2)138 (21.3)\u2003Increased risk for COPD per RHSQ191,023 (78.3)512 (77.8)511 (78.7)Comorbidity (n [%])\u2003≥1 chronic condition604 (46.2)292 (44.4)312 (48.1)\u2003Respiratory disease224 (17.1)106 (16.1)118 (18.2)\u2003Cancer53 (4.1)30 (4.6)23 (3.5)\u2003Diabetes120 (9.2)57 (8.7)63 (9.7)\u2003Cardiovascular disease200 (15.3)98 (14.9)102 (15.7)\u2003Musculoskeletal disorder90 (6.9)41 (6.2)49 (7.6)\u2003Other chronic condition124 (9.5)58 (8.8)66 (10.2)MRC dyspnea36 (n=1,305)\u2003No breathlessness359 (27.5)177 (26.9)182 (28.1)\u20031523 (40.1)264 (40.2)259 (40.0)\u20032318 (24.4)167 (25.4)151 (23.3)\u2003375 (5.7)34 (5.2)41 (6.3)\u2003419 (1.5)9 (1.4)10 (1.5)\u2003511 (0.8)6 (0.9)5 (0.8)Smoking status\u2003Currently smoking447 (34.2)241 (36.6)206 (31.7)\u2003Currently not smoking860 (65.8)417 (63.4)443 (68.3)Number of cigarettes smoked/day among smokers, n=447 (mean [SD])19.3 (12.1)19.0 (12.3)19.8 (11.9)FTND score (range 0–10)38 among smokers, n=447 (mean [SD])4.2 (2.3)4.1 (2.3)4.4 (2.3)Number of previous quit attempts among smokers, n=447 (mean [SD])3.8 (8.8)3.1 (4.0)4.8 (12.2)Intention to quit smoking (range 1–7) among smokers, n=447 (mean [SD])3.7 (1.9)3.7 (2.0)3.7 (1.9)Level of physical activity (MET per week), n=1,096 (mean [SD])4,012.6 (3,933.3)4,108.7 (4,034.0)3,914.1 (3,828.4)Intention to be more physically active (range 1–7) (mean [SD])3.2 (1.7)3.2 (1.7)3.1 (1.7)CCQ score (range 0–6)37 (mean [SD])1.0 (0.9)1.0 (0.9)1.0 (0.8)Note:*P<0.05.Abbreviations: CCQ, Clinical COPD Questionnaire; FTND, Fagerström Test for Nicotine Dependence; MET, metabolic equivalent task; MRC, Medical Research Council; RHSQ, Respiratory Health Screening Questionnaire; SD, standard deviation.Table 3Number of participants (%) who completed intervention components of the physical activity and smoking cessation modulesModuleNumber of components completed\n012≥3Physical activity465 (70.7)107 (16.3)48 (7.3)38 (5.8)Smoking cessation, among smokers190 (78.8)29 (12.0)12 (5.0)10 (4.1)Table 4Effects of the web-based COPD self-management intervention on all primary and secondary outcomesPrimary and secondary outcomesUncorrected effectsCorrected effects7-day point prevalence abstinenceaOR=1.12, (0.45; 2.77*), P=0.810OR=1.06, (0.43; 2.66), P=0.895MET minutes a weekbb=−64.70, (−455.39; 326.00), P=0.745b=−84.33, (−476.39; 307.74), P=0.67324-hour point prevalence abstinenceaOR=0.77, (0.36; 1.67), P=0.510OR=0.72, (0.33; 1.59), P=0.420Prolonged abstinenceaOR=0.90, (0.35; 2.34), P=0.834OR=0.86, (0.33; 2.25), P=0.766Continued abstinenceaOR=1.02, (0.39; 2.72), P=0.963OR=0.98, (0.37; 2.63), P=0.969Number of cigarettescb=−0.08, (−1.82; 1.65), P=0.925b=0.11, (−1.61; 1.84), P=0.899Intention to quit smokingdb=−0.01, (−0.31; 0.28), P=0.937b=−0.03, (−0.32; 0.26), P=0.826Number of quit attemptseb=−0.36, (−1.10; 0.37), P=0.334b=−0.38, (−1.11; 0.36), P=0.312Intention to increase physical activityfb=0.00, (−0.17; 0.17), P=0.991b=0.00, (−0.17; 0.17), P=0.987Clinical disease controlgb=−0.06, (−0.11; −0.01), P=0.010b=−0.03, (−0.07; 0.01), P=0.134Dyspnea statushOR=1.16, (0.89; 1.51), P=0.283OR=1.28, (0.92; 1.79), P=0.149Notes:*95% confidence intervals are shown within brackets.aLogistic regression analyses were performed. The corrected analysis only included intention to quit smoking, as including more variables would have overloaded the model. The number of smokers in the general practice group followed up was too small (n=4) to yield reliable results when including recruitment channel in the model.bLinear mixed-model analyses were performed, corrected for age, sex, recruitment channel, smoking status, employment status, comorbidity (yes/no), MRC score, and intention to increase physical activity.cLinear mixed-model analyses were performed, corrected for age, sex, marital status, CCQ score, level of education, MRC score, and FTND score.dLinear mixed-model analyses were performed, corrected for age, sex, level of education, CCQ score, MRC score, number of quit attempts, and employment status.eLinear regression analyses were performed, corrected for age, sex, level of education, CCQ score, MRC score, and FTND score.fLinear mixed-model analyses were performed, corrected for age, sex, recruitment channel, smoking status, employment status, and MRC score.gLinear mixed-model analyses were performed, corrected for age, sex, recruitment channel, smoking status, employment status, COPD status, comorbidity (yes/no), marital status, level of physical activity, MRC score, and level of education.hLogistic regression analyses were performed, corrected for age, sex, recruitment channel, smoking status, employment status, COPD status, comorbidity (yes/no), marital status, level of physical activity, CCQ score, and level of education. Dyspnea status was recoded (0= participants who experienced a form of breathlessness and scored 1–5 on the MRC dyspnea score; 1= participants who indicated to have no breathlessness).Abbreviations: b, estimated mean difference; CCQ, Clinical COPD Questionnaire; FTND, Fagerström Test for Nicotine Dependence; MET, metabolic equivalent task; MRC, Medical Research Council; OR, odds ratio.Table 5Corrected effects of the per protocol analyses for primary outcomesPrimary outcomesAt least 1 component completedAt least 2 components completedAt least 3 components completed7-day point prevalence abstinenceaOR=1.75, (0.51; 6.00), P=0.371OR=3.57, (0.87; 14.73), P=0.078No reliable resultscMET minutes a weekbb=−101.58, (−653.10; 449.94), P=0.718b=120.92, (−683.86; 925.71), P=0.768b=813.44, (−383.29; 2,010.17), P=0.182Notes: 95% confidence interval between brackets.aLogistic regression analyses were performed. This analysis did not include covariates due to the small number of events (successful behavior changes).bLinear mixed-model analyses were performed, corrected for age, sex, recruitment channel, smoking status, employment status, comorbidity (yes/no), MRC score, intention to increase physical activity;cno events (successful behavior change) in the experimental group.Abbreviations: b, estimated mean difference; MET, metabolic equivalent task; OR, odds ratio.', 'title': 'A randomized controlled trial evaluating the effectiveness of a web-based, computer-tailored self-management intervention for people with or at risk for COPD.', 'date': '2015-06-20'}}
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Family Medicine & Preventive Care
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77
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Is malaria parasite prevalence higher, lower, or the same when comparing non‐pyrethroid‐like indoor residual spraying (IRS) plus insecticide‐treated nets (ITNs) to insecticide‐treated nets (ITNs) alone?
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lower
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low
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yes
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{'29229808': {'article_id': '29229808', 'content': 'Proc Natl Acad Sci U S AProc. Natl. Acad. Sci. U.S.ApnaspnasPNASProceedings of the National Academy of Sciences of the United States of America0027-84241091-6490National Academy of Sciences29229808574819420171381410.1073/pnas.1713814114PNAS PlusBiological SciencesMedical SciencesPNAS PlusImpact of insecticide resistance in Anopheles arabiensis on malaria incidence and prevalence in Sudan and the costs of mitigationInsecticide resistance impact on malariaKafyHmooda Totoab1IsmailBashir Adambc1MnzavaAbraham PeterdLinesJonathaneAbdinMogahid Shiekh EldinfgEltaherJihad SuliemanhBanagaAnuar OsmaniWestPhilippajBradleyJohnjCookJackiejThomasBrentkSubramaniamKrishanthikHemingwayJanetk2KnoxTessa BellamydMalikElfatih M.lYukichJoshua O.mDonnellyMartin Jameskn2KleinschmidtImmojo2aVector Unit, Ministry of Health, Khartoum, Sudan;bSchool of Biological Sciences, Universiti Sains Malaysia, 11800 Pulau Penang, Malaysia;cState Malaria Control Programme, Khartoum, Sudan;dMalaria Programme, World Health Organization, 1202 Geneva, Switzerland;eDepartment of Disease Control, London School of Hygiene and Tropical Medicine (LSHTM), London WC1E 7HT, United Kingdom;fKilimanjaro Christian Medical University College, Moshi, Tanzania;gDepartment of Information, Ministry of Health, Khartoum, Sudan;hMalaria Research and Training Centre, Sennar, Sudan;iState Malaria Control Programme, Gedarif, Sudan;jDepartment of Infectious Disease Epidemiology, LSHTM, London WC1E 7HT, United Kingdom;kDepartment of Vector Biology, Liverpool School of Tropical Medicine, Liverpool L35QA, United Kingdom;lMinistry of Health, Khartoum, Sudan;mCenter for Applied Malaria Research and Evaluation, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112;nWellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, United Kingdom;oSchool of Pathology, University of Witwatersrand, Braamfontein 2000, Johannesburg, South Africa2To whom correspondence may be addressed. Email: janet.hemingway@lstmed.ac.uk, martin.donnelly@lstmed.ac.uk, or Immo.Kleinschidmt@LSHTM.ac.uk.Contributed by Janet Hemingway, October 2, 2017 (sent for review November 12, 2016; reviewed by Christen Fornadel and Kimberly Lindblade)Author contributions: A.P.M., J.L., J.H., T.B.K., M.J.D., and I.K. designed research; H.T.K., B.A.I., M.S.E.A., J.S.E., A.O.B., B.T., K.S., E.M.M., and M.J.D. performed research; H.T.K., M.S.E.A., J.S.E., B.T., K.S., and M.J.D. contributed new reagents/analytic tools; P.W., J.B., J.C., E.M.M., J.O.Y., and I.K. analyzed data; and J.H., M.J.D., and I.K. wrote the paper.Reviewers: C.F., United States Agency for International Development; and K.L., Centers for Disease Control.1H.T.K. and B.A.I. contributed equally to this work.26122017111220171112201711452E11267E11275Copyright © 2017 the Author(s). Published by PNAS.2017This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).SignificanceEmerging insecticide resistance in malaria vectors could presage a catastrophic rebound in malaria morbidity and mortality. In areas of moderate levels of resistance to pyrethroids, long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) with a carbamate insecticide were significantly more effective than IRS with pyrethroid insecticide. The impact on the effectiveness of LLINs could not be quantified. The incremental cost of using a carbamate insecticide to which vectors are susceptible was US $0.65 per person protected per year, which is considered acceptable by international standards. While the WHO recommends that different interventions, where possible, should use different insecticide classes, these data alone should not be used as the basis for a policy change in vector control interventions.Insecticide-based interventions have contributed to ∼78% of the reduction in the malaria burden in sub-Saharan Africa since 2000. Insecticide resistance in malaria vectors could presage a catastrophic rebound in disease incidence and mortality. A major impediment to the implementation of insecticide resistance management strategies is that evidence of the impact of resistance on malaria disease burden is limited. A cluster randomized trial was conducted in Sudan with pyrethroid-resistant and carbamate-susceptible malaria vectors. Clusters were randomly allocated to receive either long-lasting insecticidal nets (LLINs) alone or LLINs in combination with indoor residual spraying (IRS) with a pyrethroid (deltamethrin) insecticide in the first year and a carbamate (bendiocarb) insecticide in the two subsequent years. Malaria incidence was monitored for 3 y through active case detection in cohorts of children aged 1 to <10 y. When deltamethrin was used for IRS, incidence rates in the LLIN + IRS arm and the LLIN-only arm were similar, with the IRS providing no additional protection [incidence rate ratio (IRR) = 1.0 (95% confidence interval [CI]: 0.36–3.0; P = 0.96)]. When bendiocarb was used for IRS, there was some evidence of additional protection [interaction IRR = 0.55 (95% CI: 0.40–0.76; P < 0.001)]. In conclusion, pyrethroid resistance may have had an impact on pyrethroid-based IRS. The study was not designed to assess whether resistance had an impact on LLINs. These data alone should not be used as the basis for any policy change in vector control interventions.malariapyrethroidresistanceinsecticideAnophelesBill and Melinda Gates Foundation (Bill & Melinda Gates Foundation)10000086548499.01United Nations (UN)100004420GEF ID:2546To date, the 21st century has seen an unprecedented reduction in the global burden of malaria. While still unacceptably high, disease incidence in sub-Saharan Africa has decreased by 42% from an average of 427 cases per 1,000 persons at risk in 2,000 to 246 cases per 1,000 persons at risk in 2015; infection prevalence with Plasmodium falciparum in children aged 2–10 y has halved from 33 to 16% over the same period (1). This has resulted in an estimated 1.2 billion fewer malaria cases and 6.2 million fewer malaria deaths. Recent estimates show that the widespread deployment of insecticide-based interventions has been, overwhelmingly, the driver of the reduction in malaria in Africa (2). Of the 663 million clinical cases estimated to have been averted due to malaria control interventions since 2000, 78% were attributable to insecticide-treated nets or indoor residual spraying (IRS). These two interventions have been massively scaled up since 2000 (1).Emerging insecticide resistance in the anopheline malaria vectors could presage a catastrophic rebound in disease incidence. At present, there are only four insecticide classes available to malaria control programs; pyrethroids, organochlorines, carbamates, and organophosphates, with pyrethroids being the only class currently recommended by the WHO for use on long-lasting insecticidal nets (LLINs). Pyrethroids and the organochlorine dichlorodiphenyltrichloroethane (DDT) share the same target site, the voltage-gated sodium channel, while carbamates and organophosphates are acetylcholinesterase inhibitors. Resistance to pyrethroids is extensive throughout sub-Saharan Africa, while resistance to the three nonpyrethroid chemical classes used for IRS is simultaneously emerging in many regions (3–5). Resistance arises mainly from a combination of mutations within mosquitoes at the target site of the insecticide and enhanced detoxification/excretion of the insecticide.While conclusive evidence that resistance is directly impacting epidemiological indicators of malaria is scanty, by the time such data are available, it may well be too late. To address the problem, the WHO developed the Global Plan for Insecticide Resistance Management in malaria vectors (GPIRM), which was designed to forestall a disastrous increase in malaria burden (6). Unfortunately, most malarious countries have yet to amend their vector control strategies to align with the GPIRM despite widespread resistance to pyrethroids (7). While this is partially due to the absence of compelling data on the impact of insecticide resistance, it also reflects the lack of viable alternatives to LLINs and current insecticides.A five-country study was established to provide quantitative estimates of the impact of resistance on malaria burden (8). One study was conducted in Galabat, Sudan. In Sudan, almost the entire population lives in areas with low to moderate transmission. Malaria transmission is seasonal and unstable. Countrywide, the majority of the population (80%), including urban populations, live in areas with <1% P. falciparum infection risk in children aged 2–10 y, while the remaining 20% of the population, residing mainly in the south of the country, experience meso- to hyperendemic risk of infection (9). Reported malaria cases were reduced from an estimated 7.5 million in 1990 (10) to 1.2 million in 2014. P. falciparum accounts for 95% of the malaria burden (9, 10), with Anopheles arabiensis being the main malaria vector (11).In Sudan, artemisinin-based combination therapy has been used for malaria treatment since 2004, with artesunate plus sulfadoxine/pyrimethamine as first-line treatment, artemether/lumefantrine as second-line therapy, and quinine for the treatment of complicated malaria (10). Malaria diagnosis is based on microscopy and rapid diagnostic tests (RDTs) (10). Between 2013 and 2015, 13 million LLINs were distributed, resulting in overall coverage of 92% of households with one LLIN per two persons in 2015 according to Ministry of Health reports. Therefore, the emergence of insecticide resistance (12, 13) is a major concern as it could severely compromise the effectiveness of vector control in Sudan.Galabat, Gedarif State, was considered suitable for this study since malaria is highly seasonal and more intense there than in many other parts of Sudan, and it had no previous history of IRS. Human settlements also facilitate the formation of well-separated clusters. Twenty-six villages were selected as study clusters and received universal coverage of LLINs. Thirteen of these clusters were randomly selected to receive IRS in addition to LLINs. In 2012, deltamethrin was used for IRS, which was replaced by bendiocarb in 2013 and 2014. The protective effect of bendiocarb, to which there was no resistance, could therefore be compared with the effect of deltamethrin, to which there was insecticide resistance, with the LLIN-only clusters acting as controls. For ethical reasons, it was not feasible to assess the impact of insecticide resistance on the overall effectiveness of LLINs since this would require a neutral arm with no vector control.This study aimed to quantify:i)The impact of switching to a nonpyrethroid IRS insecticide on the incidence and prevalence of malaria infection in an area of moderate pyrethroid resistanceii)The impact of phenotypic and genotypic insecticide resistance on the incidence and prevalence of malaria infectioniii)The impact of the addition of nonpyrethroid IRS insecticide on the evolution of pyrethroid resistance in an area of universal LLIN coverageiv)The cost of using nonpyrethoid IRS in addition to LLIN coverage to mitigate the negative consequences of pyrethroid resistance on the incidence of malaria infectionResultsIntervention Coverage.Following a census to determine the number of households and population size of the study area, 72,714 LLINs (PermaNet 2.0; Vestergaard) were distributed in the 26 clusters in April 2011 to protect 139,566 individuals based upon a universal coverage approach of one net for two people. Nets were replaced in June 2014 with 72,098 new LLINs for 122,647 people. An annual intervention assessment survey showed that household net ownership was 99.6% in 2012, 82.1% in 2013, and 98.6% in 2014. LLIN usage, defined as the proportion of affirmative responses to the question “Did this child sleep under an LLIN last night?”, was generally high and very similar in study arms (Table 1), but varied by season throughout the year (data not tabulated). IRS was conducted in August and again in late December of each year. In 2012, both spray rounds utilized deltamethrin (25 mg of active ingredient per square meter; Chema Industries), while in 2013 and 2014, bendiocarb (Ficam 80% WP; Bayer; 200 mg of active ingredient per square meter) was sprayed. IRS spray coverage was 99%, 82%, and 83% in the years 2012, 2013, and 2014, respectively, as determined by annual cross-sectional surveys. The IRS coverage reported in the LLIN arm is from the householder questionnaires. It is possible that this was from private spraying, but more likely that it represents householder misreporting.Table 1.LLIN usage, IRS coverage, insecticide resistance, prevalence of infection, and malaria incidence in cohort children by study arm and study yearLLIN-only armLLIN + IRS armVariable201220132014201220132014LLIN usage, % (child nights)79 (73,375)74 (75,040)82 (78,918)79 (73,738)75 (74,612)82 (78,888)IRS coverage, % (N)9 [1–45] (1,320)1 [0–2] (1,954)4 [1–27] (2,195)99 [96–100] (1,314)82 [75–87] (1,816)83 [68–91] (2,032)Mean age, y5.1 [4.9–5.4]5.4 [5.2–5.5]6.2 [6.1–6.3]5.2 [5.0–5.4]5.5 [5.4–5.7]6.3 [6.1–6.4]Malaria cases117155981268265Malaria incidence*45 [24–87]52 [26–101]33 [14–78]47 [20–110]27 [15–50]21 [10–43]Prevalence of infection, % (N)7 [3–14] (1,272)5 [2–10] (1,791)5 [3–9] (1,961)10 [6–16] (1,246)4 [2–7] (1,654)3 [2–5] (1,880)Deltamethrin mortality (clusters), % (references)65 [49–81] (6)90 [85–95] (6)56 [48–64] (11)60 [44–76] (5)84 [71–96] (6)68 [61–75] (13)95% CIs are shown in brackets.*Cases per 1,000 child-years.During the 3-y period from June 1, 2012–May 31, 2015, there were 643 episodes of malaria in 7,529 cohort children who were followed up cumulatively for 17,284 person-years. The mean age of cohort children was similar in the two study arms in each year, but rose gradually from 5.2 y in the first study year to 6.25 y in the third year (Table 1).Incidence of Malaria and Prevalence of Malaria Infection by Study Arm and by IRS Insecticide.Mean overall incidence was 37.2 per 1,000 person-years [95% confidence interval (CI): 24.3–56.9], declining from 49.9 per 1,000 person-years in year 1, to 36.1 per 1,000 person-years in year 2, to 26.8 per 1,000 person-years in year 3.Mean incidence in the LLIN + IRS study arm was 47.2 per 1,000 person-years when deltamethrin was used (2012), but was almost halved to an average of 24.6 per 1,000 person-years during the 2 y when bendiocarb was used (2013 and 2014) (Table 2). Over the same period in the LLIN-only arm, incidence remained virtually unchanged, from 44.4 per 1,000 person-years in year 1 to 42.1 per 1,000 person-years in years 2–3. Comparing incidence between study arms, the incidence rate ratio (IRR) for LLIN + deltamethrin compared with LLIN alone (2012) was 1.0 (95% CI: 0.36–2.97; P = 0.96); for LLIN + bendiocarb versus LLINs alone (2013), it was 0.60 (95% CI: 0.39–0.91; P = 0.017), while for 2014 (LLIN + bendiocarb versus LLIN), it was 0.69 (95% CI: 0.31–1.50; P = 0.35). For the two bendiocarb years combined, the IRR for IRS + LLIN versus. LLIN alone was 0.65 (95% CI: 0.44–0.96; P = 0.032). There was strong evidence that the change in insecticide modified the effect of IRS + LLIN versus LLIN alone: The IRR for comparing the effect of IRS + LLIN in 2013 and 2014 (bendiocarb) versus LLIN alone with the effect of IRS + LLIN in 2012 (deltamethrin) versus LLIN alone was 0.51 (95% CI: 0.35–0.73; P < 0.001) and 0.62 (95% CI: 0.42–0.93; P = 0.020), respectively (overall interaction P = 0.001; Table 2). The interaction IRR comparing the effect of IRS + LLIN in 2013–2014 combined (bendiocarb) versus LLIN alone with the effect of IRS + LLIN in 2012 (deltamethrin) versus LLIN alone was 0.55 (95% CI: 0.40–0.76; P < 0.001).Table 2.Effect of year, study arm, and IRS insecticide on malaria incidence, Galabat, Sudan, 2012–2014Effects by individual study yearsEffects comparing 2013/2014 (bendiocarb) with 2012 (deltamethrin)YearStudy armCasesMean incidence (range)Unadjusted rate ratio (95% CI)Adjusted rate ratio* (95% CI)†Bendiocarb effect‡PeriodStudy armMean incidenceAdjusted rate ratio* (95% CI)‡Bendiocarb effect‡2012LLIN11745 (24–87)1112012LLIN45 (4–87)1LLIN + Delta12647 (20–110)1.0 (0.36–2.95); P = 0.961.0 (0.36–2.97); P = 0.96LLIN + Delta47 (20–110)1.0 (0.36–2.97); P = 0.9612013LLIN15552 (26–101)110.51 (0.35–0.73); P < 0.0012013/2014LLIN42 (21–85)1LLIN + Bend8227 (15–50)0.53 (0.21–1.32); P = 0.170.60 (0.39–0.91); P = 0.0172014LLIN9833 (14–78)110.62 (0.42–0.93); P = 0.020LLIN + Bend25 (13–47)0.65 (0.44–0.96); P = 0.0320.55 (0.40–0.76); P < 0.001LLIN + Bend6521 (10–43)0.62 (0.20–1.95); P = 0.420.69 (0.31–1.50); P = 0.347*Adjusted for age at time of visit and, for 2013 and 2014, the rate in 2012.†Test to determine if the effect of IRS was different between years (P = 0.001).‡Test comparing the effect of bendiocarb IRS and deltamethrin IRS (P < 0.001).In a sensitivity analysis to test the robustness of the results to the possibility of undue influence exerted by participants who had multiple episodes of malaria, follow-up was restricted to the 550 first episodes observed (i.e., censoring follow-up after the first positive test result). This analysis produced very similar findings to those obtained from the full dataset (results not tabulated).In the three cross-sectional prevalence surveys that were conducted from September to October of each of the three study years, 2,518, 3,445, and 3,841 children were tested by RDTs, of whom 214 (8.5%), 146 (4.2%), and 162 (4.2%) tested positive in 2012, 2013, and 2014, respectively. Analogous results were recorded to those comparing malaria incidence (Table 3). In the IRS + LLIN study arm, mean prevalence of infection fell from 10.4% when deltamethrin was used for IRS (2012) to 3.4% when bendiocarb was used (years 2013/2014) (P = 0.002). Over the same period, mean prevalence in the LLIN-only arm declined more moderately and nonsignificantly from 6.7 to 5.0% (P = 0.41). Comparing prevalence between study arms, the odds ratio (OR) for LLIN + deltamethrin versus LLIN alone in 2012 was 2.11 (95% CI: 0.36–2.97; P = 0.96); for LLIN + bendiocarb versus LLINs alone (2013), it was 1.39 (95% CI: 0.32–6.14; P = 0.66), while for 2014, it was 0.37 (95% CI: 0.18–0.77; P = 0.007). For the two bendiocarb years combined, the OR for LLIN + IRS versus LLIN alone was 0.61 (95% CI: 0.29–1.27; P = 0.19). There was strong evidence that the change in insecticide modified the effect of IRS with an overall interaction of P = 0.001 for interaction tests applied to individual years (left-hand side of Table 3) and P < 0.001 for interaction tests applied to 2012 versus 2013/2014 combined (right-hand side of Table 3). The interaction OR for comparing the effect of IRS + LLIN in 2013 and 2014 (bendiocarb years) versus LLIN alone with the effect of IRS + LLIN in 2012 (deltamethrin) with LLIN alone was 0.55 (95% CI: 0.35–0.87; P = 0.01) and 0.30 (95% CI: 0.19–0.47; P < 0.001), respectively. The interaction OR comparing the effect of IRS + LLIN in 2013–2014 combined (versus LLIN alone) with the effect of IRS + LLIN in 2012 (deltamethrin) (versus LLIN alone) was 0.40 (95% CI: 0.27–0.59; P < 0.001).Table 3.Effect of year, study arm, and IRS insecticide on malaria prevalence, Galabat, Sudan, 2012–2014Effects by individual study yearsEffects comparing 2013/2014 (bendiocarb) with 2012 (deltamethrin)YearStudy armPrevalence, % (N)Unadjusted ORAdjusted OR*Bendiocarb effect†PeriodStudy armMean prevalence, %Adjusted OR*Bendiocarb effect‡2012LLIN7 [3–14] (1,272)112012 DeltaLLIN7 [3–14] (1,272)1LLIN + IRS10 [6–16] (1,246)1.61 [0.60–4.35]; P = 0.332.11 [0.85–5.22]; P = 0.11LLIN + IRS10 [6–16] (1,246)2.11 [0.85–5.22]; P = 0.1112013LLIN5 [2–10] (1,791]112013–2014 BendiocarbLLIN5 [2.8–8.6] (3,752)1LLIN + IRS4 [2–7] (1,654)0.86 [0.31–2.42]; P = 0.771.39 [0.32–6.14]; P = 0.660.55 [0.35–0.87]; P = 0.012014LLIN5 [3–9] (1,961)11LLIN +I RS3.4 [2.1–5.4] (3,534)0.61 [0.29–1.27]; P = 0.190.40 [0.27–0.59]; P < 0.001LLIN + IRS3 [2–5] (1,880)0.54 [0.26–1.13]; P = 0.0980.37 [0.18–0.77]; P = 0.0070.30 [0.19–0.47]; P < 0.00195% CIs are shown in brackets. Delta, deltamethrin.*Adjusted for age, study arm, and study period.†Overall likelihood ratio test, P < 0.0001 (test to determine if effect of IRS was different between years).‡Overall likelihood ratio test, P < 0.0001 (test comparing the effect of bendiocarb IRS and deltamethrin IRS).Association Between Resistance and Incidence and Prevalence of Malaria Infection.During the course of the study, 4,680 female An. arabiensis mosquitoes were phenotyped for deltamethrin susceptibility using WHO discriminating dose tests (14), with evidence of resistance to deltamethrin in both study arms (Fig. 1). The mean percentage mortality in the LLIN arm (65.0%, 95% CI: 44.6–85.3) was not significantly different (t = 0.425; df, 9; P = 0.68) from that of the LLIN + IRS arm (60%, 95% CI: 38.2–82.2) during year 1. The assay for the Vgsc-1014F mutation was successfully conducted in 1,847 of 1,872 specimens (Fig. 1). There was a subsequent decrease in allelic frequency (two-way ANOVA, P < 0.001), but no evidence of an association between allelic frequency and the study arm (two-way ANOVA, P > 0.05; Fig. 1). There was no evidence of nonnormality of the mortality or the allele frequency data.Fig. 1.Change in deltamethrin mortality (Upper) and Vgsc-1014F (Lower) across study years and between single (LLIN) and dual (LLIN + IRS) intervention arms. Box whisker plots show the median (bold line) and interquartile range (boxes). Phenotypic data were available from six LLIN and five LLIN + IRS clusters in 2012, six LLIN and six LLIN + IRS clusters in 2013, and 11 LLIN and 13 LLIN + IRS clusters in 2014. Genotypic data were available for all 26 clusters for all years. In 2014, there was significantly (P = 0.038) higher mortality (less resistance) in the LLIN + IRS arm (n = 13; mortality = 68%; 95% CI: 60.0–76.0) compared with the LLIN-only arm (n = 11; mortality = 56.1%; 95% CI: 47.1–64.9).The association between cluster- and year-specific bioassay survivorship (phenotypic resistance) and cluster- and year-specific malaria incidence in cohort children was assessed using multiple variable Poisson regression models, adjusting for study arm and study year. Unadjusted and adjusted IRRs show no association between malaria incidence in cohort children and deltamethrin bioassay survivorship in mosquitoes from corresponding clusters (Fig. 2 and Table 4). To estimate any effect that resistance in a particular year and a particular cluster may have had on the prevalence of infection as determined by annual cross-sectional surveys, logistic regression was carried out, again adjusting for study arm and study year. Unadjusted and adjusted ORs showed no evidence of any association between resistance as measured through bioassay survivorship and infection prevalence (Table 3).Fig. 2.Cluster-specific malaria case incidence and cluster-specific malaria infection prevalence plotted against cluster-specific phenotypic resistance (bioassay mortality after standard exposure to deltamethrin) and against cluster-specific Vgsc-1014F allele frequency for 2012, 2013, and 2014 in Galabat, Sudan.Table 4.Association between malaria prevalence and malaria incidence with genotypic and phenotypic resistance, respectively, from 2012–2014Resistance statusUnadjusted OR/ rate ratio (95% CI)Adjusted OR/rate ratio* (95% CI)Malaria prevalence\u2003L1014F linear, per 1% mutation1.009 (0.99–1.03); P = 0.350.992 (0.97–1.02); P = 0.51\u2003Deltamethrin linear, per 1% survivorship0.999 (0.970–1.029); P = 0.911.007 (0.98–1.04); P = 0.67Malaria incidence\u2003L1014F linear, per 1% mutation1.462 (0.411–5.196); P = 0.560.415 (0.065–2.665); P = 0.35\u2003Deltamethrin linear, per 1% survivorship0.995 (0.959–1.032); P = 0.780.991 (0.947–1.037); P = 0.70*Adjusted for variations in year and study arm. Note that for phenotype data, there is interyear variation in the number of clusters.Similar analysis was carried out to investigate whether malaria incidence and infection prevalence were associated with Vgsc-1014F frequency, measured in mosquito specimens collected in corresponding clusters and years. There was no evidence of any association between malaria incidence or infection prevalence on the one hand and Vgsc-1014F frequency on the other (Fig. 2 and Table 4).Subgroup analysis was carried out restricted to the combined data from the LLIN-only arm for all 3 y and to the LLIN + IRS arm for the year in which deltamethrin was sprayed. There was again no association between malaria incidence and Vgsc-1014F frequency (P = 0.59), between infection prevalence and Vgsc-1014F frequency (P = 0.39), between malaria incidence and bioassay survivorship (P = 0.85), and between infection prevalence and bioassay survivorship (P = 0.98).Association Between the Addition of Nonpyrethroid IRS Insecticide and the Evolution of Insecticide Resistance to Pyrethroids in an Area of Universal LLIN Coverage.It was only possible to conduct resistance phenotyping in 11 and 12 clusters in 2012 and 2013, respectively; this figure rose to 24 in 2014. In 2012 as well as in 2013 (the first year of bendiocarb spraying), there was no significant difference in mosquito deltamethrin susceptibility between intervention arms. However, in 2014, there was significantly higher mortality (less resistance) in the LLIN + IRS arm (n = 13; mortality = 68%; 95% CI: 60–76) compared with the LLIN arm (n = 11; mortality = 56%; 95% CI: 47–65) (P = 0.038) (Fig. 1). In all clusters across all years, An. arabiensis populations were susceptible to bendiocarb.Cost and Cost-Effectiveness.The cost of protection with LLIN only in Galabat was estimated to be US $2.16 per person-year, while the cost of protection per person-year with LLIN + IRS (deltamethrin) was estimated to be US $4.36. The cost per person-year of protection with LLIN + IRS (bendiocarb) was estimated to be US $5.01. These cost estimates translate into an incremental cost of switching from IRS with deltamethrin to IRS with bendiocarb in this study of US $0.65 per person-year. With the year 1 incidence of 49.9 episodes per 1,000 person-years, this translates to an incremental cost per case averted of US $29. Assuming a case fatality rate for malaria of 0.005, the incremental cost per death averted was approximately US $6,400 and an incremental cost per disability adjusted life year (DALY) averted of US $195. These results are well within accepted standards for highly cost-effective interventions for Sudan established by the WHO (15). Sensitivity analysis indicated that changes to discount rate, prices of LLINs, or allocation of shared costs did not affect the incremental costs of the insecticide switch and that reduction of the cost of bendiocarb to the cost of deltamethrin would have resulted in nearly identical costs per person protected, indicating that there were only minor differences in delivery costs for the intervention with bendiocarb. Sudan is an area with low malaria incidence, and it is likely that in other areas with a higher incidence and more severe pyrethroid resistance, such a switch is likely to be associated with even greater cost-effectiveness.DiscussionAssociation Between Malaria Incidence/Prevalence and Switching Active Ingredients.Malaria incidence was similar and malaria prevalence was higher in the study arm in which deltamethrin IRS was sprayed in addition to LLIN use, compared with LLINs alone. The higher prevalence in the LLIN + IRS arm was likely to be the result of an imperfect balance in the two study arms. In the following 2 y when IRS with bendiocarb replaced deltamethrin, there was a significant reduction in the LLIN + IRS arm compared with the year in which deltamethrin was used, while incidence and prevalence remained stable in the clusters that only had LLINs. Compared with the LLIN-only arm, incidence was significantly lower in the IRS + LLIN arm in the 2 y in which bendiocarb was used [IRR = 0.65 (95% CI: 0.44–0.96; P = 0.032)], and this effect differed significantly from the effect of IRS + LLIN with deltamethrin [interaction IRR = 0.55 (95% CI: 0.40–0.76; P < 0.001)]. Prevalence of infection was only lower in the IRS + LLIN arm compared with the LLIN-only arm of the study in 2014; however, again, there was very strong evidence that bendiocarb significantly modified the effect of IRS when comparing the OR between study arms during the years in which bendiocarb was used with the OR between study arms when deltamethrin was used [interaction OR = 0.40 (95% CI: 0.27–0.59; P < 0.001)]. Deltamethrin has been shown to be effective when used for IRS in a variety of settings (16–19). While we cannot completely discount differential longevity of the deltamethrin and bendiocarb IRS formulations used in Sudan, the expectation from previous studies is that the deltamethrin formulation would have a marginally longer residual life than the bendiocarb formulation. We conclude that the presence of pyrethroid resistance is a plausible explanation for the loss of effectiveness of deltamethrin IRS, resulting in substantially suboptimal malaria control. To date, there are few studies assessing the impact of insecticide resistance as the design of such studies is problematic because (i) the exposure of interest, resistance to an insecticide in the local vector, cannot be randomly allocated and (ii) it is unethical to knowingly protect a human population with IRS using an insecticide that is unlikely to be effective if alternatives are available. Evidence of the impact of insecticide resistance on IRS has thus far always been generated by retrospective studies (20, 21). Our data, when considered with two retrospective studies from South Africa and Uganda, where the primary vectors were Anopheles funestus and Anopheles gambiae, respectively, provide further evidence that pyrethroid resistance is highly likely to be compromising the effectiveness of IRS.The impact of resistance in KwaZulu-Natal, South Africa, was more marked than that observed in the current study, with a near 10-fold increase in annual malaria cases witnessed from 1995 to 2000 following a switch from DDT to deltamethrin (21). Insecticide susceptibility tests later showed that there was resistance to pyrethroids in An. funestus, a vector that had previously been driven to near extinction in KwaZulu-Natal but that resurged following the change to pyrethroid IRS (22). Subsequent reversion back to IRS with DDT in 2000 was followed by a rapid decline in cases that was maintained in subsequent years (23). In a study by Kigozi et al. (20) in Uganda, routinely collected malaria health facility data were compared temporally in relation to the insecticide used in IRS: five rounds of IRS spraying DDT (n = 1), pyrethroid (n = 1), or bendiocarb (n = 3). There was known resistance to both pyrethroids and DDT, but not to bendiocarb, in the area. Small decreases in the odds of malaria infection were observed following both DDT and pyrethroid spraying, with the decrease in malaria infection being much greater following the bendiocarb spray round.The strength of the study described here was the ability to compare the change in incidence in the IRS clusters with changes in incidence in 13 contemporaneous control group clusters, which had been randomly selected and which were similar in most respects to the intervention group. The reduction in both malaria incidence and prevalence after the introduction of the carbamate insecticide may therefore be attributable to this change in insecticide. Since IRS with deltamethrin and IRS with bendiocarb are effective insecticides in settings with susceptible vectors (17, 18, 24, 25), the lack of impact of the deltamethrin IRS may be due to the presence of deltamethrin resistance in the study area. As would be expected from earlier studies (26, 27), despite resistance, some protection against malaria was provided in both study arms by high coverage with LLINs.The IRS with bendiocarb in this study provided very similar protection in addition to LLINs to that estimated in a recent cluster randomized trial in Tanzania (28). This study serves as reminder of the potential consequences of using failing insecticides, particularly if no other preventive measures are in place, and the need for insecticide policy to be informed by appropriate susceptibility testing (6).Association Between Resistance and Malaria Incidence/Infection Prevalence.There was no evidence of an association between malaria rates and insecticide resistance measured phenotypically or genotypically for target-site resistance (as Vgsc-1014F frequency). An association between malaria burden and pyrethroid insecticide resistance was expected in clusters with pyrethroid-treated LLINs only or in clusters receiving LLINs and IRS with pyrethroid. The study lacked power to detect such an association due to a number of factors: (i) the range in pyrethroid resistance in the study area may have been too small; (ii) the effect of insecticide resistance on the effectiveness of LLINs may be relatively modest in settings of moderate pyrethroid resistance; (iii) bioassay data were not available in all clusters in each study year; and (iv) bioassay survivorship is an imprecise measure of the strength of resistance (29), despite its wide use for detecting the presence of resistance in a mosquito population. Our analysis of malaria incidence and prevalence in relation to insecticide resistance relied on detecting a dose–response association between the two variables; if the latter is inadequately quantified through bioassay survivorship or Vgsc-1014F frequency, then such a trend is unlikely to be significant.Previous studies have shown that insecticide-treated nets still provide protection against malaria infection even in settings of vector resistance to pyrethroids. A meta-analysis using entomological data (26) concluded that insecticide treated nets are a more effective form of vector control than untreated nets despite insecticide resistance. A study in Malawi found that children sleeping under LLINs suffered significantly fewer malaria episodes than their counterparts who did not sleep under nets in an area where the predominant malaria vector species, An. funestus and An. arabiensis, showed moderate to high levels of pyrethroid resistance (27).Cost and Cost-Effectiveness.The current study also demonstrated the relative cost-effectiveness of switching active ingredients to mitigate the potential effects of insecticide resistance on malaria incidence. It is, to date, the only study of which we are aware that does so using direct field evidence. Even in a relatively low transmission area, such as Galabat, a switch to the marginally more expensive bendiocarb insecticide is justified.Insecticide Combination and the Evolution of Resistance.A positive finding was modest evidence of retardation in the speed of evolution of insecticide resistance when two active ingredients with differing modes of actions were used in the LLIN + IRS arm. This is important for malaria control program managers as they struggle to develop plans for the monitoring and management of insecticide resistance in line with WHO GPIRM recommendations (6). Curiously, across our study site, there was a significant decrease in the Vgsc-1014F resistance marker frequency. While there are a number of instances of kdr markers sweeping rapidly to fixation (30–32), the obverse trend shown here has not been reported elsewhere. There are numerous studies showing that in An. arabiensis, Vgsc-1014F is a strong predictor of pyrethroid resistance (33), so this may suggest a decline in its importance in conferring a resistant phenotype due to the emergence of additional resistance mechanism(s).Limitations.For ethical reasons, it was not possible to conduct a trial with a neutral control arm; therefore, the effectiveness of the IRS alone could not be directly assessed. A trial randomizing clusters to the two insecticides would have provided a more direct contemporaneous comparison of deltamethrin to bendiocarb. Instead, the opportunity of comparing each insecticide against the same LLIN-alone control arm arose when insecticide needed to be switched due to the presence of pyrethroid resistance in the area. This design lacks the strength of evidence provided by a direct comparison; however, this shortcoming was compensated for, at least in part, by the contemporaneous comparison with the randomly selected LLIN-only clusters to control for temporal change in malaria transmission. The evidence of a change in the effect of IRS coinciding with the switch to bendiocarb was statistically very strong.ConclusionIn summary this trial has shown the following: (i) loss of effectiveness of pyrethroid IRS is likely to be associated with pyrethroid resistance in malaria vectors; (ii) IRS effectiveness can be restored by switching to an insecticide to which vectors are fully susceptible for an incremental cost that is considered attractive by international standards; and (iii) modest retardation to the speed of pyrethroid resistance development may be achieved with appropriate combinations of LLINs and nonpyrethroid IRS, compared with using LLINs alone.Materials and MethodsStudy Site.Galabat is located ∼80 km from Gedarif town and borders Ethiopia. A baseline household census estimated that the area comprised ∼119,000 households in 197 villages with a total of 600,000 inhabitants who are predominantly dependent on rain-fed agriculture. Climatically, the area is within the dry savannah region, with annual rainfall ranging between 700 mm and 1,200 mm and concentrated in a short rainy season from June to September. Average daily temperatures range between 31 °C and 44 °C (34). Malaria transmission is seasonal from September to November, with P. falciparum prevalence between 1% and 10% in 2- to 10-y-old children (9). An. arabiensis is the main vector of malaria in the area, with An. funestus implicated as having a minor role in malaria transmission (34). Before this study, LLINs were the only form of vector control in Galabat.Treatment for malaria in the area is provided by 101 public sector health facilities, including 7 referral hospitals, 24 health centers, 70 health units, and 20 villages with home-based management of malaria. Diagnosis of suspected cases is based on RDTs at the majority of health and home-based management facilities, while microscopy is used at 20 facilities in the area.Study Design.The Galabat study is loosely linked to a larger multicountry study on the implications of insecticide resistance that has been described previously (8). The opportunity to compare the two insecticides arose when deltamethrin IRS had to be replaced with bendiocarb IRS. The original objective of the Galabat trial was to investigate whether IRS in combination with LLINs provided additional protection against malaria compared with LLINs alone. With 13 clusters per arm and 200 children per cluster followed up for 3 y, the trial had 80% power to observe a 38% reduction in malaria incidence or more in the LLIN + IRS arm compared with the LLIN-only arm, assuming a mean incidence of 30 per 1,000 person-years and a coefficient of variation of 0.3 between study clusters. Twenty-six villages were selected from a total of 197 to form clusters, each consisting of at least 500 households, and with the distance between the edges of adjoining clusters being at least 3 km (Fig. 3). In 2010, a baseline malaria indicator survey testing for P. falciparum infection using malaria RDTs (SD BIOLINE-Malaria Ag P.f/P.v.; Standard Diagnostics, Inc.) was carried out on a sample of 100 children <10 y of age in each of the 26 clusters. At the same time, pyrethrum spray catches were made in houses, from which a sample of 24 An. arabiensis mosquitoes from each cluster was screened for the pyrethroid resistance-associated mutations in the voltage-gated sodium channels Vgsc-1014F and Vgsc-1014S using established molecular diagnostic techniques (33).Fig. 3.Map of the study area in Galabat, southeastern Sudan. Triangles denote clusters with LLIN only, and circles denote clusters with LLIN + IRS.LLINs with a deltamethrin concentration of 55 mg of active ingredient per square meter (PermaNet 2.0) were distributed in April 2011 in all 26 study clusters to reach levels required for universal coverage, defined as one net for every two people. The LLINs were replaced with new nets of the same type in all clusters in June 2014. In 2012, clusters were randomly allocated to two study arms using restricted randomization (35, 36) to ensure that the two study arms were balanced on a number of criteria, including baseline frequency of the Vgsc-1014F mutation, baseline prevalence of infection, baseline use of LLINs, and access to health facilities. One study arm (n = 13 clusters) retained universal coverage of LLINs only, while the second arm (n = 13 clusters) received two rounds of IRS in addition to LLINs. The first round of IRS was in August of each year to cover the main transmission season (September to November), with the second round in late December. In 2012, deltamethrin insecticide (Wettable Powder 25%) was used in both IRS rounds; in 2013 and 2014, bendiocarb (Ficam WP 80%) was sprayed. Bendiocarb, a carbamate, is an acetylcholinesterase antagonist, as opposed to deltamethrin, which targets the mosquito Vgsc. While LLINs target mosquitoes that are seeking a blood meal, IRS targets mosquitoes that rest indoors either before or after blood-feeding. Quality assurance of both IRS and LLIN interventions was conducted following WHO guidelines (14) using a susceptible laboratory strain of An. arabiensis raised in the insectaries of the Sennar Malaria Research and Training Centre.Insecticide Resistance.Over the course of the study, two estimates of insecticide resistance were made yearly in each cluster: One, termed phenotypic resistance, was reliant upon collecting live mosquitoes and ascertaining their susceptibility to standard dosages of deltamethrin and bendiocarb; the other, termed genotypic resistance, involved screening for Vgsc-1014F (reviewed in ref. 33). Anopheles larvae and pupae were collected annually (2012–2014) during the rainy season. All larvae and pupae were reared to adults in a field insectary until used for insecticide susceptibility tests. Pyrethrum spray catches were also performed to collect adult Anopheles mosquitoes. Phenotypic assays for deltamethrin and bendiocarb were performed following the standard WHO discriminating dose tests (14, 37). All susceptibility tests were conducted under laboratory conditions at temperatures ranging from 24.8 to 27.1 °C and relative humidity ranging from 75.4 to 79.8%.An. gambiae complex species, the main vector, were identified to species status, with An. arabiensis the only species observed, using a standard PCR assay (38). Twenty-four An. arabiensis females per cluster were selected at random for Vgsc-1014F genotyping to estimate a cluster-specific resistance marker frequency (39).Active Case Detection.In each cluster, a community health worker (CHW) was appointed, and ∼200 children aged between 6 mo and <10 y were recruited into cohorts after explaining the study procedures to caregivers and after obtaining written informed consent. Older children were asked to assent to recruitment. CHWs visited cohort members weekly during the peak of the malaria season (September to November) and fortnightly during the remainder of the year, for a total of 30 annual visits. Cohort children who were reported to be febrile at the time of a visit had their temperature taken. Children who had a confirmed fever at the time of the visit, or a reported fever during the period since the last visit, were referred to the local health facility to be tested for malaria parasites, or were tested by the CHW using an RDT when no local facility was available. Local health facilities used either RDTs or microscopy to test for malaria parasites. If caregivers, upon questioning, reported that a child had visited the health facility for a febrile illness during the period since the last visit, the CHW visited the health facility to determine if the child had a blood test that confirmed a diagnosis of malaria. Each visit by a CHW and each clinic attendance resulting in a definitive diagnosis of malaria were recorded in the cohort register, which was collected at regular intervals for entry into an MS Access database at a central location. A study coordinator carried out regular supervisory visits to CHWs to verify the quality of data collection. Upon reaching the age of 10 y, cohort children were replaced by younger children from the same household or from another household if no younger sibling was available.Prevalence of Infection.Once each year, during September to October, cohort children were tested for P. falciparum infection using RDTs (SD BIOLINE-Malaria Ag P.f/P.v.), irrespective of symptoms. A random sample of 50% of cohort members was selected in 2012, while all cohort children who were present at the time of the survey were screened in 2013 and 2014. Any child who tested positive was referred to the local health facility for treatment.Statistical Analysis.Malaria case incidence was estimated as the number of cases per child-year of follow-up. IRRs were calculated comparing incidence between study arms for each study year, and for the 2 y combined during which bendiocarb IRS was used. Effect modification (interaction) between study arm and study year was investigated to determine the differential effect of IRS + LLINs with bendiocarb compared with IRS + LLINs with deltamethrin versus LLINs alone. Multiple variable Poisson regression was used to adjust the effect of study arm for age of child at time of visit and, for 2013 and 2014, for incidence rate in 2012. To assess whether malaria incidence was associated with insecticide resistance, IRRs were calculated per 1% change in cluster-specific vector susceptibility (mosquito mortality) and per 1% change in cluster specific Vgsc-1014F allele frequency. For this analysis, year and cluster-specific insecticide resistance measurements were linked to year and cluster-specific incidence.For cross-sectional prevalence of infection data, analogous analyses were carried out using logistic regression to estimate ORs.Multiple episodes of malaria in the same child were rare; any consecutive positive test results were counted as one episode since the second positive test result could be either a false-positive result from RDTs that measure parasite protein retained from an already cleared infection or the result of a treatment failure. To test the robustness of these results against the possibility of undue influence exerted by participants who had multiple episodes of malaria, the analysis was repeated but restricted to the 550 first-time episodes that were observed in the same cohort over the same period ( i.e., excluding children from further follow-up after their first positive test result). To calculate appropriate SEs of estimated means, a robust variance estimator using the first-order Taylor-series linearization method was used to account for variation between clusters (40, 41). Poisson regression and logistic regression were performed using random effects models.To compare the differences in mean mortalities and Vgsc-1014F allele frequencies between the two intervention arms, t tests were used, while ANOVA was used to compare the differences between years. The Shapiro–Wilks test was used to assess whether mortality and allele frequency data deviated from the normal distribution.Cost Data Collection Tools and Indicators.A microcosting (ingredients approach) activities-based framework was applied to the development of cost-collection tools. Key-informant interviews and record reviews were conducted to identify all of the activities and resources needed that were expected to be utilized during the course of the trial. Care was taken to exclude activities that were specifically related to research and not necessary for the provision or performance of the intervention; these included enhanced case finding and enhanced vector surveillance beyond what was necessary for routine use of IRS or LLINs. A standardized instrument for the collection of resource quantities and prices was developed for use at the national (central), state, and locality levels. The instrument was employed by staff of the Federal Ministry of Health Integrated Vector Management Unit to collect information on resource usage at each level of the health system.Analysis of Cost Data.Resource use was quantified and valued in Sudanese pounds (SDG) in the year during which the resource use occurred. Costs were converted to US dollars using the prevailing average exchange rate for the period. All costs were valued in 2011 US dollars, after adjusting for inflation using the consumer price index for Sudan. Prices derived from the WHO-CHOICE (choosing interventions that are cost effective) database (15) were converted from international dollars using a purchasing power parity (PPP)-to-local currency ratio (1 international dollar to 1.28 SDG) for 2009.In all cases, economic costs are presented, which are also known as opportunity costs. Economic costs represent the value of a given resource in its next most appropriate use. As such, capital costs, including vehicles, buildings, LLINs, and spray equipment, were annualized and discounted using assumed lifetimes and a social discount rate of 3%.Cost Outcomes Sensitivity Analysis.Two types of outcome were measured: a process measure, numbers of persons living in clusters with vector control per year (or person-years of protection), and the effectiveness of the interventions in terms of incident cases of malaria prevented.Because most cost models and assessments are dependent on assumptions about quantities of resources used, prices of resources, and allocation of shared costs, it is necessary to conduct a sensitivity analysis to attempt to determine the robustness of the cost assessment to various assumptions made during development of the model. A one-way sensitivity analysis was conducted to determine the robustness of the cost model to various assumptions made during the assessment. Parameters, which were varied, included discount rate, prices of LLINs and insecticides used, allocation of shared costs, numbers of persons protected by the interventions, and baseline malaria incidence.Ethics.The study was approved by the Ethics Committees of the London School of Hygiene and Tropical Medicine (approval no. 5825) and Federal Ministry of Health, Sudan (approval no.116-12-09). The study was registered on ClinicalTrials.com (registration no. NCT01713517).This project was supported financially by the United Nations Environment Programme/Global Environment Facility project: Demonstration of Sustainable Alternatives to DDT and Strengthening of National Vector Control Capabilities in the Middle East and North Africa (GEF ID 2546), and by the Bill and Melinda Gates Foundation (Grant 48499.01). This research forms part of a multicountry study coordinated by the WHO Global Malaria Programme. Additional technical support was provided by the WHO Regional Office for the Eastern Mediterranean and the WHO country office in Sudan.The authors declare no conflict of interest.1World Health Organization2015World Malaria Report 2015WHOGeneva2BhattS2015The effect of malaria control on Plasmodium falciparum in Africa between 2000 and 2015Nature526207211263750083MitchellSN2012Identification and validation of a gene causing cross-resistance between insecticide classes in Anopheles gambiae from GhanaProc Natl Acad Sci USA10961476152224607954MitchellSN2014Metabolic and target-site mechanisms combine to confer strong DDT resistance in Anopheles gambiaePLoS One9e92662246757975EdiCVAKoudouBGJonesCMWeetmanDRansonH2012Multiple-insecticide resistance in Anopheles gambiae mosquitoes, Southern Côte d’IvoireEmerg Infect Dis1815081511229324786World Health Organization-GMP2012Global Plan for Insecticide Resistance Management in Malaria VectorsWHOGeneva7RansonHLissendenN2016Insecticide resistance in 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We investigated whether the combination of long-lasting insecticidal mosquito nets (LLINs) with indoor residual spraying (IRS) or carbamate-treated plastic sheeting (CTPS) conferred enhanced protection against malaria and better management of pyrethroid-resistance in vectors than did LLINs alone.\nWe did a cluster randomised controlled trial in 28 villages in southern Benin, west Africa. Inclusion criteria of the villages were moderate level of pyrethroid resistance in malaria vectors and minimum distance between villages of 2 km. We assessed four malaria vector control interventions: LLIN targeted coverage to pregnant women and children younger than 6 years (TLLIN, reference group), LLIN universal coverage of all sleeping units (ULLIN), TLLIN plus full coverage of carbamate-IRS applied every 8 months (TLLIN+IRS), and ULLIN plus full coverage of CTPS lined up to the upper part of the household walls (ULLIN+CTPS). The interventions were allocated to villages by a block randomisation on the basis of preliminary surveys and children of each village were randomly selected to participate with computer-generated numbers. The primary endpoint was the incidence density rate of Plasmodium falciparum clinical malaria in children younger than 6 years as was analysed by Poisson regression taking into account the effect of age and the sampling design with a generalised estimating equation approach. Clinical and parasitological information were obtained by active case detection of malaria episodes during 12 periods of 6 consecutive days scheduled at six weekly intervals and by cross-sectional surveys of asymptomatic plasmodial infections. Children or study investigators were not masked to study group. This study is registered with Current Controlled Trials, number ISRCTN07404145.\nOf 58 villages assessed, 28 were randomly assigned to intervention groups. 413-429 children were followed up in each intervention group for 18 months. The clinical incidence density of malaria was not reduced in the children from the ULLIN group (incidence density rate 0·95, 95% CI 0·67-1·36, p=0·79), nor in those from the TLLIN+IRS group (1·32, 0·90-1·93, p=0·15) or from the ULLIN+CTPS group (1·05, 0·75-1·48, p=0·77) compared with the reference group (TLLIN). The same trend was observed with the prevalence and parasite density of asymptomatic infections (non significant regression coefficients).\nNo significant benefit for reducing malaria morbidity, infection, and transmission was reported when combining LLIN+IRS or LLIN+CTPS compared with a background of LLIN coverage. These findings are important for national malaria control programmes and should help the design of more cost-effective strategies for malaria control and elimination.\nMinistère Français des Affaires Etrangères et Européennes (FSP project 2006-22), Institut de Recherche pour le Développement, President's Malaria Initiative (PMI) of US Governement.", 'title': 'Combination of malaria vector control interventions in pyrethroid resistance area in Benin: a cluster randomised controlled trial.', 'date': '2012-06-12'}, '24736370': {'article_id': '24736370', 'content': "PLoS MedPLoS MedPLoSplosmedPLoS Medicine1549-12771549-1676Public Library of ScienceSan Francisco, USA247363703988001PMEDICINE-D-13-0370410.1371/journal.pmed.1001630Research ArticleBiology and Life SciencesOrganismsAnimalsInvertebratesArthropodaInsectsMosquitoesProtozoansParasitic ProtozoansMalarial ParasitesPlasmodium FalciparumMedicine and Health SciencesEpidemiologyDisease VectorsInfectious Disease EpidemiologyInfectious DiseasesInfectious Disease ControlParasitic DiseasesMalariaIndoor Residual Spraying in Combination with Insecticide-Treated Nets Compared to Insecticide-Treated Nets Alone for Protection against Malaria: A Cluster Randomised Trial in TanzaniaCombined Use of IRS and ITNs against MalariaWestPhilippa A.\n1\n\n*\nProtopopoffNatacha\n2\nWrightAlexandra\n2\nKivajuZuhura\n3\nTigererwaRobinson\n4\nMoshaFranklin W.\n5\nKisinzaWilliam\n3\nRowlandMark\n2\nKleinschmidtImmo\n6\n1Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, United Kingdom2Department of Disease Control, London School of Hygiene & Tropical Medicine, London, United Kingdom3National Institute for Medical Research, Amani Medical Research Centre, Muheza, Tanzania4Muleba District Medical Office, Department of Health, Muleba, Tanzania5Kilimanjaro Christian Medical College, Tumaini University, Moshi, Tanzania6Medical Research Council Tropical Epidemiology Group, London School of Hygiene & Tropical Medicine, London, United KingdomGethingPeter W.Academic EditorUniversity of Oxford, United Kingdom* E-mail: philippa.west@lshtm.ac.ukThe authors have declared that no competing interests exist.Conceived and designed the experiments: IK MR NP PW FM WK. Performed the experiments: PW NP AW RT ZK. Analyzed the data: PW NP. Contributed reagents/materials/analysis tools: IK. Wrote the first draft of the manuscript: PW. Contributed to the writing of the manuscript: PW IK MR NP. ICMJE criteria for authorship read and met: IK MR NP PW FM WK AW RT ZK. Agree with manuscript results and conclusions: IK MR NP PW FM WK AW RT ZK. Provided major input into the design and interpretation of the data analysis: IK. Provided overall coordination of the project: MR. Critically revised the manuscript for important content: AW RT ZK FM WK.420141542014114e100163015112013732014© 2014 West et al2014West et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.Philippa West and colleagues compare Plasmodium falciparum infection prevalence in children, anemia in young children, and entomological inoculation rate between study arms.\nPlease see later in the article for the Editors' Summary\nBackgroundInsecticide-treated nets (ITNs) and indoor residual spraying (IRS) of houses provide effective malaria transmission control. There is conflicting evidence about whether it is more beneficial to provide both interventions in combination. A cluster randomised controlled trial was conducted to investigate whether the combination provides added protection compared to ITNs alone.Methods and FindingsIn northwest Tanzania, 50 clusters (village areas) were randomly allocated to ITNs only or ITNs and IRS. Dwellings in the ITN+IRS arm were sprayed with two rounds of bendiocarb in 2012. Plasmodium falciparum prevalence rate (PfPR) in children 0.5–14 y old (primary outcome) and anaemia in children <5 y old (secondary outcome) were compared between study arms using three cross-sectional household surveys in 2012. Entomological inoculation rate (secondary outcome) was compared between study arms.IRS coverage was approximately 90%. ITN use ranged from 36% to 50%. In intention-to-treat analysis, mean PfPR was 13% in the ITN+IRS arm and 26% in the ITN only arm, odds ratio\u200a=\u200a0.43 (95% CI 0.19–0.97, n\u200a=\u200a13,146). The strongest effect was observed in the peak transmission season, 6 mo after the first IRS. Subgroup analysis showed that ITN users were additionally protected if their houses were sprayed. Mean monthly entomological inoculation rate was non-significantly lower in the ITN+IRS arm than in the ITN only arm, rate ratio\u200a=\u200a0.17 (95% CI 0.03–1.08).ConclusionsThis is the first randomised trial to our knowledge that reports significant added protection from combining IRS and ITNs compared to ITNs alone. The effect is likely to be attributable to IRS providing added protection to ITN users as well as compensating for inadequate ITN use. Policy makers should consider deploying IRS in combination with ITNs to control transmission if local ITN strategies on their own are insufficiently effective. Given the uncertain generalisability of these findings, it would be prudent for malaria control programmes to evaluate the cost-effectiveness of deploying the combination.Trial registration\nwww.ClinicalTrials.gov\nNCT01697852\n\nPlease see later in the article for the Editors' Summary\nEditors' SummaryBackgroundEvery year, more than 200 million cases of malaria occur worldwide, and more than 600,000 people, mainly children living in sub-Saharan Africa, die from this parasitic infection. Malaria parasites, which are transmitted to people through the bites of infected night-flying mosquitoes, cause a characteristic fever that needs to be treated promptly with antimalarial drugs to prevent anaemia (a reduction in red blood cell numbers) and organ damage. Prompt treatment also helps to reduce malaria transmission, but the mainstays of global malaria control efforts are the provision of insecticide-treated nets (ITNs) for people to sleep under to avoid mosquito bites, and indoor residual spraying (IRS) of houses with insecticides, which prevents mosquitoes from resting in houses. Both approaches have been scaled up in the past decade. About 54% of households in Africa now own at least one ITN, and 8% of at-risk populations are protected by IRS. As a result of the widespread deployment of these preventative tools and the increased availability of effective antimalarial drugs, malaria-related deaths in Africa fell by 45% between 2000 and 2012.Why Was This Study Done?Some countries have chosen to use ITNs and IRS in combination, reasoning that this will increase the proportion of individuals who are protected by at least one intervention and may provide additional protection to people using both interventions rather than one alone. However, providing both interventions is costly, so it is important to know whether this rationale is correct. In this cluster randomised controlled trial (a study that compares outcomes of groups of people randomly assigned to receive different interventions) undertaken in the Muleba District of Tanzania during 2012, the researchers investigate whether ITNs plus IRS provide more protection against malaria than ITNs alone. Malaria transmission occurs throughout the year in Muleba District but peaks after the October–December and March–May rains. Ninety-one percent of the district's households own at least one ITN, and 58% of households own enough ITNs to cover all their sleeping places. Annual rounds of IRS have been conducted in the region since 2007.What Did the Researchers Do and Find?The researchers allocated 50 communities to the ITN intervention or to the ITN+IRS intervention. Dwellings allocated to ITN+IRS were sprayed with insecticide just before each of the malaria transmission peaks in 2012. The researchers used household surveys to collect information about ITN coverage in the study population, the proportion of children aged 0.5–14 years infected with the malaria parasite Plasmodium falciparum (the prevalence of infection), and the proportion of children under five years old with anaemia. IRS coverage in the ITN+IRS arm was approximately 90%, and 50% of the children in both intervention arms used ITNs at the start of the trial, declining to 36% at the end of the study. In an intention-to-treat analysis (which assumed that all study participants got the planned intervention), the average prevalence of infection was 13% in the ITN+IRS arm and 26% in the ITN arm. A per-protocol analysis (which considered data only from participants who received their allocated intervention) indicated that the combined intervention had a statistically significant protective effect on the prevalence of infection compared to ITNs alone (an effect that is unlikely to have arisen by chance). Finally, the proportion of young children with anaemia was lower in the ITN+IRS arm than in the ITN arm, but this effect was not statistically significant.What Do These Findings Mean?These findings provide evidence that IRS, when used in combination with ITNs, can provide better protection against malaria infection than ITNs used alone. This effect is likely to be the result of IRS providing added protection to ITN users as well as compensating for inadequate ITN use. The findings also suggest that the combination of interventions may reduce the prevalence of anaemia better than ITNs alone, but this result needs to be confirmed. Additional trials are also needed to investigate whether ITN+IRS compared to ITN reduces clinical cases of malaria, and whether similar effects are seen in other settings. Moreover, the cost-effectiveness of ITN+IRS and ITN alone needs to be compared. For now, though, these findings suggest that national malaria control programs should consider implementing IRS in combination with ITNs if local ITN strategies alone are insufficiently effective and cannot be improved.Additional InformationPlease access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001630.Information is available from the World Health Organization on malaria (in several languages), including information on insecticide-treated bed nets and indoor residual spraying; the World Malaria Report 2013 provides details of the current global malaria situationThe US Centers for Disease Control and Prevention provides information on malaria, on insecticide-treated bed nets, and on indoor residual spraying; it also provides a selection of personal stories about malariaInformation is available from the Roll Back Malaria Partnership on the global control of malaria and on the Global Malaria Action Plan (in English and French); its website includes fact sheets about malaria in Africa and about nets and insecticides\nMedlinePlus provides links to additional information on malaria (in English and Spanish)PW is funded by the Thorpe legacy studentship from the Malaria Centre (http://malaria.lshtm.ac.uk/). This study was funded by the United States Agency for International Development (http://www.usaid.gov/) under Translating Research into Action, Cooperative Agreement No. GHS-A-00-09-00015-00. This study was made possible by the support of the American people through the United States Agency for International Development (USAID). The findings of this study are the sole responsibility of the authors and do not necessarily reflect the views of USAID or the United States Government. IRS was funded by PMI and conducted by RTI, independent of the study. ITNs were distributed by a national UCC, lead by the Ministry of Health and Social Welfare (Tanzania), and primarily financed by the GFATM, with some support from PMI. IK receives support from the Medical Research Council and Department For International Development (MR/K012126/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.IntroductionIn the past decade, insecticide-treated net (ITN) distribution has been scaled up across Africa in line with the Abuja Declaration in 2000 [1]. The percentage of households that owned at least one ITN in Africa increased from 3% in 2000 to 54% in 2013. The World Health Organization (WHO) policy that ITNs should be provided to everyone in malaria risk areas (universal coverage) [2] has been adopted by 34 of the 44 malaria endemic countries in Africa [3]. Indoor residual spraying (IRS) of houses, the second major vector control tool used to prevent malaria, has similarly been scaled up. The proportion of at-risk populations protected by IRS increased from less than 5% in 2005 to 8% in 2012 [3]. As a result of the increase in the deployment of these preventive tools and the increased availability and use of artemisinin-based combination therapies, malaria-related mortality fell by 45% between 2000 and 2012 in Africa, but there remained an estimated 165 million cases and 562,000 deaths due to malaria in 2012 [3].In an attempt to reduce the malaria burden further, a number of countries have chosen to use ITNs and IRS in combination. Fifty-seven countries, 31 of which are in Africa, use both IRS and ITNs, in at least some areas [3]. Applying ITNs and IRS in the same area can increase the proportion of individuals who are protected by at least one intervention or, more optimally, may provide additional protection for those protected by both interventions compared to those receiving one method alone [4]–[7].Since the cost of implementing both IRS and universal coverage of ITNs is much greater than the cost of implementing only one of the interventions [8], it is important to know what extra protection is gained by adding a second intervention, to help national malaria control programmes and international funding agencies such as the President's Malaria Initiative (PMI) and the Global Fund to Fight AIDS, Tuberculosis and Malaria make decisions that are based on evidence of likely impacts and costs. This is particularly significant now, since it is estimated that global funding for malaria is less than half of what is needed to attain universal coverage of malaria vector control, i.e., access to either ITNs or IRS [9].It is unclear from current evidence whether combined use of ITNs and IRS provides an additional benefit compared to using either intervention alone, and whether this will be similar across transmission settings [4]–[7],[10],[11]. A recent trial in Benin found no added benefit to using IRS in combination with ITNs compared to ITNs alone [10]. However, this trial had a relatively small sample size, and its findings may be applicable to only a particular transmission setting in west Africa [12].To help define future malaria control policy in Africa, the PMI decided to sponsor an independent two-arm cluster randomised controlled trial (CRT) to compare the protective effectiveness of IRS in combination with high coverage of ITNs with high coverage of ITNs alone for malaria transmission control.Tanzania has a high malaria disease burden, with a national average of 9% of children under 5 y being infected with malaria parasites [13]. Malaria control activities have been scaled up nationally since 2005 [14]–[16]. A universal coverage campaign (UCC) primarily funded by the Global Fund to Fight AIDS, Tuberculosis and Malaria distributed long-lasting insecticidal nets (LLINs) free of charge in 2011 to top up coverage from previous distributions [14],[15],[17]. IRS, funded by the PMI, commenced in 2007 in two districts of Kagera Region, in northwest Tanzania, and has since been extended to cover 18 districts [18]. Because IRS is costly and logistically intensive [8],[19], there is an urgent need to know whether it is necessary to continue with IRS after an ITN UCC has been successfully completed.The trial was carried out in 109 rural villages in Muleba District (1°45′S 31°40′E), Kagera Region [20],[21]. The study area includes 68,108 households at an altitude ranging from 1,100 to 1,600 m above sea level. Rainfall occurs in two seasons: the “short rains” in October–December (average monthly rainfall 160 mm) and the “long rains” in March–May (average monthly rainfall 300 mm) [22], with malaria transmission occurring throughout the year and peaking after the rainy seasons [23]. Annual rounds of IRS with the pyrethroid lambda-cyhalothrin (ICON 10CS, Syngenta) were conducted between 2007 and 2011 in Muleba District, i.e., in the entire study area. The predominant malaria vectors are Anopheles gambiae s.s. and An. arabiensis\n[24]. Tests of mosquito susceptibility using standard WHO bioassays showed resistance to pyrethroids in An. gambiae s.s. in 2011 [24]. As a result, IRS policy was changed to use the carbamate insecticide bendiocarb (Ficam 80% wettable powder, Bayer) by the PMI in 2012.MethodsEthics and Community SensitisationThe trial was approved by the ethics review committees of the Kilimanjaro Christian Medical College, the Tanzanian National Institute for Medical Research, and the London School of Hygiene and Tropical Medicine. Written informed consent was obtained from all respondents. Prior to the baseline surveys, village and hamlet leaders were invited to sensitisation sessions conducted by district health officers.The trial was registered with ClinicalTrials.gov (registration number NCT01697852) in September 2012. The trial was not registered earlier because the authors were not aware of journal requirements for prospective registration. All authors have affirmed that any trials they are involved in on the same or a related drug or intervention are registered. An accurate summary of the trial's results has been submitted to ClinicalTrials.gov.Study DesignA CRT was conducted, comparing the Plasmodium falciparum prevalence rate (PfPR) in children 0.5–14 y old between communities targeted to receive both high-coverage IRS and high coverage of ITNs (ITN+IRS arm) and communities targeted for high coverage of ITNs only (standard-care control arm). Secondary outcomes were moderate/severe anaemia (haemoglobin <8 g/dl) in children under 5 y old and entomological inoculation rate (EIR) due to An. gambiae s.l.Power calculations showed that 25 clusters per study arm were required, with 80 children per cluster, to give 80% power to detect a true absolute difference in PfPR of at least 3% between study arms (relative difference 31%) with 5% significance (two-sided), based on an expected prevalence in the ITN only arm of 9% (PfPR in first baseline survey). The between-cluster coefficient of variation (k) was calculated as 0.25 from the first pre-randomisation baseline survey [25].Each cluster consisted of at least one village and was divided into a core surveillance area consisting of at least 200 houses and approximately 1 km radius, where the surveys were conducted, and an outer buffer zone, 1 km in width, which also received the allocated treatment but in which no outcome monitoring was done. Villages were eligible for inclusion in the study if they were within daily commuting distance for survey work and had been sprayed with IRS in the baseline year.All clusters received LLINs from the UCC in 2011. Twenty-five clusters were randomly allocated to receive IRS, in addition to ITNs, using restricted randomisation to limit potential imbalance between study arms [25]. Baseline surveys provided data on seven criteria for which the study arms were balanced by constraining the randomisation (Table 1). 200,000 random allocations were generated. Mean values for each arm were calculated from cluster summaries for each of the seven restriction variables; 25,119 randomisations fulfilled the restriction criteria and were therefore eligible. These allocations were tested for independence between any two clusters. The large number of acceptable allocations, of which one was randomly selected, ensured that the restriction did not affect the validity of inference. There was no evidence of dependence between any pair of clusters [25],[26].10.1371/journal.pmed.1001630.t001Table 1Restriction variables for randomisation and realisation of balance between the study arms.VariableMaximum Difference in Means between Study Armsa\nITN Arma\nITN+IRS Arma\nActual Difference\nPfPRb in February–March 2011c\n3%9.9%9.3%0.5%\nPfPR in June–July 2011d\n3%22.4%19.6%2.7%Housing densitye\n20 HH/km2\n165.1 HH/km2\n152.6 HH/km2\n12.5 HH/km2\nMean elevation50 m1,364.8 m1,330.7 m34.1 mITN usaged\n,\nf\n5%35.0%30.4%4.6%Adequate LLIN ownershipe\n,\ng\n5%61.3%56.3%5.0%Clusters with entomological surveillanceCount of 220 clusters20 clusters0 clustersaMeans for each study arm were calculated from cluster summaries.b\nPfPR from RDTs.cRecorded in baseline survey 1(February–March 2011).dRecorded in baseline survey 2 (June–July 2011) after the UCC.eHousing density in surveillance area of clusters.fNet used the night before the survey in all age groups.gPercentage of households with at least one LLIN per two people.HH, household.InterventionsHouseholds in the study area with children aged under 5 y received LLINs from a national distribution campaign in 2009 [16]. In 2011, the district health authority, supported by Mennonite Economic Development Associates, completed a UCC that distributed 144,000 LLINs (Olyset, Sumitomo Chemicals) to the population of Muleba District, including all study clusters. The campaign aimed to top up net coverage, so that every sleeping place had one ITN. After the UCC, 91% of households owned at least one ITN, and 58% of households owned enough ITNs to cover all their sleeping places [20].Spraying was conducted by RTI International on behalf of PMI in the ITN+IRS study arm. The interior walls of each dwelling were sprayed with the carbamate insecticide bendiocarb (Ficam 80% wettable powder, Bayer) at 400 mg/m2 between December 2011 and January 2012 (round 1), and between April and May 2012 (round 2). Spray rounds were timed to precede the peak in malaria cases that normally occurs at the end of each rainy season, taking into account the relatively short residual duration of bendiocarb.Bendiocarb is a carbamate insecticide recommended by WHO for IRS [27],[28]. It is one of the few insecticides evaluated and approved by the WHO Pesticide Evaluation Scheme that has the potential to control pyrethroid-resistant mosquitoes, is odour-free, and is safe to house occupants at the recommended application rate [27]. Before obtaining WHO approval, all IRS insecticides are subject to risk assessment by WHO toxicologists [29]. Bendiocarb is an acetylcholinesterase inhibitor, but no serious adverse effects due to bendiocarb IRS have been reported in the recent medical literature.SurveysThree post-intervention cross-sectional household surveys were undertaken in 2012 (see Figure 1). Survey A (23 February–31 March) was after the short rainy season and 2 mo after the first spray round. Survey B (25 June–31 July) was after the long rainy season, 6 mo after the first spray round, and 2 mo after the second spray round. Survey C (25 October–4 December) was 6 mo after the second spray round and 10 mo after the first. Baseline surveys were conducted in 2011 during the same periods as surveys A and B.10.1371/journal.pmed.1001630.g001Figure 1Study timetable.Surveys 1 and 2 are baseline surveys. Surveys A, B, and C are post-intervention.For each survey, 80 households were randomly selected in the core area of each cluster. Households were eligible for the study if they had children aged 0.5–14 y. Any child aged 0.5–14 y was eligible to be included in the study. Up to three children per household were randomly selected for testing. Allowing for ineligible households, absence on the day of the survey, and refusals at the household and individual level, it was estimated that this would provide on average 80 children for testing per cluster.The household head or another responsible adult from the household was interviewed, after seeking written informed consent. Data on IRS coverage, bed net ownership and usage, demographics of household members, and other household characteristics were gathered using an adapted version of the standard Malaria Indicator Survey [30].Selected children were tested on the following day for malaria parasites using a rapid diagnostic test (RDT) (CareStart [Pan] Malaria, DiaSys) and had haemoglobin levels measured using HemoCue Hb 201+ (Aktiebolaget Leo Diagnostics). Individuals testing positive by RDT were treated with artemether/lumefantrine (Artefan 20/120, Ajanta Pharma) following national treatment guidelines.Entomological surveillance was carried out in the core surveillance areas of a subset of 40 of the 50 clusters from April 2011 to December 2012. For one night of each month US Centers for Disease Control and Prevention light traps for mosquito collections were set up in eight randomly selected houses in each cluster (320 houses per month). Anopheles mosquitoes collected were identified to species using a simplified morphological key adapted from Gillies and Coetzee [31]. A sub-sample of An. gambiae s.l. individuals were tested using real-time PCR TaqMan assay to distinguish between the two sibling species An. gambiae s.s. and An. arabiensis\n[32]. Mosquitoes were also tested for P. falciparum sporozoites (P. falciparum circumsporozoite protein) using ELISA [33].Statistical AnalysisStatistical analysis was done in Stata 12 (Statacorp) and R version 2.13.1 (R Foundation for Statistical Computing). The odds of PfPR and moderate/severe anaemia for individuals were compared between study arms in intention-to-treat (ITT) analysis using logistic regression. Mean haemoglobin was compared between the study arms using linear regression. A robust variance estimator was used to calculate standard errors to adjust for within-cluster correlation of responses (Stata survey commands, first-order Taylor-series linearization method) [34],[35]. PfPR was considered as P. falciparum alone or mixed infections as detected by the RDT. The overall odds ratio (OR) for the three surveys combined was calculated accounting for survey. An adjusted Wald test was performed to test whether there was evidence for effect modification between study arm and survey round. A sensitivity analysis was conducted excluding one cluster from the ITN only arm that mistakenly received IRS, to assess the impact of this protocol violation on the results of ITT analysis. Because of the wide variation in cluster-level estimates of PfPR at baseline, an OR for ITN+IRS versus ITN alone was calculated adjusting for baseline PfPR.A secondary per-protocol analysis was performed, in which individuals from the ITN+IRS arm who used an ITN and lived in a house sprayed in the most recent round of IRS were compared to individuals who used an ITN in the ITN only arm. The cluster that violated the protocol was excluded from the per-protocol analysis.The monthly EIR was calculated as the daily EIR found during the one night collection multiplied by the number of days in the month. Mean EIRs were compared between study arms using negative binomial regression and adjusting for within-cluster correlation.ResultsAt baseline, PfPR, anaemia, ITN ownership, ITN usage, and mean EIR per month (Table 2) were similar in the two study arms. PfPR in children aged 6 mo to 14 y old was 9.3% (95% CI 5.9%–14.5%) after the short rains (survey A, February–March) and 22.8% (95% CI 17.3%–29.4%) after the long rains (survey B, June–July). Anaemia in children 0.5–4 y was 6.2% (95% CI 4.5%–8.5%) after the long rains.10.1371/journal.pmed.1001630.t002Table 2Baseline characteristics of individuals and households by study arm, Muleba District, 2011.CharacteristicITN Only ArmPercent [95% CI] (n)ITN+IRS ArmPercent [95% CI] (n)\nPfPR in March 2011a\n,\nb\n,\nc\n10.3 [5.2–19.3] (2,487)8.4 [4.5–15.3] (2,655)\nPfPR in July 2011a\n,\nb\n,\nd\n24.6 [17.0–34.3] (2,121)21.0 [13.8–30.5] (2,185)Moderate/severe anaemiaa\n,\nd\n,\ne\n6.4 [3.9–10.2] (785)6.1 [4.1–8.9] (841)Mean haemoglobin (g/dl)a\n,\nd\n,\n10.6 [10.4–10.9] (785)10.6 [10.4–10.9] (841)ITN use in all age groupsa\n,\nd\n,\nf\n53.3 [48.2–58.3] (6,755)58.2 [53.8–62.5] (6,913)Households with adequate ITNsd\n,\ng\n,\nh\n54.5 [49.5–59.5] (1,243)62.3 [57.3–67.1] (1,250)Households with ≥1 ITNd\n,\ng\n88.9 [86.0–91.3] (1,248)92.6 [90.8–94.0] (1,251)Households received IRS in 2011c\n,\ng\n,\ni\n94.4 [91.3–96.5] (1,598)95.5 [93.5–96.9] (1,640)Mean An. gambiae mosquitoes per house per nightg\n,\nj\n3.1 [1.0–9.6] (1,055)2.2 [0.5–9.1] (1,120)Sporozoite ratea\n,\nk\n1.1 [0.8–1.4] (1,359)2.0 [1.4–2.8] (1,466)Mean EIR/monthl\n1.1 [0.4–2.8]1.3 [0.4–4.4]aCalculated from individual-level data.b\nPfPR from RDTs.cRecorded in baseline survey 1 (February–March 2011).dBaseline survey 2 (June–July 2011) after the UCC.eHaemoglobin <8 g/dl.fReported sleeping under an ITN the night previous to the survey.gCalculated from household-level data.hAt least one ITN per sleeping place.iApproximately 1 mo after spraying.jArithmetic mean.kProportion of mosquitoes positive for P. falciparum sporozoites.lNumber of infective bites per month.Of the 2,000 houses selected in each study arm for each post-intervention survey, 20% to 24% had no children between 0.5 and 14 y old (were ineligible), 13% to 18% were vacant on the day of survey, fewer than 1% refused to participate, and 55% to 61% participated in the survey (Figure 2). Of the children selected for RDT, 81%–84% were tested. Post-intervention IRS coverage reported by householders was 92.1% after the first spray round and 89.5% after the second (Table 3).10.1371/journal.pmed.1001630.g002Figure 2Trial profile for study households and children in the ITN only and ITN+IRS study arms.Survey A\u200a=\u200a2 mo after first intervention spray. Survey B\u200a=\u200a6 mo after first intervention spray and 2 mo after second intervention spray. Survey C\u200a=\u200a10 mo after first intervention spray and 6 mo after second intervention spray. *No children 0.5–14 y old. 1Dwelling vacant for survey duration. 2Includes not found (91.0%), not visited (2.4%), and missing data (6.6%). 3Households (HH) that were included and where children attended for testing.10.1371/journal.pmed.1001630.t003Table 3IRS coverage, ITN ownership, and ITN usage in the intervention year, Muleba District, 2012.SurveyArmReported IRS CoverageaPercent [95% CI] (n\nb)Adequate ITN OwnershipcPercent [95% CI] (n\nb)≥1 ITN OwneddPercent [95% CI] (n\nb)ITN UseePercent [95% CI] (n\nf)\nSurvey A\nITN only3.3 [1.8–5.9] (1,177)52.2 [47.8–56.5] (1,178)85.8 [83.7–87.7] (1,177)46.6 [41.7–51.6] (2,193)ITN+IRS92.1 [88.4–94.7] (1,215)57.2 [53.6–60.7] (1,215)89.0 [87.1–90.6] (1,216)53.0 [47.5–58.3] (2,349)\nSurvey B\nITN only5.2 [1.3–18.6] (1,094)51.6 [47.0–56.0] (1,094)82.5 [78.7–85.7] (1,096)40.7 [34.7–47.0] (2,045)ITN+IRS89.5 [84.0–93.2] (1,138)57.4 [54.0–60.9] (1,142)88.2 [85.7–90.3] (1,142)44.1 [39.2–49.2] (2,207)\nSurvey C\nITN only13.0 [6.6–24.1] (1,165)52.8 [47.6–58.0] (1,168)78.2 [74.3–81.6] (1,170)36.0 [29.8–42.6] (2,101)ITN+IRS89.3 [83.6–93.2] (1,209)56.8 [51.7–61.8] (1,211)83.8 [79.9–87.1] (1,211)36.1 [31.0–41.5] (2,303)Survey A\u200a=\u200a2 mo after first intervention spray. Survey B\u200a=\u200a6 mo after first intervention spray and 2 mo after second intervention spray. Survey C\u200a=\u200a10 mo after first intervention spray and 6 mo after second intervention spray.aReported spray status of household in the spray round preceding the survey.bHouseholds.cPercentage of households with sufficient ITNs for at least one per sleeping place.dPercentage of households with at least one ITN.ePercentage of study children that reported sleeping under an ITN the night previous to the survey. ITN usage in all age groups was very similar to ITN use in the study children.fIndividuals.In the intervention year, the percentage of houses with sufficient ITNs for each sleeping place remained stable over successive surveys and was similar between study arms (range 52%–57%; Table 3). 82.2% and 87.0% of households owned at least one ITN in the ITN only arm and the ITN+IRS arm, respectively (all surveys combined), with weak evidence that the percentage of households that owned at least one ITN was lower in the ITN only arm, and that it decreased from survey A to survey C in both arms (Table 3). ITN usage in children was similar between study arms but declined from 50% in survey A to 36% in survey C.The primary outcome PfPR was lower in the ITN+IRS arm than in the ITN only arm in all three surveys in the intervention year (Table 4). For all three surveys combined, the overall OR was 0.43 (95% CI 0.19–0.97), with weak evidence that the intervention effect differed between surveys (interaction p\u200a=\u200a0.08). The strongest effect was observed in survey B (OR 0.33, 95% CI 0.15–0.75), which was conducted at the peak of malaria transmission after the long rains, 6 mo after the first IRS and 2 mo after the second IRS. The evidence for an effect was weaker in survey A (OR 0.51, 95% CI 0.24–1.09), conducted shortly after the first IRS round, and in survey C (OR 0.48, 95% CI 0.18–1.24), conducted several months after the main transmission season and 6 mo after last spray round. The range of cluster-specific estimates for PfPR was 0% to 92% in the ITN only arm and 0% to 68% in the ITN+IRS arm. The sensitivity analysis showed that excluding the cluster from the ITN only arm that had received IRS did not affect the results of the ITT analysis (Table S1). The overall OR for all three surveys combined was very similar after adjusting for baseline PfPR, OR\u200a=\u200a0.41, but the precision of the estimate was increased (95% CI 0.29–0.59, p<0.0001).10.1371/journal.pmed.1001630.t004Table 4\nPfPR in children 0.5–14 y old in the ITN only and ITN+IRS arms (intention to treat) in survey A, B, and C, Muleba District, Tanzania, 2012.SurveyArm\nPfPRaPercent [95% CI] (n)OR [95% CI], p-Value\nSurvey A\nITN only23.6 [15.4–34.2] (2,191)1.00ITN+IRS13.6 [8.3–21.4] (2,342)0.51 [0.24–1.09], p\u200a=\u200a0.082\nSurvey B\nITN only30.5 [20.2–43.4] (2,033)1.00ITN+IRS12.7 [7.4–21.0] (2,204)0.33 [0.15–0.75], p\u200a=\u200a0.009\nSurvey C\nITN only24.5 [14.2–38.9] (2,091)1.00ITN+IRS13.4 [7.3–23.4] (2,285)0.48 [0.18–1.24], p\u200a=\u200a0.127\nAll three surveys combined\nITN only26.1 [16.7–38.4] (6,315)1.00ITN+IRS13.3 [7.9–21.5] (6,831)0.43 [0.19–0.97], p\u200a=\u200a0.043b\nSurvey A\u200a=\u200a2 mo after first intervention spray. Survey B\u200a=\u200a6 mo after first intervention spray and 2 mo after second intervention spray. Survey C\u200a=\u200a10 mo after first intervention spray and 6 mo after second intervention spray.a\nPfPR from RDTs.bAdjusted for survey.Prevalence of moderate to severe anaemia in children under 5 y old, a secondary outcome, was lower in the ITN+IRS arm in all post-intervention surveys, but the difference was statistically significant only in survey B (Table 5). Mean haemoglobin was higher in children under 5 y old in the ITN+IRS arm than in the ITN only arm in all three surveys. The evidence for an effect was greatest in survey B (0.49 g/dl, 95% CI 0.10–0.89, p\u200a=\u200a0.016), with a non-significant result in survey A (0.28 g/dl, 95% CI −0.02 to 0.59, p\u200a=\u200a0.065) and survey C (0.36 g/dl, 95% CI −0.02 to 0.73, p\u200a=\u200a0.060).10.1371/journal.pmed.1001630.t005Table 5Anaemia and mean haemoglobin in children under 5+IRS arms (intention to treat), for survey A, B, and C, Muleba District, Tanzania, 2012.SurveyArmAnaemia Prevalencea\nMean Haemoglobin (g/dl)Percent [95% CI] (n)OR [95% CI], p-ValueMean [95% CI] (n)Difference [95% CI], p-Value\nSurvey A\nITN only6.0 [4.1–8.7] (815)1.0010.6 [10.4–10.8] (815)ITN+IRS3.9 [2.5–6.2] (864)0.64 [0.34–1.19], p\u200a=\u200a0.15510.9 [10.7–11.1] (864)0.28 [−0.02 to 0.59], p\u200a=\u200a0.065\nSurvey B\nITN only4.7 [2.6–8.6] (737)1.0010.9 [10.6–11.2] (737)ITN+IRS2.2 [1.3–3.6] (784)0.44 [0.20–1.01], p\u200a=\u200a0.05311.4 [11.2–11.6] (784)0.49 [0.10 to 0.89], p\u200a=\u200a0.016\nSurvey C\nITN only3.2 [1.8–5.7] (739)1.0010.8 [10.6–11.1] (739)ITN+IRS2.6 [1.6–4.4] (831)0.81 [0.37–1.77], p\u200a=\u200a0.59011.2 [11.0–11.4] (831)0.36 [−0.02 to 0.73], p\u200a=\u200a0.060\nAll three surveys combined\nITN only4.7 [3.2–6.9] (2,291)1.0010.8 [10.5–11.0] (2,291)ITN+IRS2.9 [2.0–4.3] (2,479)0.62 [0.34–1.10], p\u200a=\u200a0.102b\n11.2 [11.0–11.3] (2,479)0.37 [0.07 to 0.68], p\u200a=\u200a0.017b\nSurvey A\u200a=\u200a2 mo after first intervention spray. Survey B\u200a=\u200a6 mo after first intervention spray and 2 mo after second intervention spray. Survey C\u200a=\u200a10 mo after first intervention spray and 6 mo after second intervention spray.aPrevalence of moderate/severe anaemia (haemoglobin <8 g/dl).bAdjusted for survey.Mean EIR per month, a secondary outcome, was 0.22 in the ITN+IRS arm and 1.26 in the ITN only arm (rate ratio\u200a=\u200a0.17, 95% CI 0.03–1.08, p\u200a=\u200a0.059; Table 6).10.1371/journal.pmed.1001630.t006Table 6Mean number of An. gambiae mosquitoes per household, sporozoite rate, and EIR in the ITN only and ITN+IRS arms during the post-intervention period, Muleba District, Tanzania, 2011–2012.ArmMean or Percent [95% CI] (n)a\nEffect [95% CI], p-Value\nMean\nb\nAn. gambiae\n per house per night\nITN only1.7 [0.5–6.4] (1,892)ITN+IRS0.4 [0.1–1.4] (1,893)Rate ratio\u200a=\u200a0.23 [0.04–1.44], p\u200a=\u200a0.113\nSporozoite rate\nc\nITN only2.5 [2.1–3.1] (3,059)ITN+IRS1.8 [0.5–6.2] (717)OR\u200a=\u200a0.72 [0.21–2.53], p\u200a=\u200a0.600\nMean EIR/month\nd\nITN only1.3 [0.3–4.6]ITN+IRS0.2 [0.1–0.8]Rate ratio\u200a=\u200a0.17 [0.03–1.08], p\u200a=\u200a0.059aData are mean [95% CI] (number of houses) for mean An. gambiae per house per night and percent [95% CI] (number of An. gambiae) for sporozoite rate.bArithmetic mean.cProportion of mosquitoes positive for P. falciparum sporozoites.dNumber of infective bites per month.The between-cluster coefficient of variation (k) was 0.20, 0.28, and 0.26 in the three post-intervention surveys, respectively. For each survey, k was similar in the two arms.For all surveys, per-protocol analysis showed statistically significant evidence for a protective effect of the combined intervention on PfPR (survey A: OR 0.39, 95% CI 0.18–0.81; survey B: OR 0.21, 95% CI 0.09–0.49; and survey C: OR 0.27, 95% CI 0.10–0.73; Table 7).10.1371/journal.pmed.1001630.t007Table 7Per-protocol analysis of PfPR in children 0.5–14 y old and anaemia in children under 5 y old in surveys A, B, and C.SurveyArmPrevalencePercent [95% CI] (n)OR [95% CI], p-Value\nPf\nPR\na\nSurvey AITNb\n26.7 [17.5–38.6] (954)1.00ITN+IRSc\n12.3 [7.8–18.9] (1,142)0.39 [0.18–0.81], p\u200a=\u200a0.013Survey BITNb\n35.5 [23.2–50.2] (782)1.00ITN+IRSc\n10.2 [5.7–17.7] (892)0.21 [0.09–0.49], p\u200a=\u200a0.001Survey CITNb\n29.4 [16.7–46.4] (707)1.00ITN+IRSc\n10.1 [5.4–18.2] (770)0.27 [0.10–0.73], p\u200a=\u200a0.011\nAnaemia\nd\nSurvey AITNb\n5.9 [3.5–9.7] (390)1.00ITN+IRSc\n3.8 [1.8–7.5] (453)0.62 [0.25–1.55], p\u200a=\u200a0.301Survey BITNb\n5.4 [2.2–12.5] (295)1.00ITN+IRSc\n1.9 [0.8–4.1] (374)0.33 [0.10–1.12], p\u200a=\u200a0.076Survey CITNb\n4.0 [2.2–7.0] (303)1.00ITN+IRSc\n2.3 [1.0–5.0] (305)0.57 [0.21–1.55], p\u200a=\u200a0.264Muleba, Tanzania, 2012; analysis restricted to ITN users in both study arms. Survey A\u200a=\u200a2 mo after first intervention spray. Survey B\u200a=\u200a6 mo after first intervention spray and 2 mo after second intervention spray. Survey C\u200a=\u200a10 mo after first intervention spray and 6 mo after second intervention spray.a\nPfPR from RDTs.bITN used by the individual the night preceding the survey in the ITN only arm.cITN used by the individual the night preceding the survey, and household with IRS in the ITN+IRS arm. One cluster that was allocated to be in the ITN only arm but received IRS in the second spray round was excluded from this analysis.dPrevalence of moderate/severe anaemia (haemoglobin <8 g/dl).DiscussionThis is the first randomised trial to our knowledge that provides evidence that IRS, when used in combination with ITNs, can give significant added protection against malarial infection compared to ITN use alone. There was also some evidence that anaemia prevalence was lower in communities with the combination. Exposure to infectious mosquito bites was about one-sixth in communities with the combined intervention compared to those in the ITN only arm. Two rounds of IRS with bendiocarb were conducted to overcome the short residual activity of the insecticide [27],[36] and to ensure that there was active ingredient on the walls of sprayed homes throughout the transmission season.IRS coverage in the ITN+IRS arm was high at approximately 90% in both spray rounds, which would have optimised its effectiveness [37]. On the other hand, whilst 85% of households owned at least one ITN, use of ITNs was modest, declining to 36% by the end of the study. The low usage of ITNs means that the addition of IRS may have simply protected those who were not using an ITN, thus compensating for low ITN usage rather than offering additional protection to net users. This interpretation is contradicted by the results of a per-protocol analysis, which excluded those not using ITNs, showing strong evidence that ITN users whose houses were sprayed were additionally protected by IRS. The estimated reduction in PfPR associated with the combination of interventions was greater in the per-protocol analysis than in the ITT analysis in each survey. Per-protocol analysis excludes non-compliers (for IRS and ITN) and therefore may have been influenced by confounders. It is likely that the observed overall effect of the intervention combination was a result of both IRS protecting those not using ITNs, and IRS additionally protecting ITN users.A potential negative impact of the combination of interventions is that having their house sprayed may encourage some residents to stop sleeping under an ITN. This was not observed in this study; ITN usage was similar between the villages with and without IRS in each post-intervention survey.ITN usage and ownership was slightly higher at baseline in the ITN+IRS arm compared to the ITN only arm, but the 95% confidence intervals for these estimates overlapped. This non-significant difference could have led to a slight overestimation of the effect size. PfPR was slightly lower at baseline in the ITN+IRS arm compared to the ITN only arm, but the effect size did not change after adjusting for PfPR at baseline. This suggests that baseline PfPR was not confounding the relationship between study arm and PfPR (the outcome). In the baseline year, malaria prevalence was higher in June–July after the long rainy season than in February–March after the short rains. In the intervention year, the prevalence similarly increased in June–July (survey B) in the ITN only arm, but prevalence in the ITN+IRS arm remained low, suggesting IRS and ITNs in combination prevented the seasonal increase in infections.The added protective effect of IRS peaked in the second survey, at the height of transmission after the long rains. This was probably the optimal time for the insecticide to reduce the abundance of the mosquito population (N. Protopopoff, personal communication) and thus to observe the impact of IRS on the prevalence of malarial infections. The limited residual activity of bendiocarb IRS has been shown to reduce its protective effectiveness 3–5 mo after spraying, which probably accounts for the loss of added benefit seen in the third survey, which was 6 mo after the last spray round at the beginning of the short rains [27],[36]. Implementing IRS with long-lasting insecticide formulations might be necessary to maintain the effectiveness of the combination throughout the year. Alternatively, the time between IRS rounds could be reduced, but this would considerably raise the cost of the combined intervention [38].The secondary outcomes anaemia and EIR also pointed to added protection being provided by the combination of IRS and ITNs, but the evidence for these endpoints was weaker. The combination intervention was associated with higher haemoglobin levels in children under 5 y, particularly at the peak of the transmission season. The study had been powered to show a difference in the primary outcome (PfPR), and therefore may have been underpowered for these secondary outcomes. Nevertheless, the results for all outcomes are consistent.One of the limitations of this study is that clinical incidence of malaria could not be recorded in addition to infection prevalence because recording of confirmed malaria cases was unreliable because of stock-outs of RDTs at health facilities. Implementing both IRS and universal coverage of ITNs is obviously considerably more costly than ITNs alone. Estimating the cost-effectiveness of the combination compared to ITNs alone was beyond the scope of this particular research. Although IRS is known to be highly cost-effective [8],[39]–[43], the marginal cost per case averted through using IRS in combination with ITNs should ideally be assessed in future studies. This is particularly important in light of the funding gap that has been identified for meeting the demand for universal coverage of vector control for populations in malaria endemic regions [3].Previous studies have investigated the combined use of multiple vector control methods versus one method alone, but the results have been inconsistent [4],[44]–[47]. The only published trial data are from a 28-cluster, four-arm CRT carried out in Benin that compared (1) targeted coverage of LLINs (pregnant women and children only), (2) universal coverage of LLINs, (3) targeted coverage of LLINs combined with bendiocarb IRS, and (4) universal coverage of LLINs combined with bendiocarb-treated wall linings [10]. The study found no difference in malaria incidence, geometric mean parasite density, or mosquito abundance between any of the study arms. The lack of any evidence of an added benefit of the combined interventions over the use of LLINs alone has to be viewed against the modest sample size, and hence potentially low power of this trial [12], and the lack of a comparator arm with universal coverage of ITNs.There are a number of differences between the Benin trial and the current study that may have contributed to the discordant results. In the Benin trial, the interval between IRS rounds was 8 mo, whereas it was only 4 mo in the current study, as IRS was timed according to the seasonal peaks in cases, and taking account of its short residual duration on walls. The first two cross-sectional surveys for the current trial were timed to coincide with the seasonal peaks in cases and were only 2 mo after each IRS round, whereas in Benin the cases were recorded at 6-wk intervals for 18 mo, so that the measured effect of the additional IRS may include a period when the insecticide, which is known to have a short residual duration, was no longer effective. In the Benin trial, LLINs were given only to target groups in the reference arm and in the study arm with IRS, whereas in the current trial ITNs were distributed to all age groups.Large CRTs have recently been conducted in the Gambia [48],[49] and in Sudan [50] comparing villages with IRS and LLINs to villages with only LLINs, but the results have not yet been published.Evidence of an added benefit from the combination intervention compared to IRS or ITNs alone has been shown in a number of observational studies [4],[45],[47],[51]–[55]. For example, children 2–14 y old consistently received added personal protection from using nets in addition to IRS on the island of Bioko, Equatorial Guinea (OR 0.71, 95% CI 0.59–0.86), and in Zambezia, Mozambique (OR 0.63, 95% CI 0.50–0.79) [4],[36]. In Pakistan, nets provided added protection against P. vivax and P. falciparum in refugee camps where IRS was conducted [56]. However, other studies observed no additional benefit from the combination compared to one intervention alone [46],[57],[58].One interpretation of these divergent conclusions is that if the intervention present in both study arms is compromised or poorly implemented, the second method compensates for the deficiency of the first, providing apparent added protection that would otherwise not be seen. On the other hand, if the reference arm intervention is well implemented and efficacious in both study arms, there may be little or no scope for additional protection by a second intervention. ITN usage in the present trial was moderate, and hence the IRS protected many people who were not using a net in the ITN+IRS arm, whilst non-users in the ITN only arm remained unprotected. Any community or “mass effect” of ITNs on mosquito population size would have been limited because of the low community net usage. Therefore, the protective effect of ITNs in this study was possibly suboptimal. In Bioko, ITNs provided personal protection in the presence of IRS that was rendered only partially effective by moderate coverage (77%–79%) and use of an insecticide that did not outlast the long malaria season [36],[51]. Protopopoff et al. reported that in Burundi there was no additional reduction in infection prevalence in children from adding LLINs to IRS because high coverage (90%) of IRS had already reduced the sporozoite rate to a level where nets had no further impact [57]. In Sao Tome, where the IRS programme was poorly implemented, with low coverage and long intervals between spray rounds, there was an additional benefit from using ITNs and IRS compared to IRS alone [47]. However, on the neighbouring island of Principe, where IRS coverage was high (85%) and implemented on schedule, there was no added protection from ITNs in combination with IRS compared to IRS alone [46],[47].Insecticide resistance may be another reason why differences have been seen for the effectiveness of the combination of IRS and ITNs, resulting in either an apparent “added” effect of the second effective intervention, if the first was ineffective due to insecticide resistance, or no added effect if the second intervention was ineffective due to insecticide resistance. In the study area of this trial, there was evidence for high levels of resistance to pyrethroids in An. gambiae s.s. The epidemiological impact of pyrethroid resistance on the effectiveness of ITNs is currently not known [59]. However, if the effectiveness of the ITNs was compromised [24] because of insecticide resistance, this would have enhanced our estimate of the additional benefit of non-pyrethroid IRS. If pyrethroid-treated nets were to be rendered partially ineffective in the presence of resistance, there would be a compelling case for combining ITNs with non-pyrethroid IRS.An experimental hut trial in an area of Tanzania where the main vector is An. arabiensis found that if ITNs were used, the addition of IRS using insecticides with high irritancy such as dichlorodiphenyltrichloroethane (DDT) or lambda-cyhalothrin did not increase mosquito mortality or repel mosquitoes from the house [11]. However, the addition of IRS using pirimiphos-methyl, an organophosphate that has high toxicity and low irritancy, did increase mosquito mortality. These findings underscore that the interaction between the two interventions is complex and that the added protective effect will be dependent on the feeding and resting behaviours of particular malaria vectors, on the type of IRS insecticide used, on the susceptibility of local vectors to each of the insecticides in the combination, and on ITN usage [5]–[7],[11]. As a result, added protection may not be observed in all situations. A systematic review of all the trial results estimating the effectiveness of the combination of ITNs and IRS should be undertaken once the results of the trials in Sudan and the Gambia are available.Nevertheless, this trial provides encouraging evidence for an additional benefit from applying IRS in combination with ITNs compared to ITNs alone. To our knowledge it is the first CRT to do so. The added protection from the supplementary use of IRS may in the case of bendiocarb be limited to only a few months, raising the question of whether residual insecticides of short duration are cost-effective when used in combination with ITNs. This study was conducted as an effectiveness study and not an efficacy study. The LLINs were distributed by a national UCC and therefore represented a real-life malaria control programme, including the challenges faced in achieving high coverage and usage of ITNs.In conclusion, national malaria control programmes should consider implementing IRS in combination with ITNs if local ITN strategies alone are insufficiently effective and cannot be improved. A key consideration would be the additional cost of providing the combined intervention. Given the inconsistent trial evidence and the unproven generalisability of the findings of all studies that have investigated this question, it would be prudent for malaria control programmes implementing the two methods simultaneously to monitor the impact and cost-effectiveness of the combination to verify whether the additional resources have the desired effect.Supporting InformationChecklist S1\nCONSORT checklist.\n(DOCX)Click here for additional data file.Table S1\nPf\nPR in children 0.5–14 y old in the ITN only and ITN+IRS arms (intention to treat) excluding the cluster that violated the protocol, in survey A, B, and C, Muleba District, Tanzania, 2012.\n(DOCX)Click here for additional data file.The authors express their sincere thanks to the fieldworkers, clinical teams, and all the Pan African Malaria Vector Research Consortium staff at Muleba and Moshi for their hard work collecting the data. 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College Station (Texas): Stata Press.36\nBradleyJ, MatiasA, SchwabeC, VargasD, MontiF, et al (2012) Increased risks of malaria due to limited residual life of insecticide and outdoor biting versus protection by combined use of nets and indoor residual spraying on Bioko Island, Equatorial Guinea. Malar J\n11: 242.2283504937\nRehmanAM, ColemanM, SchwabeC, BaltazarG, MatiasA, et al (2011) How much does malaria vector control quality matter: the epidemiological impact of holed nets and inadequate indoor residual spraying. PLoS ONE\n6: e19205.2155943638World Health Organization (2006) Indoor residual spraying: use of indoor residual spraying for scaling up global malaria control and elimination. Geneva: World Health Organization.39\nGoodmanCA, MillsAJ (1999) The evidence base on the cost-effectiveness of malaria control measures in Africa. Health Policy Plan\n14: 301–312.1078764640Breman JG, Mills A, Snow RW, Mulligan JA, Lengeler C, et al. (2006) Conquering malaria. In: Jamison DT, Breman JG, Measham AR, Alleyne G, Claeson M, et al., editors. Disease control priorities in developing countries. Washington (District of Columbia): World Bank International Bank for Reconstruction and Development/The World Bank Group.41Jamison DT, Breman JG, Measham AR, Alleyne G, Claeson M, et al., editors (2006) Priorities in health. Washington (District of Columbia): World Bank International Bank for Reconstruction and Development/The World Bank Group.42Jamison DT, Breman JG, Measham AR, Alleyne G, Claeson M, et al., editors (2006) Disease control priorities in developing countries. Washington (District of Columbia): World Bank International Bank for Reconstruction and Development/The World Bank Group.43\nGoodmanCA, ColemanPG, MillsAJ (1999) Cost-effectiveness of malaria control in sub-Saharan Africa. Lancet\n354: 378–385.1043786744\nOkumuFO, MooreSJ (2011) Combining indoor residual spraying and insecticide-treated nets for malaria control in Africa: a review of possible outcomes and an outline of suggestions for the future. Malar J\n10: 208.2179805345\nHamelMJ, OtienoP, BayohN, KariukiS, WereV, et al (2011) The combination of indoor residual spraying and insecticide-treated nets provides added protection against malaria compared with insecticide-treated nets alone. Am J Trop Med Hyg\n85: 1080–1086.2214444846\nLeePW, LiuCT, RampaoHS, do RosarioVE, ShaioMF (2010) Pre-elimination of malaria on the island of Principe. Malar J\n9: 26.2008915847\nLeePW, LiuCT, do RosarioVE, de SousaB, RampaoHS, et al (2010) Potential threat of malaria epidemics in a low transmission area, as exemplified by Sao Tome and Principe. Malar J\n9: 264.2092021648\nPinderM, JawaraM, JarjuLBS, KandehB, JeffriesD, et al (2011) To assess whether indoor residual spraying can provide additional protection against clinical malaria over current best practice of long-lasting insecticidal mosquito nets in The Gambia: study protocol for a two-armed cluster-randomised trial. Trials\n12: 147.2166365649Pinder M, Jawara MS, Jawara LB, Kandeh B, Jeffries D, et al. (2012) To assess whether indoor residual spraying can provide additional protection against clinical malaria over current best practice of long-lasting insecticidal mosquito nets in The Gambia: a two-armed cluster-randomized study [abstract]. American Society of Tropical Medicine and Hygiene 61st Annual Meeting; 11–15 November 2012; Atlanta, Georgia, US.50Kafy H (2013) Combination of IRS with LLINs versus LLINS alone in Sudan: results of a very large randomised trial [abstract]. 6th MIM Pan-African Malaria Conference; 6–11 October 2013; Durban, South Africa.51\nKleinschmidtI, TorrezM, SchwabeC, BenaventeL, SeocharanI, et al (2007) Factors influencing the effectiveness of malaria control in Bioko Island, equatorial Guinea. Am J Trop Med Hyg\n76: 1027–1032.1755660652\nPardoG, DescalzoMA, MolinaL, CustodioE, LwangaM, et al (2006) Impact of different strategies to control Plasmodium infection and anaemia on the island of Bioko (Equatorial Guinea). Malar J\n5: 10.1646055853\nGravesPM, OsgoodDE, ThomsonMC, SerekeK, AraiaA, et al (2008) Effectiveness of malaria control during changing climate conditions in Eritrea, 1998–2003. Trop Med Int Health\n13: 218–228.1830426854\nOverM, Bakote'eB, VelayudhanR, WilikaiP, GravesPM (2004) Impregnated nets or DDT residual spraying? Field effectiveness of malaria prevention techniques in Solomon Islands, 1993–1999. Am J Trop Med Hyg\n71: 214–223.1533184055\nNyarangoPM, GebremeskelT, MebrahtuG, MufundaJ, AbdulmuminiU, et al (2006) A steep decline of malaria morbidity and mortality trends in Eritrea between 2000 and 2004: the effect of combination of control methods. Malar J\n5: 33.1663526556\nRowlandM, HewittS, DurraniN, SalehP, BoumaM, et al (1997) Sustainability of pyrethroid-impregnated bednets for malaria control in Afghan communities. Bull World Health Organ\n75: 23–29.914174757\nProtopopoffN, Van BortelW, MarcottyT, Van HerpM, MaesP, et al (2008) Spatial targeted vector control is able to reduce malaria prevalence in the highlands of Burundi. Am J Trop Med Hyg\n79: 12–18.1860675858\nKeatingJ, LocatelliA, GebremichaelA, GhebremeskelT, MufundaJ, et al (2011) Evaluating indoor residual spray for reducing malaria infection prevalence in Eritrea: Results from a community randomized control trial. Acta Trop\n119: 107–113.2156514959World Health Organization Global Malaria Programme (2012) Global plan for insecticide resistance management. Geneva: World Health Organization.AbbreviationsCRTcluster randomised controlled trialEIRentomological inoculation rateIRSindoor residual sprayingITNinsecticide-treated netITTintention to treatLLINlong-lasting insecticidal netORodds ratioPfPR\nPlasmodium falciparum prevalence ratePMIPresident's Malaria InitiativeRDTrapid diagnostic testUCCuniversal coverage campaignWHOWorld Health Organization", 'title': 'Indoor residual spraying in combination with insecticide-treated nets compared to insecticide-treated nets alone for protection against malaria: a cluster randomised trial in Tanzania.', 'date': '2014-04-17'}, '29655496': {'article_id': '29655496', 'content': "LancetLancetLancet (London, England)0140-67361474-547XElsevier296554965910376S0140-6736(18)30427-610.1016/S0140-6736(18)30427-6ArticleEffectiveness of a long-lasting piperonyl butoxide-treated insecticidal net and indoor residual spray interventions, separately and together, against malaria transmitted by pyrethroid-resistant mosquitoes: a cluster, randomised controlled, two-by-two factorial design trialProtopopoffNatachaPhDnatacha.protopopoff@lshtm.ac.uka*MoshaJacklin FPhDcLukoleEliudMScdCharlwoodJacques DPhDaWrightAlexandraMScaMwalimuCharles DMSceManjuranoAlphaxardPhDcMoshaFranklin WProfPhDdKisinzaWilliamPhDfKleinschmidtImmoProfPhDbgRowlandMarkProfPhDaaDepartment of Disease Control, London School of Hygiene & Tropical Medicine, London, UKbMRC Tropical Epidemiology Group, London School of Hygiene & Tropical Medicine, London, UKcNational Institute for Medical Research, Mwanza Medical Research Centre, Mwanza, TanzaniadPan-African Malaria Vector Research Consortium, Kilimanjaro Christian Medical University College, Moshi, TanzaniaeMinistry of Health Community Development Gender Elderly and Children, National Malaria Control Program, Dar es Salaam, TanzaniafNational Institute for Medical Research, Amani Medical Research Centre, Muheza, TanzaniagSchool of Pathology, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa*Correspondence to: Dr Natacha Protopopoff, Department of Disease Control, London School of Hygiene & Tropical Medicine, London WC1E 7HT, UK natacha.protopopoff@lshtm.ac.uk214201821420183911013015771588© 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license2018This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).SummaryBackgroundProgress in malaria control is under threat by wide-scale insecticide resistance in malaria vectors. Two recent vector control products have been developed: a long-lasting insecticidal net that incorporates a synergist piperonyl butoxide (PBO) and a long-lasting indoor residual spraying formulation of the insecticide pirimiphos-methyl. We evaluated the effectiveness of PBO long-lasting insecticidal nets versus standard long-lasting insecticidal nets as single interventions and in combination with the indoor residual spraying of pirimiphos-methyl.MethodsWe did a four-group cluster randomised controlled trial using a two-by-two factorial design of 48 clusters derived from 40 villages in Muleba (Kagera, Tanzania). We randomly assigned these clusters using restricted randomisation to four groups: standard long-lasting insecticidal nets, PBO long-lasting insecticidal nets, standard long-lasting insecticidal nets plus indoor residual spraying, or PBO long-lasting insecticidal nets plus indoor residual spraying. Both standard and PBO nets were distributed in 2015. Indoor residual spraying was applied only once in 2015. We masked the inhabitants of each cluster to the type of nets received, as well as field staff who took blood samples. Neither the investigators nor the participants were masked to indoor residual spraying. The primary outcome was the prevalence of malaria infection in children aged 6 months to 14 years assessed by cross-sectional surveys at 4, 9, 16, and 21 months after intervention. The endpoint for assessment of indoor residual spraying was 9 months and PBO long-lasting insecticidal nets was 21 months. This trial is registered with ClinicalTrials.gov, number NCT02288637.Findings7184 (68·0%) of 10\u2008560 households were selected for post-intervention survey, and 15\u2008469 (89·0%) of 17\u2008377 eligible children from the four surveys were included in the intention-to-treat analysis. Of the 878 households visited in the two indoor residual spraying groups, 827 (94%) had been sprayed. Reported use of long-lasting insecticidal nets, across all groups, was 15\u2008341 (77·3%) of 19\u2008852 residents after 1 year, decreasing to 12\u2008503 (59·2%) of 21\u2008105 in the second year. Malaria infection prevalence after 9 months was lower in the two groups that received PBO long-lasting insecticidal nets than in the two groups that received standard long-lasting insecticidal nets (531 [29%] of 1852 children vs 767 [42%] of 1809; odds ratio [OR] 0·37, 95% CI 0·21–0·65; p=0·0011). At the same timepoint, malaria prevalence in the two groups that received indoor residual spraying was lower than in groups that did not receive indoor residual spraying (508 [28%] of 1846 children vs 790 [44%] of 1815; OR 0·33, 95% CI 0·19–0·55; p<0·0001) and there was evidence of an interaction between PBO long-lasting insecticidal nets and indoor residual spraying (OR 2·43, 95% CI 1·19–4·97; p=0·0158), indicating redundancy when combined. The PBO long-lasting insecticidal net effect was sustained after 21 months with a lower malaria prevalence than the standard long-lasting insecticidal net (865 [45%] of 1930 children vs 1255 [62%] of 2034; OR 0·40, 0·20–0·81; p=0·0122).InterpretationThe PBO long-lasting insecticidal net and non-pyrethroid indoor residual spraying interventions showed improved control of malaria transmission compared with standard long-lasting insecticidal nets where pyrethroid resistance is prevalent and either intervention could be deployed to good effect. As a result, WHO has since recommended to increase coverage of PBO long-lasting insecticidal nets. Combining indoor residual spraying with pirimiphos-methyl and PBO long-lasting insecticidal nets provided no additional benefit compared with PBO long-lasting insecticidal nets alone or standard long-lasting insecticidal nets plus indoor residual spraying.FundingUK Department for International Development, Medical Research Council, and Wellcome Trust.Research in contextEvidence before this studyWe did two searches in PubMed with no language restrictions or specified dates. In the first search on long-lasting insecticidal nets treated with piperonyl butoxide (PBO), we used the search terms “malaria” and “long lasting insecticidal net” in combination with “piperonyl butoxide”, “Olyset Plus”, or “PermaNet 3.0”, which produced no references that were randomised controlled trials (RCTs). In a 2015 review of PBO long-lasting insecticidal nets, WHO concluded that although they appeared to have an increased efficacy the evidence was too inadequate to justify a switch from pyrethroid only to PBO nets across all settings. Because of the potential for an antagonistic effect between PBO and organophosphates, WHO also recommended that PBO nets should not be used in areas programmed for indoor residual spraying with pirimiphos-methyl capsule suspension.In the second search on combined vector control interventions, we included the search term “malaria” with one or more of the following: “long lasting insecticidal net” or “insecticide treated net”, “indoor residual spraying”, “vector control”, “pirimiphos methyl”, and “combined interventions”. We identified three other RCTs that have examined combined intervention of long-lasting insecticidal nets and indoor residual spraying. The Gambian RCT, which used DDT (dichlorodiphenyltrichloroethane) as the indoor residual spraying component showed no additional protection compared with long-lasting insecticidal nets alone. This finding could be explained by the high usage of nets or the properties of the sprayed insecticide used. In Benin, there was no advantage to combining indoor residual spraying and long-lasting insecticidal nets; however, suboptimal coverage of nets and the short residual effect of the spray used (bendiocarb) might have affected the effectiveness of the combination intervention. In an earlier Tanzanian study, where coverage of long-lasting insecticidal nets was moderate and pyrethroid resistance present, two rounds of indoor residual spraying with bendiocarb combined with long-lasting insecticidal nets were more effective than long-lasting insecticidal nets alone.Added value of this studyOur study is the first RCT to report that PBO-treated long-lasting insecticidal nets were more effective than standard pyrethroid long-lasting insecticidal nets against malaria infection and transmission. It also provides the strongest evidence to date of the negative effect of high-level pyrethroid resistance on the use and efficacy of standard nets. This study is also the first RCT to provide evidence for the effect of long-term malaria control of the first long-lasting organophosphate formulation to be developed specifically for indoor residual spraying. The RCT provides new evidence on the added value and risks of combining indoor residual spraying and long-lasting insecticidal nets, particularly PBO nets.Implications of all the available evidenceThis study provides justification for the increase in deployment and use of PBO long-lasting insecticidal nets. As a direct consequence of this trial, WHO revised its policy on long-lasting insecticidal nets in September, 2017, gave interim endorsement to pyrethroid-PBO nets as a new WHO class of vector control product, and recommended that PBO nets be deployed for prevention of malaria where vectors are resistant to pyrethroids provided that vector control coverage is not compromised. This endorsement would include many endemic areas in Africa where standard long-lasting insecticidal nets are currently used. The demonstration that long-lasting insecticidal nets with an appropriate change of active ingredient can continue to tackle transmission by pyrethroid-resistant vector populations will ensure the viability of this approach as well as justifies the continued investment and search for alternative insecticides for use on nets.Finally, the organophosphate indoor residual spraying formulation is the first long-lasting, non-pyrethroid insecticide to provide malaria control for at least 9 months over two transmission seasons in the same year. This finding justifies the scale up and use of indoor residual spraying in sub-Saharan Africa and the 12-year investment into long-lasting alternatives to pyrethroid and DDT for indoor spraying between private and public sector organisations.IntroductionLong-lasting insecticidal nets and indoor residual spraying are the cornerstones of malaria control in sub-Saharan Africa. Together with effective treatment, these interventions are estimated to have globally reduced malaria morbidity by 41% and mortality by 62% between 2000 and 2015.1 Despite this public health success, recent wide-scale selection of insecticide resistance in the mosquito vectors across Africa threatens to reverse the present gains.2 Development and evaluation of new strategies and tools are needed to address the threat of resistance and will accelerate progress towards elimination.The range of insecticides available for indoor residual spraying is limited. For long-lasting insecticidal nets, the range is particularly restricted because pyrethroids are the only class of insecticides recommended by WHO for nets. Evidence from indoor residual spraying programmes suggests that pyrethroid resistance can contribute to operational control failure—eg, in South Africa, control was only restored once the pyrethroid was replaced by an insecticide to which vectors were susceptible.3 By contrast, the negative effect of pyrethroid resistance on the effectiveness of long-lasting insecticidal nets has been less clear and harder to quantify than indoor residual spraying.4 Although entomological evidence suggests that these nets are becoming less effective at killing mosquitoes in household conditions when resistance develops,5, 6 the physical barrier provided by the net, especially when new and intact, might mitigate some of the loss in bioefficacy due to resistance.7 Cohort studies have shown that long-lasting insecticidal nets remain protective against malaria infection in areas of moderate insecticide resistance in Malawi8 and Kenya,9 whereas no reduction in incidence was observed after the distribution of these nets in Uganda.10Anticipating the possible failure of current control tools due to resistance, WHO has encouraged the industry to develop new types of long-lasting insecticidal nets and new insecticides for indoor residual spraying. One of these developments is a new long-lasting insecticidal net that uses piperonyl butoxide (PBO). PBO is a chemical synergist that acts by inhibiting enzymes involved in the natural defense mechanisms of insects, which results in pyrethroid not being detoxified in the insect and the pyrethroid on the long-lasting insecticidal net remaining potent against mosquitoes despite resistance. Such PBO-pyrethroid-treated long-lasting insecticidal nets appear to have similar or better efficacy against resistant mosquitoes under controlled household conditions than standard long-lasting insecticidal nets that do not have PBO.11, 12 In September, 2015, a WHO expert group reviewed the evidence for PBO long-lasting insecticidal nets to define their deployment. Despite awaiting for more conclusive evidence from community randomised controlled trials (RCTs) with epidemiological outcomes, WHO, nevertheless, has recommended a small rollout in specific situations.13Although the range of insecticide classes suitable for indoor residual spraying use is wider than long-lasting insecticidal nets, few insecticides are effective for more than a few months when sprayed onto walls and this limitation has been a constraint on their adoption and use. The organophosphate pirimiphos-methyl is an exception, and the recently developed long-lasting formulation, Actellic 300CS (Syngenta, Switzerland), is effective for up to 10 months when used for indoor residual spraying.14 It is now being deployed in several African countries instead of carbamates.15In attempts to accelerate malaria control progress, long-lasting insecticidal nets and indoor residual spraying have been deployed together in several countries.1 The advantage of combined intervention has, however, been the focus of considerable debate because both observational and RCTs have produced contradictory evidence. In The Gambia and Benin, no difference in malarial outcomes were reported when both control strategies were deployed together compared with long-lasting insecticidal nets alone,16, 17 whereas in Tanzania an increased effectiveness was observed when they were used in combination.18 On the basis of these data, the effect observed would seem to depend on the insecticide combination used, the vectors present, the coverage and quality of the intervention, and the level and type of insecticide resistance in the vectors.To develop an improved strategy for control of malaria transmitted by pyrethroid-resistant mosquito vectors, we aimed to compare the effectiveness of PBO long-lasting insecticidal nets with standard long-lasting insecticidal nets as single interventions and in combination with the long-lasting indoor residual spraying of pirimiphos-methyl.MethodsStudy design and participantsWe did a cluster RCT of four groups using a two-by-two factorial design. The RCT started on March 1, 2014. The post-intervention assessment period was initially planned for 18 months (from Jan 1, 2015, to June 30, 2016) and was subsequently extended on our request to the funding agency to 24 months (from Jan 1, 2014, to Dec 31, 2016) to enable further assessment of the PBO long-lasting insecticidal net (figure 1).Figure 1Study timetableRCT=randomised controlled trial.The study area was Muleba district of the Kagera region in northwest Tanzania, and comprised 40 villages. In 2011, malaria infection prevalence in children was 23%.18\nAnopheles gambiae and Anopheles arabiensis were the only vectors found in 2012. High levels of resistance to pyrethroids have been reported in A gambiae in the study area, and synergy bioassay tests done with PBO and pyrethroid together partially restored the toxicity of pyrethroids.19 All villages and hamlets with malaria prevalence more than 20% in 2011 were eligible for inclusion in the present trial. Our trial comprised 48 clusters, each divided into an inner core area, which was used for the measurement of study outcomes, and an outer buffer zone of at least 300 m to reduce spill-over effects between clusters.20 Core and buffer areas of each cluster received the same intervention. All households in the core area with children aged 6 months to 14 years were eligible for malaria cross-sectional survey and mosquito surveillance. We excluded children who were severely ill. Village meetings were held with village leaders, hamlet representatives, community health agents, and villagers to inform them about the trial.The trial was approved by the ethics review committees of the Kilimanjaro Christian Medical University College, the London School of Hygiene & Tropical Medicine, and the Tanzanian Medical Research Coordinating Committee (NIMR/HQ/R.8a/VolIX/1803). A trial steering committee reviewed progress. Written informed consent from parents or guardians was obtained for each survey and entomology collection.Randomisation and maskingWe used restricted randomisation to allocate the 48 clusters to the four study groups: standard long-lasting insecticidal nets, PBO long-lasting insecticidal nets, standard long-lasting insecticidal nets plus indoor residual spraying, and PBO long-lasting insecticidal nets plus indoor residual spraying. We limited potential imbalance using three restriction variables: malaria infection prevalence in children aged 6 months to 14 years, usage of long-lasting insecticidal nets, and socioeconomic status, as recorded in the baseline survey between September and October, 2014. Of the 200\u2008000 random allocations, 29\u2008478 met the restriction criteria of no more than 7% difference in mean malaria prevalence, 10% in mean usage of long-lasting insecticidal nets, and 10% of households in the lowest socioeconomic status tertile between study groups. After verifying that clusters were independently allocated to study groups, we randomly chose one of the eligible allocations.We masked the inhabitants of each cluster to the type of long-lasting insecticidal nets received. The two types of nets were of similar colour and shape, and only distinguishable by label codes and coloured thread inserted during manufacture. Additionally, we masked field staff, who took blood samples in the cross-sectional surveys, to the study groups the clusters were assigned to. It was not possible to mask either the investigators or the participants to the treatment allocation of indoor residual spraying.ProceduresWe used the following vector control products: Olyset Net (Sumitomo Chemicals, Japan) containing 2% permethrin (standard long-lasting insecticidal net), Olyset Plus (Sumitomo Chemicals, Japan) containing 2% permethrin and 1% PBO (PBO long-lasting insecticidal net), and Actellic 300CS containing microencapsulated pirimiphos-methyl (indoor residual spraying).We georeferenced all houses in the study using hand-held global positioning system units (Legend eTrex, Garmin, USA). The indoor residual spraying campaign was done once only in February, 2015, by the Research Triangle Institute funded by the President's Malaria Initiative. In the two groups assigned to indoor residual spraying intervention, Actellic 300CS was sprayed to the interior walls and ceilings of each dwelling at the recommended dosage of 1 g/m2. The residual decay of Actellic 300CS was monitored by a laboratory technician every 3 months on representative wall surfaces in several houses using WHO Cone bioassay tests (Universiti Sains Malaysia, Malaysia) and a reference strain of susceptible A gambiae. The permethrin and PBO contents of the long-lasting insecticidal nets were determined by high-performance liquid chromatography at yearly intervals for 2 years.Distribution of long-lasting insecticidal nets and health education communication on net usage were done in each cluster by the Tanzania Communication and Development Centre. On the basis of census data, each household received one net per two people. Altogether, 45\u2008000 standard long-lasting insecticidal nets and 45\u2008000 PBO long-lasting insecticidal nets were distributed in February, 2015. Nets already owned were not removed but householders were requested to use the study nets provided.Cross-sectional household and malaria infection prevalence surveys were done by project field assistants and nurses at baseline in September and October, 2014, and after intervention at the end of each malaria transmission season (June to July and November to December) in 2015 and 2016 (figure 1). During each survey, we randomly sampled 55 households with children aged 6 months to 14 years from the core area of each cluster using the census lists. We then selected up to three eligible children per house at random and recorded information about the number of residents, household assets, house structure, educational status, and use of malaria preventive measures (long-lasting insecticidal nets or other). The minimum target was 80 children per cluster. Enrolled children reported to the clinical team the next day and were tested for malaria using a rapid diagnostic test (CareStart Malaria HRP2/pLDH(pf/PAN) Combo, DiaSys, UK) and for haemoglobin concentration using HemoCue Hb 201+ (HemoCue AB, Sweden). Children diagnosed as malaria positive by the rapid diagnostic test were treated with artemether-lumefantrine according to national guidelines. Any child presenting with illness during the surveys was treated or referred to the nearest health facility if symptoms were severe.Mosquito surveillance was done from March, 2015, to December, 2016, in each cluster by a project field assistant for one night per month in seven randomly selected houses per cluster using CDC Miniature Light Trap Model 512 (John W Hock Company, USA) as a proxy for human biting rates.17 We morphologically identified the collected anophelines to species level21 and tested a subsample for Plasmodium falciparum circumsporozoite protein.22 PCR TaqMan assay23 was used to distinguish the two sibling species (A gambiae and A arabiensis) and to identify mutation in the voltage-gated sodium channel (Vgsc-1014F and Vgsc-1014S) associated with resistance to pyrethroids.24 Using wild caught A gambiae and Anopheles funestus of unknown age, the frequency of pyrethroid resistance was determined using 0·75% permethrin papers in WHO cylinder tests. We determined resistance intensity using CDC bottle bioassays and probit analysis to estimate the ratio of the permethrin concentration needed to kill 50% of wild mosquitoes relative to the susceptible strain.OutcomesThe primary outcome was the prevalence of Plasmodium spp infection measured by the rapid diagnostic test in children aged 6 months to 14 years assessed by the cross-sectional surveys. The trial was initially funded for 18 months after intervention. Although this period could have been chosen as the endpoint, it was not known for how long the PBO and pyrethroid active ingredients in the long-lasting insecticidal nets would last. This effect needed to be monitored every transmission season. We subsequently secured extension from the funding agency for 24 months. WHO then reset the policy agenda declaring that new types of long-lasting insecticidal nets (such as the PBO net) should be effective for at least two transmission seasons or 2 years. The primary endpoint for the indoor residual spraying was 1 year, based on reports of duration of residual activity. Because the two intervention products were being assessed separately and in combination, the main endpoint for assessment of the indoor residual spraying was 9 months and the PBO long-lasting insecticidal nets was 9 months and then 21 months.The secondary main outcome was malaria transmission or entomological inoculation rate, defined as the mean number of infective mosquito bites per household per month, during the first year and second year after intervention. Other secondary endpoints were the proportion of children with moderate-to-severe anaemia (defined as haemoglobin <8 g/dL), the sporozoite rate (the proportion of anopheline mosquitoes collected that were infected with malaria sporozoites), and anopheline population density.Statistical analysisThis study had 80% power25 to detect a relative reduction in prevalence of infection of at least 28% (prevalence ratio 0·72) for each of the two main effects (ie, indoor residual spraying vs no indoor residual spraying, and PBO long-lasting insecticidal nets vs no PBO long-lasting insecticidal nets) and a 40% difference between any of the individual groups, with 24 clusters of 80 individuals per cluster being tested in each of these comparisons, and assuming a mean prevalence of 20% in the reference groups and a coefficient of variation of 0·3 (based on data from the earlier study).18Statistical analysis was done using Stata (version 12). All statistical inferences allowed for within-cluster correlation of responses by use of a robust variance estimator to calculate SEs. No allowance was made for multiplicity of testing in the analyses. In the intention-to-treat analysis, logistic regression was used to estimate odds ratios (ORs) of the effect of each of the two interventions (PBO long-lasting insecticidal nets vs standard long-lasting insecticidal nets, and indoor residual spraying vs no indoor residual spraying) on prevalence of infection and prevalence of anaemia. We estimated interaction between the two main effects by including an appropriate term in the model. We also examined the effect of each intervention (PBO long-lasting insecticidal nets, combination of standard long-lasting insecticidal nets plus indoor residual spraying, and combination of PBO long-lasting insecticidal nets plus indoor residual spraying) compared with the control group (standard long-lasting insecticidal net). Effects were interpreted in relation to a postulated minimum difference of 28% for factorial analysis and 40% for the analysis of each intervention. Analysis of anaemia was restricted to children aged 6 months to 4 years. The per-protocol analysis is available in the appendix.Vector density and entomological inoculation rate were analysed with negative binomial regression, after adjusting for baseline. Entomological inoculation rate was estimated as the mean number of sporozoite-infected Anopheles per house per night26 and weighted to account for the proportion of collected Anopheles processed for sporozoites. The proportion of sporozoite-infected mosquitoes (the sporozoite rate) was compared using logistic regression.This trial is registered with ClinicalTrials.gov, number NCT02288637.Role of the funding sourceThe funder of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.ResultsThe study area comprised 29\u2008365 households and a population of 135\u2008900. Of the 10\u2008560 households selected for post-intervention survey, 7184 (68·0%) were included whereas 1127 (10·7%) were ineligible (no children younger than 15 years), 150 (1·4%) refused, 1543 (14·6%) were absent, and 556 (5·3%) were unvisited. Of the 17\u2008377 eligible children selected, 15\u2008492 (89·2%) attended for testing (figure 2). Pre-intervention household and demographic characteristics, as well as coverage and usage of long-lasting insecticidal nets were similar between study groups (table 1). Malaria infection prevalence was reported in 2499 (65%) of 3861 children at baseline, and any difference between groups were within the tolerances set for the constrained randomisation. The average indoor Anopheles density was 27·6 per house per night and the proportion of mosquitoes with sporozoites was 4·5%. Of the 13\u2008689 Anopheline mosquitoes collected, 13\u2008106 (95·7%) were A gambiae sensu lato and 510 (3·7%) were A funestus. Of the 990 A gambiae sensu lato identified to species, 946 (95·6%) were A gambiae sensu stricto and 44 (4·4%) were A arabiensis.Figure 2Trial profileLLIN=long-lasting insecticidal net. PBO=piperonyl butoxide. IRS=indoor residual spraying.Table 1Baseline characteristicsStandard LLINPBO LLINStandard LLIN plus IRSPBO LLIN plus IRSStudy cluster characteristicsTotal population in core and buffer areas33\u200882032\u200886138\u200808131\u2008138Population in core area15\u200894716\u200828216\u200835814\u2008845Household characteristicsMedian altitude of the households selected (range; N)1330 (1138–1654; 465)1275 (1138–1563; 500)1298 (1129–1486; 508)1338 (1152–1543; 510)Households in the lowest socioeconomic category146/464 (31%)166/534 (31%)198/528 (38%)163/467 (35%)Households with adequate long-lasting insecticidal nets174/545 (32%)223/582 (38%)230/580 (40%)211/561 (38%)Households with ≥1 long-lasting insecticidal nets356/545 (65%)410/582 (70%)402/581 (69%)378/561 (67%)Long-lasting insecticidal nets use in all age groups902/2996 (30%)810/3078 (26%)882/3197 (28%)810/3078 (26%)Children characteristicsMedian age, years (IQR; N)6 (3–10; 885)6 (3–9; 991)6 (3–10; 1017)6 (3–10; 967)Long-lasting insecticidal net use in selected children348/891 (39%)315/992 (32%)315/1018 (31%)307/970 (32%)Malaria infection prevalence600/885 (68%)606/991 (61%)678/1018 (67%)615/967 (64%)Anaemia prevalence in children <5 years*36/328 (11%)36/378 (10%)34/372 (9%)29/362 (8%)Median haemoglobin concentration in children <5 years, g/dL (IQR; N)10·4 (9·2–11·5; 328)10·6 (9·1–11·7; 378)10·6 (9·2–11·7; 372)10·6 (9·6–11·6; 362)Entomological characteristicsMean number of vectors found indoors per house per night (95% CI; N)17·0 (0–34·7; 129)37·0 (4·0–70·1; 119)11·8 (0–24·7; 117)43·6 (9·7–77·6; 129)Sporozoite rate39/809 (5%)59/1085 (5%)37/733 (5%)35/1161 (3%)Data are n/N (%), unless stated otherwise. Data for household, children, and entomological characteristics are only for the core area. LLIN=long-lasting insecticidal net. PBO=piperonyl butoxide. IRS=indoor residual spraying.*Anaemia was clinically diagnosed as <8 g/dL.Between baseline and the first cross-sectional survey 4 months after intervention, long-lasting insecticidal net ownership (≥one net per household) increased to 1690 (97·6%) of 1732 households, access (household with enough long-lasting insecticidal net per sleeping place) increased to 1550 (89·6%) of 1730, and long-lasting insecticidal net use increased to 7807 (76·9%) of 10\u2008152 (appendix). Long-lasting insecticidal net usage was similar between groups and between surveys during the first year. In the second year, 21 months after intervention, access decreased to 1291 (70·2%) of 1839 households and usage to 5905 (56·0%) of 10\u2008551 residents. Most long-lasting insecticidal nets observed were those deployed from this study. In the standard long-lasting insecticidal net (Olyset Net), permethrin concentration at 0 months of use was 21·4 g/kg and 21·5 g/kg after 12 months of use and decreased to 16·7 g/kg after 21 months of use. For the PBO long-lasting insecticidal net (Olyset Plus), permethrin concentration at 0 months of use was 20·9 g/kg, which decreased to 14·7 g/kg after 12 months and to 12·2 g/kg after 21 months, while PBO concentration on Olyset Plus also decreased from 9·5 g/kg at 0 months to 2·9 g/kg after 12 months and to 1·6 g/kg after 21 months of use.827 (94%) of 878 households selected for the survey received indoor residual spraying in the two groups assigned to this intervention. The insecticide residues on sprayed walls decayed gradually over the year; mosquito mortality in WHO cone bioassays was 99% (566 of 570 exposed mosquitoes died, 95% CI 97·9–100) shortly after spraying, 82% (356 of 432, 75·4–89·5) after 9 months, and 59% (495 of 840, 51·4–66·4) after 12 months.In the intention-to-treat factorial analysis for the prevalence of malaria infection, the effect of indoor residual spraying versus no indoor residual spraying was evident at 4 months (OR 0·50, 95% CI 0·31–0·82; p=0·0071) whereas there was no evidence of a difference between PBO long-lasting insecticidal nets and standard long-lasting insecticidal nets (0·68, 0·39–1·18; p=0·1630; table 2). A clear effect was observed 9 months after intervention for indoor residual spraying versus no indoor spraying (OR 0·33, 95% CI 0·19–0·55; p<0·0001) and PBO long-lasting insecticidal nets versus standard nets (OR 0·37, 0·21–0·65; p=0·0011). During the second year, the prevalence of malaria infection in the PBO long-lasting insecticidal net groups remained less than in the standard long-lasting insecticidal net groups (OR 0·47, 95% CI 0·26–0·87; p=0·0173 after 16 months of intervention; and 0·40, 0·20–0·81; p=0·0122 after 21 months of intervention), whereas the effect of the single round of indoor residual spraying applied previously waned over time (OR 0·59, 95% CI 0·34–1·04 after 16 months; and 0·58, 0·29–1·14 after 21 months; table 2). The only significant interaction was at 9 months (OR 2·43, 95% CI 1·19–4·97; p=0·0158), suggesting that at this point in time the combined effect of indoor residual spraying and PBO long-lasting insecticidal net was less than the additive effect of each of the two effects alone.Table 2ITT analysis of malaria infection prevalence by main effect and for each individual intervention at 4, 9, 16, and 21 months after interventionn/N (%)OR (95% CI)p valueSurvey A, 2015, 4 months after interventionMain effect comparison (factorial analysis)No PBO LLIN*936/1991 (47%)1 (ref)..PBO LLIN†798/1926 (41%)0·68‡ (0·39–1·18)0·1630No IRS§998/1968 (51%)1 (ref)..IRS¶736/1949 (38%)0·50‡ (0·31–0·82)0·0071Interaction coefficient..1·37 (0·66–2·86)0·3825Individual group comparisonStandard LLIN553/997 (55%)1 (ref)..PBO LLIN445/971 (46%)0·68‖ (0·39–1·18)0·1630Standard LLIN plus IRS383/994 (39%)0·50‖ (0·31–0·82)0·0071PBO LLIN plus IRS353/955 (37%)0·47‖ (0·28–0·79)0·0048Survey B, 2015, 9 months after interventionMain effect comparison (factorial analysis)No PBO LLIN*767/1809 (42%)1 (ref)..PBO LLIN†531/1852 (29%)0·37 (0·21–0·65)0·0011No IRS§790/1815 (44%)1 (ref)..IRS¶508/1846 (28%)0·33 (0·19–0·55)<0·0001Interaction coefficient..2·43 (1·19–4·97)0·0158Individual group comparisonStandard LLIN515/932 (55%)1 (ref)..PBO LLIN275/883 (31%)0·37 (0·21–0·65)0·0011Standard LLIN plus IRS252/877 (29%)0·33 (0·19–0·55)<0·0001PBO LLIN plus IRS256/969 (26%)0·29 (0·17–0·49)0·0001Survey C, 2016, 16 months after interventionMain effect comparison (factorial analysis)No PBO LLIN*941/2017 (47%)1 (ref)..PBO LLIN†611/1910 (32%)0·47 (0·26–0·87)0·0173No IRS§890/2018 (44%)1 (ref)..IRS¶662/1909 (35%)0·59‡ (0·34–1·04)0·0652Interaction coefficient..1·30 (0·59-2·86)0·5045Individual group comparisonStandard LLIN548/1034 (53%)1 (ref)..PBO LLIN342/984 (35%)0·47‖ (0·26–0·87)0·0173Standard LLIN plus IRS393/983 (40%)0·59‖ (0·34–1·04)0·0652PBO LLIN plus IRS269/926 (29%)0·36 (0·20–0·66)0·0014Survey D, 2016, 21 months after interventionMain effect comparison (factorial analysis)No PBO LLIN*1255/2034 (62%)1 (ref)..PBO LLIN†865/1930 (45%)0·40‡ (0·20–0·81)0·0122No IRS§1150/2002 (57%)1 (ref)..IRS¶970/1962 (49%)0·58‡ (0·29–1·14)0·1130Interaction coefficient..1·59 (0·62–4·07)0·3282Individual group comparisonStandard LLIN710/1044 (68%)1 (ref)..PBO LLIN440/958 (46%)0·40‖ (0·20–0·81)0·0122Standard LLIN plus IRS545/990 (55%)0·58‖ (0·29–1·14)0·1130PBO LLIN plus IRS425/972 (44%)0·37‖ (0·19–0·73)0·0056ORs for the factorial analysis compared the two main intervention effects (no PBO LLIN vs PBO LLIN, and no IRS vs IRS) and their interaction, and compared each of the intervention to the standard LLIN in the individual group analysis. OR was unadjusted for baseline plasmodium infection prevalence. Plasmodium infection prevalence is reported for children aged 6 months to 14 years. OR=odds ratio. LLIN=long-lasting insecticidal net. PBO=piperonyl butoxide. IRS=indoor residual spraying. ITT=intention to treat.*Standard LLIN and standard LLIN plus IRS.†PBO LLIN and PBO LLIN plus IRS.‡Reduction in prevalence is less than the 28% difference defined a priori for the main effect.§Standard LLIN and PBO LLIN.¶Standard LLIN plus IRS and PBO LLIN plus IRS.‖Reduction in prevalence is less than the 40% defined a priori for the individual arm comparison.In the analysis of the individual group comparisons, the difference in malaria infection prevalence between the reference group (standard long-lasting insecticidal net) and the PBO long-lasting insecticidal net group or the combination of the standard net plus indoor residual spraying group was greater than that observed in the factorial analysis at every timepoint between PBO nets and non-PBO nets or between indoor residual spraying and no indoor spraying (table 2). The individual group comparison also provides information about the effect of the PBO long-lasting insecticidal net plus indoor residual spraying intervention.Prevalence of severe-to-moderate anaemia was lower for the groups receiving PBO long-lasting insecticidal net compared with their standard long-lasting insecticidal net reference groups, and was also lower in the groups receiving indoor residual spraying than in the non-indoor residual spraying reference groups in the surveys after 9 months and 16 months intervention (table 3). Results of the per-protocol analyses of malaria infection and anaemia were similar to that of the intention-to-treat analyses (appendix).Table 3ITT analysis of anaemia prevalence by main effect and for each individual intervention at 4, 9, 16 and 21 months after interventionn/N (%)OR (95% CI)p valueSurvey A, 2015, 4 months after interventionMain effect comparison (factorial analysis)No PBO LLIN*28/664 (4%)1 (ref)..PBO LLIN†15/675 (2%)0·39 (0·11–1·30)0·1221No IRS‡23/665 (3%)1 (ref)..IRS§20/674 (3%)0·69 (0·24–1·98)0·4792Interaction coefficient..1·75 (0·37–8·14)0·4696Individual group comparisonStandard LLIN16/320 (5%)1 (ref)..PBO LLIN7/345 (2%)0·39 (0·11–1·30)0·1221Standard LLIN plus IRS12/344 (3%)0·69 (0·24–1·98)0·4792PBO LLIN plus IRS8/330 (2%)0·47 (0·18–1·25)0·1268Survey B, 2015, 9 months after interventionMain effect comparison (factorial analysis)No PBO LLIN*20/580 (3%)1 (ref)..PBO LLIN†13/603 (2%)0·31 (0·11–0·88)0·0292No IRS‡23/584 (4%)1 (ref)..IRS§10/599 (2%)0·16 (0·04–0·69)0·0149Interaction coefficient..7·51 (1·09–51·69)0·0408Individual group comparisonStandard LLIN17/281 (6%)1 (ref)..PBO LLIN6/303 (2%)0·31 (0·11–0·88)0·0292Standard LLIN plus IRS3/299 (1%)0·16 (0·04–0·69)0·0149PBO LLIN plus IRS7/300 (2%)0·37 (0·11–1·22)0·1004Survey C, 2016, 16 months after interventionMain effect comparison (factorial analysis)No PBO LLIN*20/577 (3%)1 (ref)..PBO LLIN†7/574 (1%)0·23 (0·08–0·65)0·0068No IRS‡20/571 (4%)1 (ref)..IRS§7/580 (1%)0·22 (0·08–0·64)0·0064Interaction coefficient..3·46 (0·48–24·80)0·2108Individual group comparisonStandard LLIN16/279 (6%)1 (ref)..PBO LLIN4/292 (1%)0·23 (0·08–0·65)0·0068Standard LLIN plus IRS4/298 (1%)0·22 (0·08–0·64)0·0064PBO LLIN plus IRS3/282 (1%)0·18 (0·05–0·84)0·0301Survey D, 2016, 21 months after interventionMain effect comparison (factorial analysis)No PBO LLIN*19/586 (3%)1 (ref)..PBO LLIN†24/582 (4%)1·67 (0·49–5·75)0·4080No IRS‡19/564 (3%)1 (ref)..IRS§24/604 (4%)1·55 (0·36–6·58)0·5468Interaction coefficient..0·63 (0·12–3·43)0·5881Individual group comparisonStandard LLIN7/276 (3%)1 (ref)..PBO LLIN12/288 (4%)1·67 (0·49–5·75)0·4080Standard LLIN plus IRS12/310 (4%)1·55 (0·36–6·58)0·5468PBO LLIN plus IRS12/294 (4%)1·64 (0·47–5·65)0·4287ORs for the factorial analysis compared the two main intervention effects (no PBO LLIN vs PBO LLIN, and no IRS vs IRS) and their interaction, and compared each of the intervention to the standard LLIN in the individual group analysis. OR was unadjusted for baseline anaemia prevalence. Prevalence of moderate-to-severe anaemia reported in children younger than 5 years with haemoglobin concentrations <8 g/dL. OR=odds ratio. LLIN=long-lasting insecticidal net. PBO=piperonyl butoxide. IRS=indoor residual spraying. ITT=intention to treat.*Standard LLIN and standard LLIN plus IRS.†PBO LLIN and PBO LLIN plus IRS.‡Standard LLIN and PBO LLIN.§Standard LLIN plus IRS and PBO LLIN plus IRS.A total of 16\u2008371 vector mosquitoes were collected in 5756 indoor light-trap collections over the 2 years. In the first year, vector densities, sporozoite rates, and entomological inoculation rates were lower in the PBO long-lasting insecticidal net groups than in the standard long-lasting insecticidal net groups (table 4), but only entomological inoculation rate was significantly lower in the indoor residual spraying groups than in the non-indoor residual spraying groups. In the second year, the entomological inoculation rate in the PBO long-lasting insecticidal groups remained lower than in the standard long-lasting insecticidal net groups but the effect of indoor residual spraying on entomological inoculation rate had largely diminished by this time compared with the entomological inoculation rates of 2015.Table 4Entomological outcomes by intervention (PBO LLIN vs no PBO LLIN, and IRS vs no IRS) in 2015 and 2016Vector density per night per householdSporozoite rateEIR per month per household*NMean (SD)DR (95% CI)p valuen/N (%)OR (95% CI)p valueNMean (SD)DR (95% CI)p valueYear 1: 2015No PBO LLIN†8962·61 (8·97)1 (ref)..20/952 (2%)1 (ref)..8620·90 (5·42)1 (ref)..PBO LLIN‡9611·85 (7·12)0·33 (0·16–0·69)0·00382/648 (<1%)0·25 (0·07–0·88)0·03179110·13 (2·.07)0·13 (0·03–0·53)0·0055No IRS§9392·34 (8·18)1 (ref)..21/988 (2%)1 (ref)..9011·01 (5·85)1 (ref)..IRS¶9182·09 (7·96)0·63 (0·27–1·43)0·26521/612 (<1%)0·15 (0·02–1·02)0·05198720·25 (0·89)0·03 (0·00–0·24)0·0014Interaction coefficient....1·35 (0·44–4·18)0·5940..NANA....NANAYear 2: 2016No PBO LLIN†19463·60 (16·86)1 (ref)..80/2236 (4%)1 (ref)..17931·15 (6·53)1 (ref)..PBO LLIN‡19532·68 (11·33)0·40 (0·20–0·80)0·010127/1931 (1%)0·38 (0·15–0·92)0·033118450·39 (3·91)0·33 (0·13–0·83)0·0189No IRS§19422·82 (9·34)1 (ref)..64/2207 (3%)1 (ref)..18011·00 (6·04)1 (ref)..IRS¶19573·46 (18.01)0·93 (0·47–1·85)0·830943/1960 (2%)0·81 (0·37–1·78)0·589018370·58 (4·87)0·48 (0·25–0·94)0·0340Interaction coefficient....1·00 (0·36–2·75)0·9970..1·13 (0·35–3·63)0·8308....1·38 (0·47–4·08)0·5532DR for vector density and EIR and OR for sporozoite rates are adjusted for their respective baseline value. EIR=entomological inoculation rate. DR=density ratio. OR=odds ratio. LLIN=long-lasting insecticidal net. PBO=piperonyl butoxide. IRS=indoor residual spraying. NA=not applicable.*The mean and DR of the EIR are weighted to account for the proportion of mosquitoes sampled to be tested for sporozoites. Interaction not estimated in year 1 for sporozoite and EIR outcomes, because sporozoite rate was null in the PBO LLIN plus IRS group.†Standard LLIN and standard LLIN plus IRS.‡PBO LLIN and PBO LLIN plus IRS.§Standard LLIN and PBO LLIN.¶Standard LLIN plus IRS and PBO LLIN plus IRS.The mortality of mosquitoes exposed to permethrin for resistance determination in the WHO cylinder tests was 8·8% (95% CI 5·3–12·3; n/N=54/613) for A gambiae sensu lato and 54·5% (36·8–76·2; n/N=59/108) for A funestus. The lethal concentration required to kill 50% of the wild A gambiae sensu lato was 38-times higher and of wild A funestus was 34-times higher than for the susceptible reference mosquitoes. The Vgsc gene mutation was found in all tested A gambiae with co-occurrence of Vgsc-1014F and Vgsc-1014S in 22 (9%) of 234 A gambiae mosquitoes. No mutation was found in the 247 A arabiensis tested.DiscussionThis trial showed that long-lasting insecticidal nets incorporating the synergist PBO (Olyset Plus) were more effective than the standard pyrethroid long-lasting insecticidal net (Olyset Net) in reducing malaria infection prevalence in an area of high usage of these nets and high pyrethroid resistance in the primary vectors. The additional effect of the PBO long-lasting insecticidal nets on malaria prevalence was evident at the end of the first year with a 44% protective efficacy and at the end of the second year with a 33% protective efficacy compared with the standard long-lasting insecticidal nets. These findings were supported by the entomological outcomes, which showed a significant reduction in malaria transmission, with entomological inoculation rates being reduced by 87% during the first year and 67% during the second year in areas receiving PBO long-lasting insecticidal nets compared with standard long-lasting insecticidal nets. At 9 months, the addition of pirimiphos-methyl indoor residual spraying to the standard long-lasting insecticidal nets provided similar protection against malaria (44% protective efficacy) relative to the standard nets alone, whereas the addition of indoor residual spraying to PBO long-lasting insecticidal nets did not significantly improve protection based on the interaction observed when both indoor spraying and PBO long-lasting insecticidal nets effect were at their strongest. The impact of indoor residual spraying on the entomological inoculation rates was more than 95% in the first year. This effect on malaria transmission occurred shortly after implementation of indoor residual spraying whereas the effect of PBO long-lasting insecticidal nets took longer. This rapid impact of indoor residual spraying is one reason why this intervention is sometimes more favoured than long-lasting insecticidal net distribution during malaria epidemics, although there has been a paucity of evidence to justify this advice.27 Our cluster RCT would support this recommendation, provided high indoor residual spraying coverage can be quickly achieved. Residual insecticidal activity of pirimiphos-methyl on the sprayed walls was observed up to 12 months after a single round of spraying. Following the decay in residual activity during the second year when no spraying was done, the effect of indoor residual spraying on entomological inoculation rates diminished and malaria prevalence increased but not to the level observed in the standard long-lasting insecticidal net control group, which had not received indoor residual spraying in year 1. A sustained effect on malaria transmission would require recurrent annual campaigns of indoor residual spraying.This trial is the first to provide evidence to suggest that incorporation of the synergist PBO to long-lasting insecticidal nets provides improved community protection compared with standard pyrethroid-only nets against malaria transmission by pyrethroid-resistant vector populations. Previous small-scale experimental hut studies of PBO long-lasting insecticidal nets measured entomological outcomes such as mosquito mortality and biting rates. In Benin, these studies showed that Olyset Plus was more effective than standard Olyset Net against pyrethroid-resistant A gambiae, both before and after multiple washing of the nets.12 In Tanzania where A gambiae was still susceptible to pyrethroids, the differential effect between Olyset Plus and standard Olyset Net was less evident.28 Parallel studies with a different type of PBO long-lasting insecticidal net (PermaNet 3.0) showed improved outcomes with the unwashed PBO net compared with the standard long-lasting insecticidal net, but in some studies the efficacy was lost after several washes.29 Although these small-scale studies11, 12, 28, 29 indicate the potential of PBO nets, they could not capture the full effect of this new class of net on transmission, which is only understood at high coverage levels and in community randomised trials because of the additional community protection that arises from the reduction in mosquito life-span and population density, often called the vectorial mass effect.27 With the relatively high coverage and usage of long-lasting insecticidal nets achieved in the present trial (77% usage in the first year and 60% in the second year), we were able to observe a mass effect of the PBO nets on transmission, with concomitant reductions in mosquito density, sporozoite rate, and entomological inoculation rates.Despite the 83% loss in PBO content after 21 months, the PBO and permethrin retained on the net remained highly effective against malaria infection and entomological inoculation rates throughout. By contrast, the loss of residual activity of the single round of indoor residual spraying of Actellic 300CS led to resumption of transmission and to increasing entomological inoculation rates and malaria prevalence in the second year. The PBO nets will be monitored during a third year to assess whether effectiveness is maintained at low PBO content. There was also a 42% loss of permethrin content in Olyset Plus and 22% in Olyset Net over the two years. The differential release rate of permethrin in the two nets has been observed in other studies, and it has been suggested in an earlier WHO review of Olyset Plus that the more effective performance of the PBO net is due to the higher release rate and surface concentration of permethrin in this net compared with Olyset Net.28 Although this argument cannot be completely refuted by our data, the A gambiae and A funestus vectors in the Muleba area are highly resistant to pyrethroid and any difference in surface permethrin between Olyset Plus and Olyset Net in our trial is unlikely to result in differential mortality rate. A study has shown that under household conditions a 20-times increase in the surface content of permethrin on hand-treated nets causes no increase in mortality to free-flying pyrethroid-resistant A gambiae.30 Furthermore, synergy tests with PBO showed that pyrethroid-resistant A gambiae from our study area are killed by a permethrin concentration they would normally survive if it were not mixed with PBO.19The more effective performance of PBO long-lasting insecticidal nets compared with standard long-lasting insecticidal nets in reducing the prevalence of malaria infection, together with no change in prevalence following the initial distribution and high usage of standard nets, suggests that insecticide resistance of the magnitude reported is compromising the effectiveness of standard pyrethroid nets in northwest Tanzania. A recent study in neighbouring Uganda reported no change in incidence of malaria before and after the distribution of standard long-lasting insecticidal nets.10 Other studies have reported the failure of these nets to reduce entomological indicators after the standard long-lasting insecticidal nets developed holes.5, 6 From our study design, it is not clear whether the standard nets still provide some degree of protection. Although a previous study in Muleba done in 2012 showed that users of standard long-lasting insecticidal nets were slightly better protected (OR 0·83) against malaria infection prevalence than non-users of nets,31 this finding should be contrasted with the much larger effect of PBO long-lasting insecticidal nets versus standard nets (OR 0·37) in the present study. In areas with more moderate levels of pyrethroid resistance, standard nets still provide personal protection. A study in Malawi, for example, showed that standard nets reduced malaria incidence by 30% in children in an area where pyrethroid-resistant A funestus was the main vector.8 In Kenya, the use of standard nets provided 45% protection against the incidence of malaria infection as compared with those not using long-lasting insecticidal nets, but incidence still remained high in net users.9 The strength or intensity of resistance in the local primary vector species might be the factor defining the level of protection to be derived from standard long-lasting insecticidal nets.Our study provides further insight into the question of whether indoor residual spraying and long-lasting insecticidal nets should be combined to accelerate the control of malaria. In a previous cluster RCT in Muleba, where conditions of high pyrethroid resistance and moderate usage of long-lasting insecticidal nets (50%), indoor residual spraying with the carbamate bendiocarb provided an added benefit (OR 0·43).18 In the present study, a single round of indoor residual spraying with the long-lasting pirimiphos-methyl capsule suspension in combination with standard nets was sufficient to give long-term additional protection over two transmission seasons (OR 0·33), whereas the bendiocarb required two rounds to achieve an effect of similar size, owing to its shorter residual activity on walls.The combination of indoor residual spraying of pirimiphos-methyl and PBO long-last insecticidal nets have been suggested to be antagonistic.13 This concern arose because pirimiphos-methyl requires oxidation by cytochrome P450 enzymes within the mosquito before it becomes toxic. Uptake of PBO from previous contact with Olyset Plus nets might potentially inhibit this activation process. Although the present cluster RCT neither confirmed nor disproved any antagonistic effect, it showed there was limited benefit to be gained from adding this indoor residual spraying product to PBO nets. Whether another indoor residual spraying insecticide, which does not require activation by cytochrome P450s, would prove an effective partner to PBO long-lasting insecticidal nets is not known. The present cluster RCT also implies that where indoor spraying with pirimiphos-methyl is being applied annually, the substitution of PBO nets for standard nets would provide little or no additional benefit. Considering the focal coverage of indoor residual spraying compared with the much wider coverage of long-lasting insecticidal nets in Africa, an important question from a public health standpoint is which strategy should be adopted in areas where standard long-lasting insecticidal nets might be losing effectiveness because of high intensity of pyrethroid resistance in the local vector? The substitution of PBO long-lasting insecticidal nets in such areas would provide a substantial benefit, similar to that which annual indoor residual spraying campaigns might provide.This trial has several potential limitations. Buffer areas of 300 m were small compared with what has been used in other trials,17, 18 which might not have totally prevented contamination. However, any spill-over would have lessened rather than increased the effect size between intervention groups. Additionally, the community was not masked to the indoor residual spraying allocation, which might have led to reduced child attendance at clinic sessions. However, such bias has not been observed and attendance was similar across all intervention groups. Furthermore, we used vector density in CDC light trap collections as a proxy to estimate entomological inoculation rate, rather than vector biting rate in human landing catches. The light trap approach is becoming more common in trials for pragmatic and ethical reasons; and although it could have led to error in the estimation of transmission intensity, it would not have affected the relative difference in entomological inoculation rates observed between the study groups. Finally, our trial was not powered to detect interactions.In conclusion, this trial shows the residual efficacy of indoor residual spraying with pirimiphos-methyl for malaria control of over 1 year, and provides strong evidence for increasing the coverage of PBO long-lasting insecticidal nets over standard long-lasting insecticidal nets of pyrethroid to meet the increasing challenge of pyrethroid resistance and to improve personal and community protection from malaria, particularly in areas of intense pyrethroid resistance. As a consequence of the trial, WHO has made this policy recommendation.32References1WHOWorld malaria report 20162016World Health OrganizationGeneva2RansonHN'GuessanRLinesJMoirouxNNkuniZCorbelVPyrethroid resistance in African anopheline mosquitoes: what are the implications for malaria control?Trends Parasitol2720119198208437453BarnesKIDurrheimDNLittleFEffect of artemether-lumefantrine policy and improved vector control on malaria burden in KwaZulu-Natal, South AfricaPLoS Med22005e330161877984KleinschmidtIMnzavaAPKafyHTDesign of a study to determine the impact of insecticide resistance on malaria vector control: a multi-country investigationMalar J142015282261946485AsidiAN'GuessanRAkogbetoMCurtisCRowlandMLoss of household protection from use of insecticide-treated nets against pyrethroid-resistant mosquitoes, BeninEmerg Infect Dis18201211011106227099306OchomoEOBayohNMWalkerEDThe efficacy of long-lasting nets with declining physical integrity may be compromised in areas with high levels of pyrethroid resistanceMalar J122013368241567157VianaMHughesAMatthiopoulosJRansonHFergusonHMDelayed mortality effects cut the malaria transmission potential of insecticide-resistant mosquitoesProc Natl Acad Sci USA113201689758980274027408LindbladeKAMwandamaDMzilahowaTA cohort study of the effectiveness of insecticide-treated bed nets to prevent malaria in an area of moderate pyrethroid resistance, MalawiMalar J14201531256279879OchomoEChahiluMCookJInsecticide-treated nets and protection against insecticide-resistant malaria vectors in western KenyaEmerg Infect Dis2320177587642841829310KatureebeAZinszerKArinaitweEMeasures of malaria burden after long-lasting insecticidal net distribution and indoor residual spraying at three sites in Uganda: a prospective observational studyPLoS Med132016e10021672782488511CorbelVChabiJDabireRKField efficacy of a new mosaic long-lasting mosquito net (PermaNet 3.0) against pyrethroid-resistant malaria vectors: a multi centre study in western and central AfricaMalar J920101132042347912PennetierCBouraimaAChandreFEfficacy of Olyset Plus, a new long-lasting insecticidal net incorporating permethrin and piperonyl-butoxide against multi-resistant malaria vectorsPLoS One82013e751342411602913WHOConditions for use of long-lasting insecticidal nets treated with a pyrethroid and piperonyl butoxide2015World Health OrganizationGeneva14RowlandMBokoPOdjoAAsidiAAkogbetoMN'GuessanRA new long-lasting indoor residual formulation of the organophosphate insecticide pirimiphos methyl for prolonged control of pyrethroid-resistant mosquitoes: an experimental hut trial in BeninPLoS One82013e695162393603315OxboroughRMTrends in US President's Malaria Initiative-funded indoor residual spray coverage and insecticide choice in sub-Saharan Africa (2008–2015): urgent need for affordable, long-lasting insecticidesMalar J1520161462695721016CorbelVAkogbetoMDamienGBCombination of malaria vector control interventions in pyrethroid resistance area in Benin: a cluster randomised controlled trialLancet Infect Dis1220126176262268253617PinderMJawaraMJarjuLBEfficacy of indoor residual spraying with dichlorodiphenyltrichloroethane against malaria in Gambian communities with high usage of long-lasting insecticidal mosquito nets: a cluster-randomised controlled trialLancet3852015143614462549884718WestPAProtopopoffNWrightAIndoor residual spraying in combination with insecticide-treated nets compared to insecticide-treated nets alone for protection against malaria: a cluster randomised trial in TanzaniaPLoS Med112014e10016302473637019MatowoJKitauJKaayaRTrends in the selection of insecticide resistance in Anopheles gambiae s.l. mosquitoes in northwest Tanzania during a community randomized trial of longlasting insecticidal nets and indoor residual sprayingMed Vet Entomol29201551592553775420HawleyWAPhillips-HowardPAter KuileFOCommunity-wide effects of permethrin-treated bed nets on child mortality and malaria morbidity in western KenyaAm J Trop Med Hyg68suppl 420031211271274949521GilliesMTCoetzeeMA supplement to the Anophelinae of Africa south of the Sahara (Afrotropical region)1987South African Institute for Medical ResearchJohannesburg22WirtzRAZavalaFCharoenvitYComparative testing of monoclonal antibodies against Plasmodium falciparum sporozoites for ELISA developmentBull World Health Organ6519873945355587923BassCWilliamsonMSFieldLMDevelopment of a multiplex real-time PCR assay for identification of members of the Anopheles gambiae species complexActa Trop107200850531849000024BassCNikouDDonnellyMJDetection of knockdown resistance (kdr) mutations in Anopheles gambiae: a comparison of two new high-throughput assays with existing methodsMalar J620071111769732525HayesRJMoultonLHCluster randomised trials2009Chapman and Hall/CRCNew York26DrakeleyCSchellenbergDKihondaJAn estimation of the entomological inoculation rate for Ifakara: a semi-urban area in a region of intense malaria transmission in TanzaniaTrop Med Int Health820037677741295066227PluessBTanserFCLengelerCSharpBLIndoor residual spraying for preventing malariaCochrane Database Syst Rev42010CD006657.28WHOReport of the fifteenth WHOPES working group meeting: WHO/HQ, Geneva, 18–22 June 20122012World Health OrganizationGeneva29WHOReport of the twelfth WHOPES working group meeting, WHO/HQ, Geneva 8–11 December 20082009World Health OrganizationGeneva30CorbelVChandreFBrenguesCDosage-dependent effects of permethrin-treated nets on the behaviour of Anopheles gambiae and the selection of pyrethroid resistanceMalar J32004221524251331WestPAProtopopoffNWrightAEnhanced protection against malaria by indoor residual spraying in addition to insecticide treated nets: is it dependent on transmission intensity or net usage?PLoS One102015e01156612581137932WHOConditions for deployment of mosquito nets treated with a pyrethroid and piperonyl butoxide2017World Health OrganizationGenevaSupplementary MaterialSupplementary appendixAcknowledgmentsThis study was funded by the Joint Global Health Trials Scheme of the UK Department for International Development, Medical Research Council, and Wellcome Trust (MR/L004437/). We thank colleagues and staff at the Kilimanjaro Christian Medical University College in Muleba and Moshi, and those at the National Institute of Medical Research in Muheza and Mwanza who were involved in the project. We acknowledge the assistance provided by staff at the Muleba District Medical Office, at both the village and hamlet level. Additionally, we thank the study trial steering committee members (John Gimnig, Jan Kolaczinski, and Mark Paine). We thank USAID/President's Malaria Initiative and RTI International for funding and implementing the indoor residual spraying operation in the study area, and the Tanzania Communication and Development Center for communications and implementation of the distribution campaign of the long-lasting insecticidal nets. We thank Hanafy Ismail (Liverpool School of Tropical Medicine, Liverpool, UK) for chemical analysis of the long-lasting insecticidal net samples and Philippa West (The London School of Hygiene & Tropical Medicine, London, UK) for the constrained randomisation. Finally, we thank all the participating children and their parents.ContributorsNP, IK, and MR conceived and designed the study. CDM, FWM, and WK advised on interventions, study communities, and coordination with local and national authorities. NP, JFM, EL, JDC, AW, and AM implemented the study. NP and JFM analysed the data. NP, JFM, IK, and MR interpreted the data. NP and JFM wrote the first draft of the manuscript. IK and MR critically revised the manuscript for important content. MR led the coordination with international policy authorities. EL, JDC, AW, CDM, AM, FWM, and WK revised the manuscript. All authors read and approved the final version of the manuscript.Declaration of interestsWe declare no competing interests.", 'title': 'Effectiveness of a long-lasting piperonyl butoxide-treated insecticidal net and indoor residual spray interventions, separately and together, against malaria transmitted by pyrethroid-resistant mosquitoes: a cluster, randomised controlled, two-by-two factorial design trial.', 'date': '2018-04-16'}}
| 0.5
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Public Health, Epidemiology & Health Systems
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78
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Is malaria incidence higher, lower, or the same when comparing non‐pyrethroid‐like indoor residual spraying (IRS) plus insecticide‐treated nets (ITNs) to insecticide‐treated nets (ITNs) alone?
|
uncertain effect
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very low
|
no
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['29229808', '22682536']
| 31,120,132
| 2,019
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{'29229808': {'article_id': '29229808', 'content': 'Proc Natl Acad Sci U S AProc. Natl. Acad. Sci. U.S.ApnaspnasPNASProceedings of the National Academy of Sciences of the United States of America0027-84241091-6490National Academy of Sciences29229808574819420171381410.1073/pnas.1713814114PNAS PlusBiological SciencesMedical SciencesPNAS PlusImpact of insecticide resistance in Anopheles arabiensis on malaria incidence and prevalence in Sudan and the costs of mitigationInsecticide resistance impact on malariaKafyHmooda Totoab1IsmailBashir Adambc1MnzavaAbraham PeterdLinesJonathaneAbdinMogahid Shiekh EldinfgEltaherJihad SuliemanhBanagaAnuar OsmaniWestPhilippajBradleyJohnjCookJackiejThomasBrentkSubramaniamKrishanthikHemingwayJanetk2KnoxTessa BellamydMalikElfatih M.lYukichJoshua O.mDonnellyMartin Jameskn2KleinschmidtImmojo2aVector Unit, Ministry of Health, Khartoum, Sudan;bSchool of Biological Sciences, Universiti Sains Malaysia, 11800 Pulau Penang, Malaysia;cState Malaria Control Programme, Khartoum, Sudan;dMalaria Programme, World Health Organization, 1202 Geneva, Switzerland;eDepartment of Disease Control, London School of Hygiene and Tropical Medicine (LSHTM), London WC1E 7HT, United Kingdom;fKilimanjaro Christian Medical University College, Moshi, Tanzania;gDepartment of Information, Ministry of Health, Khartoum, Sudan;hMalaria Research and Training Centre, Sennar, Sudan;iState Malaria Control Programme, Gedarif, Sudan;jDepartment of Infectious Disease Epidemiology, LSHTM, London WC1E 7HT, United Kingdom;kDepartment of Vector Biology, Liverpool School of Tropical Medicine, Liverpool L35QA, United Kingdom;lMinistry of Health, Khartoum, Sudan;mCenter for Applied Malaria Research and Evaluation, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112;nWellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, United Kingdom;oSchool of Pathology, University of Witwatersrand, Braamfontein 2000, Johannesburg, South Africa2To whom correspondence may be addressed. Email: janet.hemingway@lstmed.ac.uk, martin.donnelly@lstmed.ac.uk, or Immo.Kleinschidmt@LSHTM.ac.uk.Contributed by Janet Hemingway, October 2, 2017 (sent for review November 12, 2016; reviewed by Christen Fornadel and Kimberly Lindblade)Author contributions: A.P.M., J.L., J.H., T.B.K., M.J.D., and I.K. designed research; H.T.K., B.A.I., M.S.E.A., J.S.E., A.O.B., B.T., K.S., E.M.M., and M.J.D. performed research; H.T.K., M.S.E.A., J.S.E., B.T., K.S., and M.J.D. contributed new reagents/analytic tools; P.W., J.B., J.C., E.M.M., J.O.Y., and I.K. analyzed data; and J.H., M.J.D., and I.K. wrote the paper.Reviewers: C.F., United States Agency for International Development; and K.L., Centers for Disease Control.1H.T.K. and B.A.I. contributed equally to this work.26122017111220171112201711452E11267E11275Copyright © 2017 the Author(s). Published by PNAS.2017This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).SignificanceEmerging insecticide resistance in malaria vectors could presage a catastrophic rebound in malaria morbidity and mortality. In areas of moderate levels of resistance to pyrethroids, long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) with a carbamate insecticide were significantly more effective than IRS with pyrethroid insecticide. The impact on the effectiveness of LLINs could not be quantified. The incremental cost of using a carbamate insecticide to which vectors are susceptible was US $0.65 per person protected per year, which is considered acceptable by international standards. While the WHO recommends that different interventions, where possible, should use different insecticide classes, these data alone should not be used as the basis for a policy change in vector control interventions.Insecticide-based interventions have contributed to ∼78% of the reduction in the malaria burden in sub-Saharan Africa since 2000. Insecticide resistance in malaria vectors could presage a catastrophic rebound in disease incidence and mortality. A major impediment to the implementation of insecticide resistance management strategies is that evidence of the impact of resistance on malaria disease burden is limited. A cluster randomized trial was conducted in Sudan with pyrethroid-resistant and carbamate-susceptible malaria vectors. Clusters were randomly allocated to receive either long-lasting insecticidal nets (LLINs) alone or LLINs in combination with indoor residual spraying (IRS) with a pyrethroid (deltamethrin) insecticide in the first year and a carbamate (bendiocarb) insecticide in the two subsequent years. Malaria incidence was monitored for 3 y through active case detection in cohorts of children aged 1 to <10 y. When deltamethrin was used for IRS, incidence rates in the LLIN + IRS arm and the LLIN-only arm were similar, with the IRS providing no additional protection [incidence rate ratio (IRR) = 1.0 (95% confidence interval [CI]: 0.36–3.0; P = 0.96)]. When bendiocarb was used for IRS, there was some evidence of additional protection [interaction IRR = 0.55 (95% CI: 0.40–0.76; P < 0.001)]. In conclusion, pyrethroid resistance may have had an impact on pyrethroid-based IRS. The study was not designed to assess whether resistance had an impact on LLINs. These data alone should not be used as the basis for any policy change in vector control interventions.malariapyrethroidresistanceinsecticideAnophelesBill and Melinda Gates Foundation (Bill & Melinda Gates Foundation)10000086548499.01United Nations (UN)100004420GEF ID:2546To date, the 21st century has seen an unprecedented reduction in the global burden of malaria. While still unacceptably high, disease incidence in sub-Saharan Africa has decreased by 42% from an average of 427 cases per 1,000 persons at risk in 2,000 to 246 cases per 1,000 persons at risk in 2015; infection prevalence with Plasmodium falciparum in children aged 2–10 y has halved from 33 to 16% over the same period (1). This has resulted in an estimated 1.2 billion fewer malaria cases and 6.2 million fewer malaria deaths. Recent estimates show that the widespread deployment of insecticide-based interventions has been, overwhelmingly, the driver of the reduction in malaria in Africa (2). Of the 663 million clinical cases estimated to have been averted due to malaria control interventions since 2000, 78% were attributable to insecticide-treated nets or indoor residual spraying (IRS). These two interventions have been massively scaled up since 2000 (1).Emerging insecticide resistance in the anopheline malaria vectors could presage a catastrophic rebound in disease incidence. At present, there are only four insecticide classes available to malaria control programs; pyrethroids, organochlorines, carbamates, and organophosphates, with pyrethroids being the only class currently recommended by the WHO for use on long-lasting insecticidal nets (LLINs). Pyrethroids and the organochlorine dichlorodiphenyltrichloroethane (DDT) share the same target site, the voltage-gated sodium channel, while carbamates and organophosphates are acetylcholinesterase inhibitors. Resistance to pyrethroids is extensive throughout sub-Saharan Africa, while resistance to the three nonpyrethroid chemical classes used for IRS is simultaneously emerging in many regions (3–5). Resistance arises mainly from a combination of mutations within mosquitoes at the target site of the insecticide and enhanced detoxification/excretion of the insecticide.While conclusive evidence that resistance is directly impacting epidemiological indicators of malaria is scanty, by the time such data are available, it may well be too late. To address the problem, the WHO developed the Global Plan for Insecticide Resistance Management in malaria vectors (GPIRM), which was designed to forestall a disastrous increase in malaria burden (6). Unfortunately, most malarious countries have yet to amend their vector control strategies to align with the GPIRM despite widespread resistance to pyrethroids (7). While this is partially due to the absence of compelling data on the impact of insecticide resistance, it also reflects the lack of viable alternatives to LLINs and current insecticides.A five-country study was established to provide quantitative estimates of the impact of resistance on malaria burden (8). One study was conducted in Galabat, Sudan. In Sudan, almost the entire population lives in areas with low to moderate transmission. Malaria transmission is seasonal and unstable. Countrywide, the majority of the population (80%), including urban populations, live in areas with <1% P. falciparum infection risk in children aged 2–10 y, while the remaining 20% of the population, residing mainly in the south of the country, experience meso- to hyperendemic risk of infection (9). Reported malaria cases were reduced from an estimated 7.5 million in 1990 (10) to 1.2 million in 2014. P. falciparum accounts for 95% of the malaria burden (9, 10), with Anopheles arabiensis being the main malaria vector (11).In Sudan, artemisinin-based combination therapy has been used for malaria treatment since 2004, with artesunate plus sulfadoxine/pyrimethamine as first-line treatment, artemether/lumefantrine as second-line therapy, and quinine for the treatment of complicated malaria (10). Malaria diagnosis is based on microscopy and rapid diagnostic tests (RDTs) (10). Between 2013 and 2015, 13 million LLINs were distributed, resulting in overall coverage of 92% of households with one LLIN per two persons in 2015 according to Ministry of Health reports. Therefore, the emergence of insecticide resistance (12, 13) is a major concern as it could severely compromise the effectiveness of vector control in Sudan.Galabat, Gedarif State, was considered suitable for this study since malaria is highly seasonal and more intense there than in many other parts of Sudan, and it had no previous history of IRS. Human settlements also facilitate the formation of well-separated clusters. Twenty-six villages were selected as study clusters and received universal coverage of LLINs. Thirteen of these clusters were randomly selected to receive IRS in addition to LLINs. In 2012, deltamethrin was used for IRS, which was replaced by bendiocarb in 2013 and 2014. The protective effect of bendiocarb, to which there was no resistance, could therefore be compared with the effect of deltamethrin, to which there was insecticide resistance, with the LLIN-only clusters acting as controls. For ethical reasons, it was not feasible to assess the impact of insecticide resistance on the overall effectiveness of LLINs since this would require a neutral arm with no vector control.This study aimed to quantify:i)The impact of switching to a nonpyrethroid IRS insecticide on the incidence and prevalence of malaria infection in an area of moderate pyrethroid resistanceii)The impact of phenotypic and genotypic insecticide resistance on the incidence and prevalence of malaria infectioniii)The impact of the addition of nonpyrethroid IRS insecticide on the evolution of pyrethroid resistance in an area of universal LLIN coverageiv)The cost of using nonpyrethoid IRS in addition to LLIN coverage to mitigate the negative consequences of pyrethroid resistance on the incidence of malaria infectionResultsIntervention Coverage.Following a census to determine the number of households and population size of the study area, 72,714 LLINs (PermaNet 2.0; Vestergaard) were distributed in the 26 clusters in April 2011 to protect 139,566 individuals based upon a universal coverage approach of one net for two people. Nets were replaced in June 2014 with 72,098 new LLINs for 122,647 people. An annual intervention assessment survey showed that household net ownership was 99.6% in 2012, 82.1% in 2013, and 98.6% in 2014. LLIN usage, defined as the proportion of affirmative responses to the question “Did this child sleep under an LLIN last night?”, was generally high and very similar in study arms (Table 1), but varied by season throughout the year (data not tabulated). IRS was conducted in August and again in late December of each year. In 2012, both spray rounds utilized deltamethrin (25 mg of active ingredient per square meter; Chema Industries), while in 2013 and 2014, bendiocarb (Ficam 80% WP; Bayer; 200 mg of active ingredient per square meter) was sprayed. IRS spray coverage was 99%, 82%, and 83% in the years 2012, 2013, and 2014, respectively, as determined by annual cross-sectional surveys. The IRS coverage reported in the LLIN arm is from the householder questionnaires. It is possible that this was from private spraying, but more likely that it represents householder misreporting.Table 1.LLIN usage, IRS coverage, insecticide resistance, prevalence of infection, and malaria incidence in cohort children by study arm and study yearLLIN-only armLLIN + IRS armVariable201220132014201220132014LLIN usage, % (child nights)79 (73,375)74 (75,040)82 (78,918)79 (73,738)75 (74,612)82 (78,888)IRS coverage, % (N)9 [1–45] (1,320)1 [0–2] (1,954)4 [1–27] (2,195)99 [96–100] (1,314)82 [75–87] (1,816)83 [68–91] (2,032)Mean age, y5.1 [4.9–5.4]5.4 [5.2–5.5]6.2 [6.1–6.3]5.2 [5.0–5.4]5.5 [5.4–5.7]6.3 [6.1–6.4]Malaria cases117155981268265Malaria incidence*45 [24–87]52 [26–101]33 [14–78]47 [20–110]27 [15–50]21 [10–43]Prevalence of infection, % (N)7 [3–14] (1,272)5 [2–10] (1,791)5 [3–9] (1,961)10 [6–16] (1,246)4 [2–7] (1,654)3 [2–5] (1,880)Deltamethrin mortality (clusters), % (references)65 [49–81] (6)90 [85–95] (6)56 [48–64] (11)60 [44–76] (5)84 [71–96] (6)68 [61–75] (13)95% CIs are shown in brackets.*Cases per 1,000 child-years.During the 3-y period from June 1, 2012–May 31, 2015, there were 643 episodes of malaria in 7,529 cohort children who were followed up cumulatively for 17,284 person-years. The mean age of cohort children was similar in the two study arms in each year, but rose gradually from 5.2 y in the first study year to 6.25 y in the third year (Table 1).Incidence of Malaria and Prevalence of Malaria Infection by Study Arm and by IRS Insecticide.Mean overall incidence was 37.2 per 1,000 person-years [95% confidence interval (CI): 24.3–56.9], declining from 49.9 per 1,000 person-years in year 1, to 36.1 per 1,000 person-years in year 2, to 26.8 per 1,000 person-years in year 3.Mean incidence in the LLIN + IRS study arm was 47.2 per 1,000 person-years when deltamethrin was used (2012), but was almost halved to an average of 24.6 per 1,000 person-years during the 2 y when bendiocarb was used (2013 and 2014) (Table 2). Over the same period in the LLIN-only arm, incidence remained virtually unchanged, from 44.4 per 1,000 person-years in year 1 to 42.1 per 1,000 person-years in years 2–3. Comparing incidence between study arms, the incidence rate ratio (IRR) for LLIN + deltamethrin compared with LLIN alone (2012) was 1.0 (95% CI: 0.36–2.97; P = 0.96); for LLIN + bendiocarb versus LLINs alone (2013), it was 0.60 (95% CI: 0.39–0.91; P = 0.017), while for 2014 (LLIN + bendiocarb versus LLIN), it was 0.69 (95% CI: 0.31–1.50; P = 0.35). For the two bendiocarb years combined, the IRR for IRS + LLIN versus. LLIN alone was 0.65 (95% CI: 0.44–0.96; P = 0.032). There was strong evidence that the change in insecticide modified the effect of IRS + LLIN versus LLIN alone: The IRR for comparing the effect of IRS + LLIN in 2013 and 2014 (bendiocarb) versus LLIN alone with the effect of IRS + LLIN in 2012 (deltamethrin) versus LLIN alone was 0.51 (95% CI: 0.35–0.73; P < 0.001) and 0.62 (95% CI: 0.42–0.93; P = 0.020), respectively (overall interaction P = 0.001; Table 2). The interaction IRR comparing the effect of IRS + LLIN in 2013–2014 combined (bendiocarb) versus LLIN alone with the effect of IRS + LLIN in 2012 (deltamethrin) versus LLIN alone was 0.55 (95% CI: 0.40–0.76; P < 0.001).Table 2.Effect of year, study arm, and IRS insecticide on malaria incidence, Galabat, Sudan, 2012–2014Effects by individual study yearsEffects comparing 2013/2014 (bendiocarb) with 2012 (deltamethrin)YearStudy armCasesMean incidence (range)Unadjusted rate ratio (95% CI)Adjusted rate ratio* (95% CI)†Bendiocarb effect‡PeriodStudy armMean incidenceAdjusted rate ratio* (95% CI)‡Bendiocarb effect‡2012LLIN11745 (24–87)1112012LLIN45 (4–87)1LLIN + Delta12647 (20–110)1.0 (0.36–2.95); P = 0.961.0 (0.36–2.97); P = 0.96LLIN + Delta47 (20–110)1.0 (0.36–2.97); P = 0.9612013LLIN15552 (26–101)110.51 (0.35–0.73); P < 0.0012013/2014LLIN42 (21–85)1LLIN + Bend8227 (15–50)0.53 (0.21–1.32); P = 0.170.60 (0.39–0.91); P = 0.0172014LLIN9833 (14–78)110.62 (0.42–0.93); P = 0.020LLIN + Bend25 (13–47)0.65 (0.44–0.96); P = 0.0320.55 (0.40–0.76); P < 0.001LLIN + Bend6521 (10–43)0.62 (0.20–1.95); P = 0.420.69 (0.31–1.50); P = 0.347*Adjusted for age at time of visit and, for 2013 and 2014, the rate in 2012.†Test to determine if the effect of IRS was different between years (P = 0.001).‡Test comparing the effect of bendiocarb IRS and deltamethrin IRS (P < 0.001).In a sensitivity analysis to test the robustness of the results to the possibility of undue influence exerted by participants who had multiple episodes of malaria, follow-up was restricted to the 550 first episodes observed (i.e., censoring follow-up after the first positive test result). This analysis produced very similar findings to those obtained from the full dataset (results not tabulated).In the three cross-sectional prevalence surveys that were conducted from September to October of each of the three study years, 2,518, 3,445, and 3,841 children were tested by RDTs, of whom 214 (8.5%), 146 (4.2%), and 162 (4.2%) tested positive in 2012, 2013, and 2014, respectively. Analogous results were recorded to those comparing malaria incidence (Table 3). In the IRS + LLIN study arm, mean prevalence of infection fell from 10.4% when deltamethrin was used for IRS (2012) to 3.4% when bendiocarb was used (years 2013/2014) (P = 0.002). Over the same period, mean prevalence in the LLIN-only arm declined more moderately and nonsignificantly from 6.7 to 5.0% (P = 0.41). Comparing prevalence between study arms, the odds ratio (OR) for LLIN + deltamethrin versus LLIN alone in 2012 was 2.11 (95% CI: 0.36–2.97; P = 0.96); for LLIN + bendiocarb versus LLINs alone (2013), it was 1.39 (95% CI: 0.32–6.14; P = 0.66), while for 2014, it was 0.37 (95% CI: 0.18–0.77; P = 0.007). For the two bendiocarb years combined, the OR for LLIN + IRS versus LLIN alone was 0.61 (95% CI: 0.29–1.27; P = 0.19). There was strong evidence that the change in insecticide modified the effect of IRS with an overall interaction of P = 0.001 for interaction tests applied to individual years (left-hand side of Table 3) and P < 0.001 for interaction tests applied to 2012 versus 2013/2014 combined (right-hand side of Table 3). The interaction OR for comparing the effect of IRS + LLIN in 2013 and 2014 (bendiocarb years) versus LLIN alone with the effect of IRS + LLIN in 2012 (deltamethrin) with LLIN alone was 0.55 (95% CI: 0.35–0.87; P = 0.01) and 0.30 (95% CI: 0.19–0.47; P < 0.001), respectively. The interaction OR comparing the effect of IRS + LLIN in 2013–2014 combined (versus LLIN alone) with the effect of IRS + LLIN in 2012 (deltamethrin) (versus LLIN alone) was 0.40 (95% CI: 0.27–0.59; P < 0.001).Table 3.Effect of year, study arm, and IRS insecticide on malaria prevalence, Galabat, Sudan, 2012–2014Effects by individual study yearsEffects comparing 2013/2014 (bendiocarb) with 2012 (deltamethrin)YearStudy armPrevalence, % (N)Unadjusted ORAdjusted OR*Bendiocarb effect†PeriodStudy armMean prevalence, %Adjusted OR*Bendiocarb effect‡2012LLIN7 [3–14] (1,272)112012 DeltaLLIN7 [3–14] (1,272)1LLIN + IRS10 [6–16] (1,246)1.61 [0.60–4.35]; P = 0.332.11 [0.85–5.22]; P = 0.11LLIN + IRS10 [6–16] (1,246)2.11 [0.85–5.22]; P = 0.1112013LLIN5 [2–10] (1,791]112013–2014 BendiocarbLLIN5 [2.8–8.6] (3,752)1LLIN + IRS4 [2–7] (1,654)0.86 [0.31–2.42]; P = 0.771.39 [0.32–6.14]; P = 0.660.55 [0.35–0.87]; P = 0.012014LLIN5 [3–9] (1,961)11LLIN +I RS3.4 [2.1–5.4] (3,534)0.61 [0.29–1.27]; P = 0.190.40 [0.27–0.59]; P < 0.001LLIN + IRS3 [2–5] (1,880)0.54 [0.26–1.13]; P = 0.0980.37 [0.18–0.77]; P = 0.0070.30 [0.19–0.47]; P < 0.00195% CIs are shown in brackets. Delta, deltamethrin.*Adjusted for age, study arm, and study period.†Overall likelihood ratio test, P < 0.0001 (test to determine if effect of IRS was different between years).‡Overall likelihood ratio test, P < 0.0001 (test comparing the effect of bendiocarb IRS and deltamethrin IRS).Association Between Resistance and Incidence and Prevalence of Malaria Infection.During the course of the study, 4,680 female An. arabiensis mosquitoes were phenotyped for deltamethrin susceptibility using WHO discriminating dose tests (14), with evidence of resistance to deltamethrin in both study arms (Fig. 1). The mean percentage mortality in the LLIN arm (65.0%, 95% CI: 44.6–85.3) was not significantly different (t = 0.425; df, 9; P = 0.68) from that of the LLIN + IRS arm (60%, 95% CI: 38.2–82.2) during year 1. The assay for the Vgsc-1014F mutation was successfully conducted in 1,847 of 1,872 specimens (Fig. 1). There was a subsequent decrease in allelic frequency (two-way ANOVA, P < 0.001), but no evidence of an association between allelic frequency and the study arm (two-way ANOVA, P > 0.05; Fig. 1). There was no evidence of nonnormality of the mortality or the allele frequency data.Fig. 1.Change in deltamethrin mortality (Upper) and Vgsc-1014F (Lower) across study years and between single (LLIN) and dual (LLIN + IRS) intervention arms. Box whisker plots show the median (bold line) and interquartile range (boxes). Phenotypic data were available from six LLIN and five LLIN + IRS clusters in 2012, six LLIN and six LLIN + IRS clusters in 2013, and 11 LLIN and 13 LLIN + IRS clusters in 2014. Genotypic data were available for all 26 clusters for all years. In 2014, there was significantly (P = 0.038) higher mortality (less resistance) in the LLIN + IRS arm (n = 13; mortality = 68%; 95% CI: 60.0–76.0) compared with the LLIN-only arm (n = 11; mortality = 56.1%; 95% CI: 47.1–64.9).The association between cluster- and year-specific bioassay survivorship (phenotypic resistance) and cluster- and year-specific malaria incidence in cohort children was assessed using multiple variable Poisson regression models, adjusting for study arm and study year. Unadjusted and adjusted IRRs show no association between malaria incidence in cohort children and deltamethrin bioassay survivorship in mosquitoes from corresponding clusters (Fig. 2 and Table 4). To estimate any effect that resistance in a particular year and a particular cluster may have had on the prevalence of infection as determined by annual cross-sectional surveys, logistic regression was carried out, again adjusting for study arm and study year. Unadjusted and adjusted ORs showed no evidence of any association between resistance as measured through bioassay survivorship and infection prevalence (Table 3).Fig. 2.Cluster-specific malaria case incidence and cluster-specific malaria infection prevalence plotted against cluster-specific phenotypic resistance (bioassay mortality after standard exposure to deltamethrin) and against cluster-specific Vgsc-1014F allele frequency for 2012, 2013, and 2014 in Galabat, Sudan.Table 4.Association between malaria prevalence and malaria incidence with genotypic and phenotypic resistance, respectively, from 2012–2014Resistance statusUnadjusted OR/ rate ratio (95% CI)Adjusted OR/rate ratio* (95% CI)Malaria prevalence\u2003L1014F linear, per 1% mutation1.009 (0.99–1.03); P = 0.350.992 (0.97–1.02); P = 0.51\u2003Deltamethrin linear, per 1% survivorship0.999 (0.970–1.029); P = 0.911.007 (0.98–1.04); P = 0.67Malaria incidence\u2003L1014F linear, per 1% mutation1.462 (0.411–5.196); P = 0.560.415 (0.065–2.665); P = 0.35\u2003Deltamethrin linear, per 1% survivorship0.995 (0.959–1.032); P = 0.780.991 (0.947–1.037); P = 0.70*Adjusted for variations in year and study arm. Note that for phenotype data, there is interyear variation in the number of clusters.Similar analysis was carried out to investigate whether malaria incidence and infection prevalence were associated with Vgsc-1014F frequency, measured in mosquito specimens collected in corresponding clusters and years. There was no evidence of any association between malaria incidence or infection prevalence on the one hand and Vgsc-1014F frequency on the other (Fig. 2 and Table 4).Subgroup analysis was carried out restricted to the combined data from the LLIN-only arm for all 3 y and to the LLIN + IRS arm for the year in which deltamethrin was sprayed. There was again no association between malaria incidence and Vgsc-1014F frequency (P = 0.59), between infection prevalence and Vgsc-1014F frequency (P = 0.39), between malaria incidence and bioassay survivorship (P = 0.85), and between infection prevalence and bioassay survivorship (P = 0.98).Association Between the Addition of Nonpyrethroid IRS Insecticide and the Evolution of Insecticide Resistance to Pyrethroids in an Area of Universal LLIN Coverage.It was only possible to conduct resistance phenotyping in 11 and 12 clusters in 2012 and 2013, respectively; this figure rose to 24 in 2014. In 2012 as well as in 2013 (the first year of bendiocarb spraying), there was no significant difference in mosquito deltamethrin susceptibility between intervention arms. However, in 2014, there was significantly higher mortality (less resistance) in the LLIN + IRS arm (n = 13; mortality = 68%; 95% CI: 60–76) compared with the LLIN arm (n = 11; mortality = 56%; 95% CI: 47–65) (P = 0.038) (Fig. 1). In all clusters across all years, An. arabiensis populations were susceptible to bendiocarb.Cost and Cost-Effectiveness.The cost of protection with LLIN only in Galabat was estimated to be US $2.16 per person-year, while the cost of protection per person-year with LLIN + IRS (deltamethrin) was estimated to be US $4.36. The cost per person-year of protection with LLIN + IRS (bendiocarb) was estimated to be US $5.01. These cost estimates translate into an incremental cost of switching from IRS with deltamethrin to IRS with bendiocarb in this study of US $0.65 per person-year. With the year 1 incidence of 49.9 episodes per 1,000 person-years, this translates to an incremental cost per case averted of US $29. Assuming a case fatality rate for malaria of 0.005, the incremental cost per death averted was approximately US $6,400 and an incremental cost per disability adjusted life year (DALY) averted of US $195. These results are well within accepted standards for highly cost-effective interventions for Sudan established by the WHO (15). Sensitivity analysis indicated that changes to discount rate, prices of LLINs, or allocation of shared costs did not affect the incremental costs of the insecticide switch and that reduction of the cost of bendiocarb to the cost of deltamethrin would have resulted in nearly identical costs per person protected, indicating that there were only minor differences in delivery costs for the intervention with bendiocarb. Sudan is an area with low malaria incidence, and it is likely that in other areas with a higher incidence and more severe pyrethroid resistance, such a switch is likely to be associated with even greater cost-effectiveness.DiscussionAssociation Between Malaria Incidence/Prevalence and Switching Active Ingredients.Malaria incidence was similar and malaria prevalence was higher in the study arm in which deltamethrin IRS was sprayed in addition to LLIN use, compared with LLINs alone. The higher prevalence in the LLIN + IRS arm was likely to be the result of an imperfect balance in the two study arms. In the following 2 y when IRS with bendiocarb replaced deltamethrin, there was a significant reduction in the LLIN + IRS arm compared with the year in which deltamethrin was used, while incidence and prevalence remained stable in the clusters that only had LLINs. Compared with the LLIN-only arm, incidence was significantly lower in the IRS + LLIN arm in the 2 y in which bendiocarb was used [IRR = 0.65 (95% CI: 0.44–0.96; P = 0.032)], and this effect differed significantly from the effect of IRS + LLIN with deltamethrin [interaction IRR = 0.55 (95% CI: 0.40–0.76; P < 0.001)]. Prevalence of infection was only lower in the IRS + LLIN arm compared with the LLIN-only arm of the study in 2014; however, again, there was very strong evidence that bendiocarb significantly modified the effect of IRS when comparing the OR between study arms during the years in which bendiocarb was used with the OR between study arms when deltamethrin was used [interaction OR = 0.40 (95% CI: 0.27–0.59; P < 0.001)]. Deltamethrin has been shown to be effective when used for IRS in a variety of settings (16–19). While we cannot completely discount differential longevity of the deltamethrin and bendiocarb IRS formulations used in Sudan, the expectation from previous studies is that the deltamethrin formulation would have a marginally longer residual life than the bendiocarb formulation. We conclude that the presence of pyrethroid resistance is a plausible explanation for the loss of effectiveness of deltamethrin IRS, resulting in substantially suboptimal malaria control. To date, there are few studies assessing the impact of insecticide resistance as the design of such studies is problematic because (i) the exposure of interest, resistance to an insecticide in the local vector, cannot be randomly allocated and (ii) it is unethical to knowingly protect a human population with IRS using an insecticide that is unlikely to be effective if alternatives are available. Evidence of the impact of insecticide resistance on IRS has thus far always been generated by retrospective studies (20, 21). Our data, when considered with two retrospective studies from South Africa and Uganda, where the primary vectors were Anopheles funestus and Anopheles gambiae, respectively, provide further evidence that pyrethroid resistance is highly likely to be compromising the effectiveness of IRS.The impact of resistance in KwaZulu-Natal, South Africa, was more marked than that observed in the current study, with a near 10-fold increase in annual malaria cases witnessed from 1995 to 2000 following a switch from DDT to deltamethrin (21). Insecticide susceptibility tests later showed that there was resistance to pyrethroids in An. funestus, a vector that had previously been driven to near extinction in KwaZulu-Natal but that resurged following the change to pyrethroid IRS (22). Subsequent reversion back to IRS with DDT in 2000 was followed by a rapid decline in cases that was maintained in subsequent years (23). In a study by Kigozi et al. (20) in Uganda, routinely collected malaria health facility data were compared temporally in relation to the insecticide used in IRS: five rounds of IRS spraying DDT (n = 1), pyrethroid (n = 1), or bendiocarb (n = 3). There was known resistance to both pyrethroids and DDT, but not to bendiocarb, in the area. Small decreases in the odds of malaria infection were observed following both DDT and pyrethroid spraying, with the decrease in malaria infection being much greater following the bendiocarb spray round.The strength of the study described here was the ability to compare the change in incidence in the IRS clusters with changes in incidence in 13 contemporaneous control group clusters, which had been randomly selected and which were similar in most respects to the intervention group. The reduction in both malaria incidence and prevalence after the introduction of the carbamate insecticide may therefore be attributable to this change in insecticide. Since IRS with deltamethrin and IRS with bendiocarb are effective insecticides in settings with susceptible vectors (17, 18, 24, 25), the lack of impact of the deltamethrin IRS may be due to the presence of deltamethrin resistance in the study area. As would be expected from earlier studies (26, 27), despite resistance, some protection against malaria was provided in both study arms by high coverage with LLINs.The IRS with bendiocarb in this study provided very similar protection in addition to LLINs to that estimated in a recent cluster randomized trial in Tanzania (28). This study serves as reminder of the potential consequences of using failing insecticides, particularly if no other preventive measures are in place, and the need for insecticide policy to be informed by appropriate susceptibility testing (6).Association Between Resistance and Malaria Incidence/Infection Prevalence.There was no evidence of an association between malaria rates and insecticide resistance measured phenotypically or genotypically for target-site resistance (as Vgsc-1014F frequency). An association between malaria burden and pyrethroid insecticide resistance was expected in clusters with pyrethroid-treated LLINs only or in clusters receiving LLINs and IRS with pyrethroid. The study lacked power to detect such an association due to a number of factors: (i) the range in pyrethroid resistance in the study area may have been too small; (ii) the effect of insecticide resistance on the effectiveness of LLINs may be relatively modest in settings of moderate pyrethroid resistance; (iii) bioassay data were not available in all clusters in each study year; and (iv) bioassay survivorship is an imprecise measure of the strength of resistance (29), despite its wide use for detecting the presence of resistance in a mosquito population. Our analysis of malaria incidence and prevalence in relation to insecticide resistance relied on detecting a dose–response association between the two variables; if the latter is inadequately quantified through bioassay survivorship or Vgsc-1014F frequency, then such a trend is unlikely to be significant.Previous studies have shown that insecticide-treated nets still provide protection against malaria infection even in settings of vector resistance to pyrethroids. A meta-analysis using entomological data (26) concluded that insecticide treated nets are a more effective form of vector control than untreated nets despite insecticide resistance. A study in Malawi found that children sleeping under LLINs suffered significantly fewer malaria episodes than their counterparts who did not sleep under nets in an area where the predominant malaria vector species, An. funestus and An. arabiensis, showed moderate to high levels of pyrethroid resistance (27).Cost and Cost-Effectiveness.The current study also demonstrated the relative cost-effectiveness of switching active ingredients to mitigate the potential effects of insecticide resistance on malaria incidence. It is, to date, the only study of which we are aware that does so using direct field evidence. Even in a relatively low transmission area, such as Galabat, a switch to the marginally more expensive bendiocarb insecticide is justified.Insecticide Combination and the Evolution of Resistance.A positive finding was modest evidence of retardation in the speed of evolution of insecticide resistance when two active ingredients with differing modes of actions were used in the LLIN + IRS arm. This is important for malaria control program managers as they struggle to develop plans for the monitoring and management of insecticide resistance in line with WHO GPIRM recommendations (6). Curiously, across our study site, there was a significant decrease in the Vgsc-1014F resistance marker frequency. While there are a number of instances of kdr markers sweeping rapidly to fixation (30–32), the obverse trend shown here has not been reported elsewhere. There are numerous studies showing that in An. arabiensis, Vgsc-1014F is a strong predictor of pyrethroid resistance (33), so this may suggest a decline in its importance in conferring a resistant phenotype due to the emergence of additional resistance mechanism(s).Limitations.For ethical reasons, it was not possible to conduct a trial with a neutral control arm; therefore, the effectiveness of the IRS alone could not be directly assessed. A trial randomizing clusters to the two insecticides would have provided a more direct contemporaneous comparison of deltamethrin to bendiocarb. Instead, the opportunity of comparing each insecticide against the same LLIN-alone control arm arose when insecticide needed to be switched due to the presence of pyrethroid resistance in the area. This design lacks the strength of evidence provided by a direct comparison; however, this shortcoming was compensated for, at least in part, by the contemporaneous comparison with the randomly selected LLIN-only clusters to control for temporal change in malaria transmission. The evidence of a change in the effect of IRS coinciding with the switch to bendiocarb was statistically very strong.ConclusionIn summary this trial has shown the following: (i) loss of effectiveness of pyrethroid IRS is likely to be associated with pyrethroid resistance in malaria vectors; (ii) IRS effectiveness can be restored by switching to an insecticide to which vectors are fully susceptible for an incremental cost that is considered attractive by international standards; and (iii) modest retardation to the speed of pyrethroid resistance development may be achieved with appropriate combinations of LLINs and nonpyrethroid IRS, compared with using LLINs alone.Materials and MethodsStudy Site.Galabat is located ∼80 km from Gedarif town and borders Ethiopia. A baseline household census estimated that the area comprised ∼119,000 households in 197 villages with a total of 600,000 inhabitants who are predominantly dependent on rain-fed agriculture. Climatically, the area is within the dry savannah region, with annual rainfall ranging between 700 mm and 1,200 mm and concentrated in a short rainy season from June to September. Average daily temperatures range between 31 °C and 44 °C (34). Malaria transmission is seasonal from September to November, with P. falciparum prevalence between 1% and 10% in 2- to 10-y-old children (9). An. arabiensis is the main vector of malaria in the area, with An. funestus implicated as having a minor role in malaria transmission (34). Before this study, LLINs were the only form of vector control in Galabat.Treatment for malaria in the area is provided by 101 public sector health facilities, including 7 referral hospitals, 24 health centers, 70 health units, and 20 villages with home-based management of malaria. Diagnosis of suspected cases is based on RDTs at the majority of health and home-based management facilities, while microscopy is used at 20 facilities in the area.Study Design.The Galabat study is loosely linked to a larger multicountry study on the implications of insecticide resistance that has been described previously (8). The opportunity to compare the two insecticides arose when deltamethrin IRS had to be replaced with bendiocarb IRS. The original objective of the Galabat trial was to investigate whether IRS in combination with LLINs provided additional protection against malaria compared with LLINs alone. With 13 clusters per arm and 200 children per cluster followed up for 3 y, the trial had 80% power to observe a 38% reduction in malaria incidence or more in the LLIN + IRS arm compared with the LLIN-only arm, assuming a mean incidence of 30 per 1,000 person-years and a coefficient of variation of 0.3 between study clusters. Twenty-six villages were selected from a total of 197 to form clusters, each consisting of at least 500 households, and with the distance between the edges of adjoining clusters being at least 3 km (Fig. 3). In 2010, a baseline malaria indicator survey testing for P. falciparum infection using malaria RDTs (SD BIOLINE-Malaria Ag P.f/P.v.; Standard Diagnostics, Inc.) was carried out on a sample of 100 children <10 y of age in each of the 26 clusters. At the same time, pyrethrum spray catches were made in houses, from which a sample of 24 An. arabiensis mosquitoes from each cluster was screened for the pyrethroid resistance-associated mutations in the voltage-gated sodium channels Vgsc-1014F and Vgsc-1014S using established molecular diagnostic techniques (33).Fig. 3.Map of the study area in Galabat, southeastern Sudan. Triangles denote clusters with LLIN only, and circles denote clusters with LLIN + IRS.LLINs with a deltamethrin concentration of 55 mg of active ingredient per square meter (PermaNet 2.0) were distributed in April 2011 in all 26 study clusters to reach levels required for universal coverage, defined as one net for every two people. The LLINs were replaced with new nets of the same type in all clusters in June 2014. In 2012, clusters were randomly allocated to two study arms using restricted randomization (35, 36) to ensure that the two study arms were balanced on a number of criteria, including baseline frequency of the Vgsc-1014F mutation, baseline prevalence of infection, baseline use of LLINs, and access to health facilities. One study arm (n = 13 clusters) retained universal coverage of LLINs only, while the second arm (n = 13 clusters) received two rounds of IRS in addition to LLINs. The first round of IRS was in August of each year to cover the main transmission season (September to November), with the second round in late December. In 2012, deltamethrin insecticide (Wettable Powder 25%) was used in both IRS rounds; in 2013 and 2014, bendiocarb (Ficam WP 80%) was sprayed. Bendiocarb, a carbamate, is an acetylcholinesterase antagonist, as opposed to deltamethrin, which targets the mosquito Vgsc. While LLINs target mosquitoes that are seeking a blood meal, IRS targets mosquitoes that rest indoors either before or after blood-feeding. Quality assurance of both IRS and LLIN interventions was conducted following WHO guidelines (14) using a susceptible laboratory strain of An. arabiensis raised in the insectaries of the Sennar Malaria Research and Training Centre.Insecticide Resistance.Over the course of the study, two estimates of insecticide resistance were made yearly in each cluster: One, termed phenotypic resistance, was reliant upon collecting live mosquitoes and ascertaining their susceptibility to standard dosages of deltamethrin and bendiocarb; the other, termed genotypic resistance, involved screening for Vgsc-1014F (reviewed in ref. 33). Anopheles larvae and pupae were collected annually (2012–2014) during the rainy season. All larvae and pupae were reared to adults in a field insectary until used for insecticide susceptibility tests. Pyrethrum spray catches were also performed to collect adult Anopheles mosquitoes. Phenotypic assays for deltamethrin and bendiocarb were performed following the standard WHO discriminating dose tests (14, 37). All susceptibility tests were conducted under laboratory conditions at temperatures ranging from 24.8 to 27.1 °C and relative humidity ranging from 75.4 to 79.8%.An. gambiae complex species, the main vector, were identified to species status, with An. arabiensis the only species observed, using a standard PCR assay (38). Twenty-four An. arabiensis females per cluster were selected at random for Vgsc-1014F genotyping to estimate a cluster-specific resistance marker frequency (39).Active Case Detection.In each cluster, a community health worker (CHW) was appointed, and ∼200 children aged between 6 mo and <10 y were recruited into cohorts after explaining the study procedures to caregivers and after obtaining written informed consent. Older children were asked to assent to recruitment. CHWs visited cohort members weekly during the peak of the malaria season (September to November) and fortnightly during the remainder of the year, for a total of 30 annual visits. Cohort children who were reported to be febrile at the time of a visit had their temperature taken. Children who had a confirmed fever at the time of the visit, or a reported fever during the period since the last visit, were referred to the local health facility to be tested for malaria parasites, or were tested by the CHW using an RDT when no local facility was available. Local health facilities used either RDTs or microscopy to test for malaria parasites. If caregivers, upon questioning, reported that a child had visited the health facility for a febrile illness during the period since the last visit, the CHW visited the health facility to determine if the child had a blood test that confirmed a diagnosis of malaria. Each visit by a CHW and each clinic attendance resulting in a definitive diagnosis of malaria were recorded in the cohort register, which was collected at regular intervals for entry into an MS Access database at a central location. A study coordinator carried out regular supervisory visits to CHWs to verify the quality of data collection. Upon reaching the age of 10 y, cohort children were replaced by younger children from the same household or from another household if no younger sibling was available.Prevalence of Infection.Once each year, during September to October, cohort children were tested for P. falciparum infection using RDTs (SD BIOLINE-Malaria Ag P.f/P.v.), irrespective of symptoms. A random sample of 50% of cohort members was selected in 2012, while all cohort children who were present at the time of the survey were screened in 2013 and 2014. Any child who tested positive was referred to the local health facility for treatment.Statistical Analysis.Malaria case incidence was estimated as the number of cases per child-year of follow-up. IRRs were calculated comparing incidence between study arms for each study year, and for the 2 y combined during which bendiocarb IRS was used. Effect modification (interaction) between study arm and study year was investigated to determine the differential effect of IRS + LLINs with bendiocarb compared with IRS + LLINs with deltamethrin versus LLINs alone. Multiple variable Poisson regression was used to adjust the effect of study arm for age of child at time of visit and, for 2013 and 2014, for incidence rate in 2012. To assess whether malaria incidence was associated with insecticide resistance, IRRs were calculated per 1% change in cluster-specific vector susceptibility (mosquito mortality) and per 1% change in cluster specific Vgsc-1014F allele frequency. For this analysis, year and cluster-specific insecticide resistance measurements were linked to year and cluster-specific incidence.For cross-sectional prevalence of infection data, analogous analyses were carried out using logistic regression to estimate ORs.Multiple episodes of malaria in the same child were rare; any consecutive positive test results were counted as one episode since the second positive test result could be either a false-positive result from RDTs that measure parasite protein retained from an already cleared infection or the result of a treatment failure. To test the robustness of these results against the possibility of undue influence exerted by participants who had multiple episodes of malaria, the analysis was repeated but restricted to the 550 first-time episodes that were observed in the same cohort over the same period ( i.e., excluding children from further follow-up after their first positive test result). To calculate appropriate SEs of estimated means, a robust variance estimator using the first-order Taylor-series linearization method was used to account for variation between clusters (40, 41). Poisson regression and logistic regression were performed using random effects models.To compare the differences in mean mortalities and Vgsc-1014F allele frequencies between the two intervention arms, t tests were used, while ANOVA was used to compare the differences between years. The Shapiro–Wilks test was used to assess whether mortality and allele frequency data deviated from the normal distribution.Cost Data Collection Tools and Indicators.A microcosting (ingredients approach) activities-based framework was applied to the development of cost-collection tools. Key-informant interviews and record reviews were conducted to identify all of the activities and resources needed that were expected to be utilized during the course of the trial. Care was taken to exclude activities that were specifically related to research and not necessary for the provision or performance of the intervention; these included enhanced case finding and enhanced vector surveillance beyond what was necessary for routine use of IRS or LLINs. A standardized instrument for the collection of resource quantities and prices was developed for use at the national (central), state, and locality levels. The instrument was employed by staff of the Federal Ministry of Health Integrated Vector Management Unit to collect information on resource usage at each level of the health system.Analysis of Cost Data.Resource use was quantified and valued in Sudanese pounds (SDG) in the year during which the resource use occurred. Costs were converted to US dollars using the prevailing average exchange rate for the period. All costs were valued in 2011 US dollars, after adjusting for inflation using the consumer price index for Sudan. Prices derived from the WHO-CHOICE (choosing interventions that are cost effective) database (15) were converted from international dollars using a purchasing power parity (PPP)-to-local currency ratio (1 international dollar to 1.28 SDG) for 2009.In all cases, economic costs are presented, which are also known as opportunity costs. Economic costs represent the value of a given resource in its next most appropriate use. As such, capital costs, including vehicles, buildings, LLINs, and spray equipment, were annualized and discounted using assumed lifetimes and a social discount rate of 3%.Cost Outcomes Sensitivity Analysis.Two types of outcome were measured: a process measure, numbers of persons living in clusters with vector control per year (or person-years of protection), and the effectiveness of the interventions in terms of incident cases of malaria prevented.Because most cost models and assessments are dependent on assumptions about quantities of resources used, prices of resources, and allocation of shared costs, it is necessary to conduct a sensitivity analysis to attempt to determine the robustness of the cost assessment to various assumptions made during development of the model. A one-way sensitivity analysis was conducted to determine the robustness of the cost model to various assumptions made during the assessment. Parameters, which were varied, included discount rate, prices of LLINs and insecticides used, allocation of shared costs, numbers of persons protected by the interventions, and baseline malaria incidence.Ethics.The study was approved by the Ethics Committees of the London School of Hygiene and Tropical Medicine (approval no. 5825) and Federal Ministry of Health, Sudan (approval no.116-12-09). The study was registered on ClinicalTrials.com (registration no. NCT01713517).This project was supported financially by the United Nations Environment Programme/Global Environment Facility project: Demonstration of Sustainable Alternatives to DDT and Strengthening of National Vector Control Capabilities in the Middle East and North Africa (GEF ID 2546), and by the Bill and Melinda Gates Foundation (Grant 48499.01). This research forms part of a multicountry study coordinated by the WHO Global Malaria Programme. 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introduction of malaria control interventions on Bioko Island, Equatorial GuineaAm J Trop Med Hyg749729781676050620KigoziR2012Indoor residual spraying of insecticide and malaria morbidity in a high transmission intensity area of UgandaPLoS One7e428572288012321MaharajRMthembuDJSharpBL2005Impact of DDT re-introduction on malaria transmission in KwaZulu-NatalS Afr Med J958718741634488522HargreavesK2000Anopheles funestus resistant to pyrethroid insecticides in South AfricaMed Vet Entomol141811891087286223MaharajR2013Epidemiology of malaria in South Africa: From control to eliminationS Afr Med J1037797832407963324KleinschmidtI2007Factors influencing the effectiveness of malaria control in Bioko Island, Equatorial GuineaAm J Trop Med Hyg76102710321755660625SharpBL2007Seven years of regional malaria control collaboration–Mozambique, South Africa, and SwazilandAm J Trop Med Hyg7642471725522726StrodeCDoneganSGarnerPEnayatiAAHemingwayJ2014The impact of pyrethroid resistance on the efficacy of insecticide-treated bed nets against African anopheline mosquitoes: Systematic review and meta-analysisPLoS Med11e10016192464279127LindbladeKA2015A cohort study of the effectiveness of insecticide-treated bed nets to prevent malaria in an area of moderate pyrethroid resistance, MalawiMalar J14312562798728WestPA2014Indoor residual spraying in combination with insecticide-treated nets compared to insecticide-treated nets alone for protection against malaria: A cluster randomised trial in TanzaniaPLoS Med11e10016302473637029BagiJ2015When a discriminating dose assay is not enough: Measuring the intensity of insecticide resistance in malaria vectorsMalar J142102598589630ClarksonCS2014Adaptive introgression between anopheles sibling species eliminates a major genomic island but not reproductive isolationNat Commun542482496364931MathiasDK2011Spatial and temporal variation in the kdr allele L1014S in Anopheles gambiae s.s. and phenotypic variability in susceptibility to insecticides in Western KenyaMalar J10102123578332NorrisLC2015Adaptive introgression in an African malaria mosquito coincident with the increased usage of insecticide-treated bed netsProc Natl Acad Sci USA1128158202556152533DonnellyMJIsaacsATWeetmanD2016Identification, validation, and application of molecular diagnostics for insecticide resistance in malaria vectorsTrends Parasitol321972062675086434HamadAA2002A marked seasonality of malaria transmission in two rural sites in eastern SudanActa Trop8371821206279535HayesRJMoultonLH2009IntroductionCluster Randomised Trials, Interdisciplinary StatisticsChapman and Hall/CRCBoca Raton, FL336SismanidisC2008Restricted randomization of ZAMSTAR: A 2 x 2 factorial cluster randomized trialClin Trials53163271869784637World Health Organization1998Test procedures for insecticide resistance monitoring in malaria vectors, bio-efficacy and persistence of insecticides on treated surfaces (WHO, Geneva), Technical Report WHO/CDS/CPC/MAL/98.1238ScottJABrogdonWGCollinsFH1993Identification of single specimens of the Anopheles gambiae complex by the polymerase chain reactionAm J Trop Med Hyg49520529821428339BassC2007Detection of knockdown resistance (kdr) mutations in Anopheles gambiae: A comparison of two new high-throughput assays with existing methodsMalar J61111769732540RaoJNScottAJ1992A simple method for the analysis of clustered binary dataBiometrics48577585163798041Stata Corporation2013Stata Survey Data Reference Manual: Release 14Stata PressCollege Station, TX', 'title': 'Impact of insecticide resistance in ', 'date': '2017-12-13'}, '22682536': {'article_id': '22682536', 'content': "Malaria control efforts and elimination in Africa are being challenged by the development of resistance of parasites to antimalarial drugs and vectors to insecticides. We investigated whether the combination of long-lasting insecticidal mosquito nets (LLINs) with indoor residual spraying (IRS) or carbamate-treated plastic sheeting (CTPS) conferred enhanced protection against malaria and better management of pyrethroid-resistance in vectors than did LLINs alone.\nWe did a cluster randomised controlled trial in 28 villages in southern Benin, west Africa. Inclusion criteria of the villages were moderate level of pyrethroid resistance in malaria vectors and minimum distance between villages of 2 km. We assessed four malaria vector control interventions: LLIN targeted coverage to pregnant women and children younger than 6 years (TLLIN, reference group), LLIN universal coverage of all sleeping units (ULLIN), TLLIN plus full coverage of carbamate-IRS applied every 8 months (TLLIN+IRS), and ULLIN plus full coverage of CTPS lined up to the upper part of the household walls (ULLIN+CTPS). The interventions were allocated to villages by a block randomisation on the basis of preliminary surveys and children of each village were randomly selected to participate with computer-generated numbers. The primary endpoint was the incidence density rate of Plasmodium falciparum clinical malaria in children younger than 6 years as was analysed by Poisson regression taking into account the effect of age and the sampling design with a generalised estimating equation approach. Clinical and parasitological information were obtained by active case detection of malaria episodes during 12 periods of 6 consecutive days scheduled at six weekly intervals and by cross-sectional surveys of asymptomatic plasmodial infections. Children or study investigators were not masked to study group. This study is registered with Current Controlled Trials, number ISRCTN07404145.\nOf 58 villages assessed, 28 were randomly assigned to intervention groups. 413-429 children were followed up in each intervention group for 18 months. The clinical incidence density of malaria was not reduced in the children from the ULLIN group (incidence density rate 0·95, 95% CI 0·67-1·36, p=0·79), nor in those from the TLLIN+IRS group (1·32, 0·90-1·93, p=0·15) or from the ULLIN+CTPS group (1·05, 0·75-1·48, p=0·77) compared with the reference group (TLLIN). The same trend was observed with the prevalence and parasite density of asymptomatic infections (non significant regression coefficients).\nNo significant benefit for reducing malaria morbidity, infection, and transmission was reported when combining LLIN+IRS or LLIN+CTPS compared with a background of LLIN coverage. These findings are important for national malaria control programmes and should help the design of more cost-effective strategies for malaria control and elimination.\nMinistère Français des Affaires Etrangères et Européennes (FSP project 2006-22), Institut de Recherche pour le Développement, President's Malaria Initiative (PMI) of US Governement.", 'title': 'Combination of malaria vector control interventions in pyrethroid resistance area in Benin: a cluster randomised controlled trial.', 'date': '2012-06-12'}}
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Public Health, Epidemiology & Health Systems
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79
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Is anaemia prevalence higher, lower, or the same when comparing non‐pyrethroid‐like indoor residual spraying (IRS) plus insecticide‐treated nets (ITNs) to insecticide‐treated nets (ITNs) alone?
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lower
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low
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yes
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['24736370', '29655496']
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{'24736370': {'article_id': '24736370', 'content': "PLoS MedPLoS MedPLoSplosmedPLoS Medicine1549-12771549-1676Public Library of ScienceSan Francisco, USA247363703988001PMEDICINE-D-13-0370410.1371/journal.pmed.1001630Research ArticleBiology and Life SciencesOrganismsAnimalsInvertebratesArthropodaInsectsMosquitoesProtozoansParasitic ProtozoansMalarial ParasitesPlasmodium FalciparumMedicine and Health SciencesEpidemiologyDisease VectorsInfectious Disease EpidemiologyInfectious DiseasesInfectious Disease ControlParasitic DiseasesMalariaIndoor Residual Spraying in Combination with Insecticide-Treated Nets Compared to Insecticide-Treated Nets Alone for Protection against Malaria: A Cluster Randomised Trial in TanzaniaCombined Use of IRS and ITNs against MalariaWestPhilippa A.\n1\n\n*\nProtopopoffNatacha\n2\nWrightAlexandra\n2\nKivajuZuhura\n3\nTigererwaRobinson\n4\nMoshaFranklin W.\n5\nKisinzaWilliam\n3\nRowlandMark\n2\nKleinschmidtImmo\n6\n1Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, United Kingdom2Department of Disease Control, London School of Hygiene & Tropical Medicine, London, United Kingdom3National Institute for Medical Research, Amani Medical Research Centre, Muheza, Tanzania4Muleba District Medical Office, Department of Health, Muleba, Tanzania5Kilimanjaro Christian Medical College, Tumaini University, Moshi, Tanzania6Medical Research Council Tropical Epidemiology Group, London School of Hygiene & Tropical Medicine, London, United KingdomGethingPeter W.Academic EditorUniversity of Oxford, United Kingdom* E-mail: philippa.west@lshtm.ac.ukThe authors have declared that no competing interests exist.Conceived and designed the experiments: IK MR NP PW FM WK. Performed the experiments: PW NP AW RT ZK. Analyzed the data: PW NP. Contributed reagents/materials/analysis tools: IK. Wrote the first draft of the manuscript: PW. Contributed to the writing of the manuscript: PW IK MR NP. ICMJE criteria for authorship read and met: IK MR NP PW FM WK AW RT ZK. Agree with manuscript results and conclusions: IK MR NP PW FM WK AW RT ZK. Provided major input into the design and interpretation of the data analysis: IK. Provided overall coordination of the project: MR. Critically revised the manuscript for important content: AW RT ZK FM WK.420141542014114e100163015112013732014© 2014 West et al2014West et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.Philippa West and colleagues compare Plasmodium falciparum infection prevalence in children, anemia in young children, and entomological inoculation rate between study arms.\nPlease see later in the article for the Editors' Summary\nBackgroundInsecticide-treated nets (ITNs) and indoor residual spraying (IRS) of houses provide effective malaria transmission control. There is conflicting evidence about whether it is more beneficial to provide both interventions in combination. A cluster randomised controlled trial was conducted to investigate whether the combination provides added protection compared to ITNs alone.Methods and FindingsIn northwest Tanzania, 50 clusters (village areas) were randomly allocated to ITNs only or ITNs and IRS. Dwellings in the ITN+IRS arm were sprayed with two rounds of bendiocarb in 2012. Plasmodium falciparum prevalence rate (PfPR) in children 0.5–14 y old (primary outcome) and anaemia in children <5 y old (secondary outcome) were compared between study arms using three cross-sectional household surveys in 2012. Entomological inoculation rate (secondary outcome) was compared between study arms.IRS coverage was approximately 90%. ITN use ranged from 36% to 50%. In intention-to-treat analysis, mean PfPR was 13% in the ITN+IRS arm and 26% in the ITN only arm, odds ratio\u200a=\u200a0.43 (95% CI 0.19–0.97, n\u200a=\u200a13,146). The strongest effect was observed in the peak transmission season, 6 mo after the first IRS. Subgroup analysis showed that ITN users were additionally protected if their houses were sprayed. Mean monthly entomological inoculation rate was non-significantly lower in the ITN+IRS arm than in the ITN only arm, rate ratio\u200a=\u200a0.17 (95% CI 0.03–1.08).ConclusionsThis is the first randomised trial to our knowledge that reports significant added protection from combining IRS and ITNs compared to ITNs alone. The effect is likely to be attributable to IRS providing added protection to ITN users as well as compensating for inadequate ITN use. Policy makers should consider deploying IRS in combination with ITNs to control transmission if local ITN strategies on their own are insufficiently effective. Given the uncertain generalisability of these findings, it would be prudent for malaria control programmes to evaluate the cost-effectiveness of deploying the combination.Trial registration\nwww.ClinicalTrials.gov\nNCT01697852\n\nPlease see later in the article for the Editors' Summary\nEditors' SummaryBackgroundEvery year, more than 200 million cases of malaria occur worldwide, and more than 600,000 people, mainly children living in sub-Saharan Africa, die from this parasitic infection. Malaria parasites, which are transmitted to people through the bites of infected night-flying mosquitoes, cause a characteristic fever that needs to be treated promptly with antimalarial drugs to prevent anaemia (a reduction in red blood cell numbers) and organ damage. Prompt treatment also helps to reduce malaria transmission, but the mainstays of global malaria control efforts are the provision of insecticide-treated nets (ITNs) for people to sleep under to avoid mosquito bites, and indoor residual spraying (IRS) of houses with insecticides, which prevents mosquitoes from resting in houses. Both approaches have been scaled up in the past decade. About 54% of households in Africa now own at least one ITN, and 8% of at-risk populations are protected by IRS. As a result of the widespread deployment of these preventative tools and the increased availability of effective antimalarial drugs, malaria-related deaths in Africa fell by 45% between 2000 and 2012.Why Was This Study Done?Some countries have chosen to use ITNs and IRS in combination, reasoning that this will increase the proportion of individuals who are protected by at least one intervention and may provide additional protection to people using both interventions rather than one alone. However, providing both interventions is costly, so it is important to know whether this rationale is correct. In this cluster randomised controlled trial (a study that compares outcomes of groups of people randomly assigned to receive different interventions) undertaken in the Muleba District of Tanzania during 2012, the researchers investigate whether ITNs plus IRS provide more protection against malaria than ITNs alone. Malaria transmission occurs throughout the year in Muleba District but peaks after the October–December and March–May rains. Ninety-one percent of the district's households own at least one ITN, and 58% of households own enough ITNs to cover all their sleeping places. Annual rounds of IRS have been conducted in the region since 2007.What Did the Researchers Do and Find?The researchers allocated 50 communities to the ITN intervention or to the ITN+IRS intervention. Dwellings allocated to ITN+IRS were sprayed with insecticide just before each of the malaria transmission peaks in 2012. The researchers used household surveys to collect information about ITN coverage in the study population, the proportion of children aged 0.5–14 years infected with the malaria parasite Plasmodium falciparum (the prevalence of infection), and the proportion of children under five years old with anaemia. IRS coverage in the ITN+IRS arm was approximately 90%, and 50% of the children in both intervention arms used ITNs at the start of the trial, declining to 36% at the end of the study. In an intention-to-treat analysis (which assumed that all study participants got the planned intervention), the average prevalence of infection was 13% in the ITN+IRS arm and 26% in the ITN arm. A per-protocol analysis (which considered data only from participants who received their allocated intervention) indicated that the combined intervention had a statistically significant protective effect on the prevalence of infection compared to ITNs alone (an effect that is unlikely to have arisen by chance). Finally, the proportion of young children with anaemia was lower in the ITN+IRS arm than in the ITN arm, but this effect was not statistically significant.What Do These Findings Mean?These findings provide evidence that IRS, when used in combination with ITNs, can provide better protection against malaria infection than ITNs used alone. This effect is likely to be the result of IRS providing added protection to ITN users as well as compensating for inadequate ITN use. The findings also suggest that the combination of interventions may reduce the prevalence of anaemia better than ITNs alone, but this result needs to be confirmed. Additional trials are also needed to investigate whether ITN+IRS compared to ITN reduces clinical cases of malaria, and whether similar effects are seen in other settings. Moreover, the cost-effectiveness of ITN+IRS and ITN alone needs to be compared. For now, though, these findings suggest that national malaria control programs should consider implementing IRS in combination with ITNs if local ITN strategies alone are insufficiently effective and cannot be improved.Additional InformationPlease access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001630.Information is available from the World Health Organization on malaria (in several languages), including information on insecticide-treated bed nets and indoor residual spraying; the World Malaria Report 2013 provides details of the current global malaria situationThe US Centers for Disease Control and Prevention provides information on malaria, on insecticide-treated bed nets, and on indoor residual spraying; it also provides a selection of personal stories about malariaInformation is available from the Roll Back Malaria Partnership on the global control of malaria and on the Global Malaria Action Plan (in English and French); its website includes fact sheets about malaria in Africa and about nets and insecticides\nMedlinePlus provides links to additional information on malaria (in English and Spanish)PW is funded by the Thorpe legacy studentship from the Malaria Centre (http://malaria.lshtm.ac.uk/). This study was funded by the United States Agency for International Development (http://www.usaid.gov/) under Translating Research into Action, Cooperative Agreement No. GHS-A-00-09-00015-00. This study was made possible by the support of the American people through the United States Agency for International Development (USAID). The findings of this study are the sole responsibility of the authors and do not necessarily reflect the views of USAID or the United States Government. IRS was funded by PMI and conducted by RTI, independent of the study. ITNs were distributed by a national UCC, lead by the Ministry of Health and Social Welfare (Tanzania), and primarily financed by the GFATM, with some support from PMI. IK receives support from the Medical Research Council and Department For International Development (MR/K012126/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.IntroductionIn the past decade, insecticide-treated net (ITN) distribution has been scaled up across Africa in line with the Abuja Declaration in 2000 [1]. The percentage of households that owned at least one ITN in Africa increased from 3% in 2000 to 54% in 2013. The World Health Organization (WHO) policy that ITNs should be provided to everyone in malaria risk areas (universal coverage) [2] has been adopted by 34 of the 44 malaria endemic countries in Africa [3]. Indoor residual spraying (IRS) of houses, the second major vector control tool used to prevent malaria, has similarly been scaled up. The proportion of at-risk populations protected by IRS increased from less than 5% in 2005 to 8% in 2012 [3]. As a result of the increase in the deployment of these preventive tools and the increased availability and use of artemisinin-based combination therapies, malaria-related mortality fell by 45% between 2000 and 2012 in Africa, but there remained an estimated 165 million cases and 562,000 deaths due to malaria in 2012 [3].In an attempt to reduce the malaria burden further, a number of countries have chosen to use ITNs and IRS in combination. Fifty-seven countries, 31 of which are in Africa, use both IRS and ITNs, in at least some areas [3]. Applying ITNs and IRS in the same area can increase the proportion of individuals who are protected by at least one intervention or, more optimally, may provide additional protection for those protected by both interventions compared to those receiving one method alone [4]–[7].Since the cost of implementing both IRS and universal coverage of ITNs is much greater than the cost of implementing only one of the interventions [8], it is important to know what extra protection is gained by adding a second intervention, to help national malaria control programmes and international funding agencies such as the President's Malaria Initiative (PMI) and the Global Fund to Fight AIDS, Tuberculosis and Malaria make decisions that are based on evidence of likely impacts and costs. This is particularly significant now, since it is estimated that global funding for malaria is less than half of what is needed to attain universal coverage of malaria vector control, i.e., access to either ITNs or IRS [9].It is unclear from current evidence whether combined use of ITNs and IRS provides an additional benefit compared to using either intervention alone, and whether this will be similar across transmission settings [4]–[7],[10],[11]. A recent trial in Benin found no added benefit to using IRS in combination with ITNs compared to ITNs alone [10]. However, this trial had a relatively small sample size, and its findings may be applicable to only a particular transmission setting in west Africa [12].To help define future malaria control policy in Africa, the PMI decided to sponsor an independent two-arm cluster randomised controlled trial (CRT) to compare the protective effectiveness of IRS in combination with high coverage of ITNs with high coverage of ITNs alone for malaria transmission control.Tanzania has a high malaria disease burden, with a national average of 9% of children under 5 y being infected with malaria parasites [13]. Malaria control activities have been scaled up nationally since 2005 [14]–[16]. A universal coverage campaign (UCC) primarily funded by the Global Fund to Fight AIDS, Tuberculosis and Malaria distributed long-lasting insecticidal nets (LLINs) free of charge in 2011 to top up coverage from previous distributions [14],[15],[17]. IRS, funded by the PMI, commenced in 2007 in two districts of Kagera Region, in northwest Tanzania, and has since been extended to cover 18 districts [18]. Because IRS is costly and logistically intensive [8],[19], there is an urgent need to know whether it is necessary to continue with IRS after an ITN UCC has been successfully completed.The trial was carried out in 109 rural villages in Muleba District (1°45′S 31°40′E), Kagera Region [20],[21]. The study area includes 68,108 households at an altitude ranging from 1,100 to 1,600 m above sea level. Rainfall occurs in two seasons: the “short rains” in October–December (average monthly rainfall 160 mm) and the “long rains” in March–May (average monthly rainfall 300 mm) [22], with malaria transmission occurring throughout the year and peaking after the rainy seasons [23]. Annual rounds of IRS with the pyrethroid lambda-cyhalothrin (ICON 10CS, Syngenta) were conducted between 2007 and 2011 in Muleba District, i.e., in the entire study area. The predominant malaria vectors are Anopheles gambiae s.s. and An. arabiensis\n[24]. Tests of mosquito susceptibility using standard WHO bioassays showed resistance to pyrethroids in An. gambiae s.s. in 2011 [24]. As a result, IRS policy was changed to use the carbamate insecticide bendiocarb (Ficam 80% wettable powder, Bayer) by the PMI in 2012.MethodsEthics and Community SensitisationThe trial was approved by the ethics review committees of the Kilimanjaro Christian Medical College, the Tanzanian National Institute for Medical Research, and the London School of Hygiene and Tropical Medicine. Written informed consent was obtained from all respondents. Prior to the baseline surveys, village and hamlet leaders were invited to sensitisation sessions conducted by district health officers.The trial was registered with ClinicalTrials.gov (registration number NCT01697852) in September 2012. The trial was not registered earlier because the authors were not aware of journal requirements for prospective registration. All authors have affirmed that any trials they are involved in on the same or a related drug or intervention are registered. An accurate summary of the trial's results has been submitted to ClinicalTrials.gov.Study DesignA CRT was conducted, comparing the Plasmodium falciparum prevalence rate (PfPR) in children 0.5–14 y old between communities targeted to receive both high-coverage IRS and high coverage of ITNs (ITN+IRS arm) and communities targeted for high coverage of ITNs only (standard-care control arm). Secondary outcomes were moderate/severe anaemia (haemoglobin <8 g/dl) in children under 5 y old and entomological inoculation rate (EIR) due to An. gambiae s.l.Power calculations showed that 25 clusters per study arm were required, with 80 children per cluster, to give 80% power to detect a true absolute difference in PfPR of at least 3% between study arms (relative difference 31%) with 5% significance (two-sided), based on an expected prevalence in the ITN only arm of 9% (PfPR in first baseline survey). The between-cluster coefficient of variation (k) was calculated as 0.25 from the first pre-randomisation baseline survey [25].Each cluster consisted of at least one village and was divided into a core surveillance area consisting of at least 200 houses and approximately 1 km radius, where the surveys were conducted, and an outer buffer zone, 1 km in width, which also received the allocated treatment but in which no outcome monitoring was done. Villages were eligible for inclusion in the study if they were within daily commuting distance for survey work and had been sprayed with IRS in the baseline year.All clusters received LLINs from the UCC in 2011. Twenty-five clusters were randomly allocated to receive IRS, in addition to ITNs, using restricted randomisation to limit potential imbalance between study arms [25]. Baseline surveys provided data on seven criteria for which the study arms were balanced by constraining the randomisation (Table 1). 200,000 random allocations were generated. Mean values for each arm were calculated from cluster summaries for each of the seven restriction variables; 25,119 randomisations fulfilled the restriction criteria and were therefore eligible. These allocations were tested for independence between any two clusters. The large number of acceptable allocations, of which one was randomly selected, ensured that the restriction did not affect the validity of inference. There was no evidence of dependence between any pair of clusters [25],[26].10.1371/journal.pmed.1001630.t001Table 1Restriction variables for randomisation and realisation of balance between the study arms.VariableMaximum Difference in Means between Study Armsa\nITN Arma\nITN+IRS Arma\nActual Difference\nPfPRb in February–March 2011c\n3%9.9%9.3%0.5%\nPfPR in June–July 2011d\n3%22.4%19.6%2.7%Housing densitye\n20 HH/km2\n165.1 HH/km2\n152.6 HH/km2\n12.5 HH/km2\nMean elevation50 m1,364.8 m1,330.7 m34.1 mITN usaged\n,\nf\n5%35.0%30.4%4.6%Adequate LLIN ownershipe\n,\ng\n5%61.3%56.3%5.0%Clusters with entomological surveillanceCount of 220 clusters20 clusters0 clustersaMeans for each study arm were calculated from cluster summaries.b\nPfPR from RDTs.cRecorded in baseline survey 1(February–March 2011).dRecorded in baseline survey 2 (June–July 2011) after the UCC.eHousing density in surveillance area of clusters.fNet used the night before the survey in all age groups.gPercentage of households with at least one LLIN per two people.HH, household.InterventionsHouseholds in the study area with children aged under 5 y received LLINs from a national distribution campaign in 2009 [16]. In 2011, the district health authority, supported by Mennonite Economic Development Associates, completed a UCC that distributed 144,000 LLINs (Olyset, Sumitomo Chemicals) to the population of Muleba District, including all study clusters. The campaign aimed to top up net coverage, so that every sleeping place had one ITN. After the UCC, 91% of households owned at least one ITN, and 58% of households owned enough ITNs to cover all their sleeping places [20].Spraying was conducted by RTI International on behalf of PMI in the ITN+IRS study arm. The interior walls of each dwelling were sprayed with the carbamate insecticide bendiocarb (Ficam 80% wettable powder, Bayer) at 400 mg/m2 between December 2011 and January 2012 (round 1), and between April and May 2012 (round 2). Spray rounds were timed to precede the peak in malaria cases that normally occurs at the end of each rainy season, taking into account the relatively short residual duration of bendiocarb.Bendiocarb is a carbamate insecticide recommended by WHO for IRS [27],[28]. It is one of the few insecticides evaluated and approved by the WHO Pesticide Evaluation Scheme that has the potential to control pyrethroid-resistant mosquitoes, is odour-free, and is safe to house occupants at the recommended application rate [27]. Before obtaining WHO approval, all IRS insecticides are subject to risk assessment by WHO toxicologists [29]. Bendiocarb is an acetylcholinesterase inhibitor, but no serious adverse effects due to bendiocarb IRS have been reported in the recent medical literature.SurveysThree post-intervention cross-sectional household surveys were undertaken in 2012 (see Figure 1). Survey A (23 February–31 March) was after the short rainy season and 2 mo after the first spray round. Survey B (25 June–31 July) was after the long rainy season, 6 mo after the first spray round, and 2 mo after the second spray round. Survey C (25 October–4 December) was 6 mo after the second spray round and 10 mo after the first. Baseline surveys were conducted in 2011 during the same periods as surveys A and B.10.1371/journal.pmed.1001630.g001Figure 1Study timetable.Surveys 1 and 2 are baseline surveys. Surveys A, B, and C are post-intervention.For each survey, 80 households were randomly selected in the core area of each cluster. Households were eligible for the study if they had children aged 0.5–14 y. Any child aged 0.5–14 y was eligible to be included in the study. Up to three children per household were randomly selected for testing. Allowing for ineligible households, absence on the day of the survey, and refusals at the household and individual level, it was estimated that this would provide on average 80 children for testing per cluster.The household head or another responsible adult from the household was interviewed, after seeking written informed consent. Data on IRS coverage, bed net ownership and usage, demographics of household members, and other household characteristics were gathered using an adapted version of the standard Malaria Indicator Survey [30].Selected children were tested on the following day for malaria parasites using a rapid diagnostic test (RDT) (CareStart [Pan] Malaria, DiaSys) and had haemoglobin levels measured using HemoCue Hb 201+ (Aktiebolaget Leo Diagnostics). Individuals testing positive by RDT were treated with artemether/lumefantrine (Artefan 20/120, Ajanta Pharma) following national treatment guidelines.Entomological surveillance was carried out in the core surveillance areas of a subset of 40 of the 50 clusters from April 2011 to December 2012. For one night of each month US Centers for Disease Control and Prevention light traps for mosquito collections were set up in eight randomly selected houses in each cluster (320 houses per month). Anopheles mosquitoes collected were identified to species using a simplified morphological key adapted from Gillies and Coetzee [31]. A sub-sample of An. gambiae s.l. individuals were tested using real-time PCR TaqMan assay to distinguish between the two sibling species An. gambiae s.s. and An. arabiensis\n[32]. Mosquitoes were also tested for P. falciparum sporozoites (P. falciparum circumsporozoite protein) using ELISA [33].Statistical AnalysisStatistical analysis was done in Stata 12 (Statacorp) and R version 2.13.1 (R Foundation for Statistical Computing). The odds of PfPR and moderate/severe anaemia for individuals were compared between study arms in intention-to-treat (ITT) analysis using logistic regression. Mean haemoglobin was compared between the study arms using linear regression. A robust variance estimator was used to calculate standard errors to adjust for within-cluster correlation of responses (Stata survey commands, first-order Taylor-series linearization method) [34],[35]. PfPR was considered as P. falciparum alone or mixed infections as detected by the RDT. The overall odds ratio (OR) for the three surveys combined was calculated accounting for survey. An adjusted Wald test was performed to test whether there was evidence for effect modification between study arm and survey round. A sensitivity analysis was conducted excluding one cluster from the ITN only arm that mistakenly received IRS, to assess the impact of this protocol violation on the results of ITT analysis. Because of the wide variation in cluster-level estimates of PfPR at baseline, an OR for ITN+IRS versus ITN alone was calculated adjusting for baseline PfPR.A secondary per-protocol analysis was performed, in which individuals from the ITN+IRS arm who used an ITN and lived in a house sprayed in the most recent round of IRS were compared to individuals who used an ITN in the ITN only arm. The cluster that violated the protocol was excluded from the per-protocol analysis.The monthly EIR was calculated as the daily EIR found during the one night collection multiplied by the number of days in the month. Mean EIRs were compared between study arms using negative binomial regression and adjusting for within-cluster correlation.ResultsAt baseline, PfPR, anaemia, ITN ownership, ITN usage, and mean EIR per month (Table 2) were similar in the two study arms. PfPR in children aged 6 mo to 14 y old was 9.3% (95% CI 5.9%–14.5%) after the short rains (survey A, February–March) and 22.8% (95% CI 17.3%–29.4%) after the long rains (survey B, June–July). Anaemia in children 0.5–4 y was 6.2% (95% CI 4.5%–8.5%) after the long rains.10.1371/journal.pmed.1001630.t002Table 2Baseline characteristics of individuals and households by study arm, Muleba District, 2011.CharacteristicITN Only ArmPercent [95% CI] (n)ITN+IRS ArmPercent [95% CI] (n)\nPfPR in March 2011a\n,\nb\n,\nc\n10.3 [5.2–19.3] (2,487)8.4 [4.5–15.3] (2,655)\nPfPR in July 2011a\n,\nb\n,\nd\n24.6 [17.0–34.3] (2,121)21.0 [13.8–30.5] (2,185)Moderate/severe anaemiaa\n,\nd\n,\ne\n6.4 [3.9–10.2] (785)6.1 [4.1–8.9] (841)Mean haemoglobin (g/dl)a\n,\nd\n,\n10.6 [10.4–10.9] (785)10.6 [10.4–10.9] (841)ITN use in all age groupsa\n,\nd\n,\nf\n53.3 [48.2–58.3] (6,755)58.2 [53.8–62.5] (6,913)Households with adequate ITNsd\n,\ng\n,\nh\n54.5 [49.5–59.5] (1,243)62.3 [57.3–67.1] (1,250)Households with ≥1 ITNd\n,\ng\n88.9 [86.0–91.3] (1,248)92.6 [90.8–94.0] (1,251)Households received IRS in 2011c\n,\ng\n,\ni\n94.4 [91.3–96.5] (1,598)95.5 [93.5–96.9] (1,640)Mean An. gambiae mosquitoes per house per nightg\n,\nj\n3.1 [1.0–9.6] (1,055)2.2 [0.5–9.1] (1,120)Sporozoite ratea\n,\nk\n1.1 [0.8–1.4] (1,359)2.0 [1.4–2.8] (1,466)Mean EIR/monthl\n1.1 [0.4–2.8]1.3 [0.4–4.4]aCalculated from individual-level data.b\nPfPR from RDTs.cRecorded in baseline survey 1 (February–March 2011).dBaseline survey 2 (June–July 2011) after the UCC.eHaemoglobin <8 g/dl.fReported sleeping under an ITN the night previous to the survey.gCalculated from household-level data.hAt least one ITN per sleeping place.iApproximately 1 mo after spraying.jArithmetic mean.kProportion of mosquitoes positive for P. falciparum sporozoites.lNumber of infective bites per month.Of the 2,000 houses selected in each study arm for each post-intervention survey, 20% to 24% had no children between 0.5 and 14 y old (were ineligible), 13% to 18% were vacant on the day of survey, fewer than 1% refused to participate, and 55% to 61% participated in the survey (Figure 2). Of the children selected for RDT, 81%–84% were tested. Post-intervention IRS coverage reported by householders was 92.1% after the first spray round and 89.5% after the second (Table 3).10.1371/journal.pmed.1001630.g002Figure 2Trial profile for study households and children in the ITN only and ITN+IRS study arms.Survey A\u200a=\u200a2 mo after first intervention spray. Survey B\u200a=\u200a6 mo after first intervention spray and 2 mo after second intervention spray. Survey C\u200a=\u200a10 mo after first intervention spray and 6 mo after second intervention spray. *No children 0.5–14 y old. 1Dwelling vacant for survey duration. 2Includes not found (91.0%), not visited (2.4%), and missing data (6.6%). 3Households (HH) that were included and where children attended for testing.10.1371/journal.pmed.1001630.t003Table 3IRS coverage, ITN ownership, and ITN usage in the intervention year, Muleba District, 2012.SurveyArmReported IRS CoverageaPercent [95% CI] (n\nb)Adequate ITN OwnershipcPercent [95% CI] (n\nb)≥1 ITN OwneddPercent [95% CI] (n\nb)ITN UseePercent [95% CI] (n\nf)\nSurvey A\nITN only3.3 [1.8–5.9] (1,177)52.2 [47.8–56.5] (1,178)85.8 [83.7–87.7] (1,177)46.6 [41.7–51.6] (2,193)ITN+IRS92.1 [88.4–94.7] (1,215)57.2 [53.6–60.7] (1,215)89.0 [87.1–90.6] (1,216)53.0 [47.5–58.3] (2,349)\nSurvey B\nITN only5.2 [1.3–18.6] (1,094)51.6 [47.0–56.0] (1,094)82.5 [78.7–85.7] (1,096)40.7 [34.7–47.0] (2,045)ITN+IRS89.5 [84.0–93.2] (1,138)57.4 [54.0–60.9] (1,142)88.2 [85.7–90.3] (1,142)44.1 [39.2–49.2] (2,207)\nSurvey C\nITN only13.0 [6.6–24.1] (1,165)52.8 [47.6–58.0] (1,168)78.2 [74.3–81.6] (1,170)36.0 [29.8–42.6] (2,101)ITN+IRS89.3 [83.6–93.2] (1,209)56.8 [51.7–61.8] (1,211)83.8 [79.9–87.1] (1,211)36.1 [31.0–41.5] (2,303)Survey A\u200a=\u200a2 mo after first intervention spray. Survey B\u200a=\u200a6 mo after first intervention spray and 2 mo after second intervention spray. Survey C\u200a=\u200a10 mo after first intervention spray and 6 mo after second intervention spray.aReported spray status of household in the spray round preceding the survey.bHouseholds.cPercentage of households with sufficient ITNs for at least one per sleeping place.dPercentage of households with at least one ITN.ePercentage of study children that reported sleeping under an ITN the night previous to the survey. ITN usage in all age groups was very similar to ITN use in the study children.fIndividuals.In the intervention year, the percentage of houses with sufficient ITNs for each sleeping place remained stable over successive surveys and was similar between study arms (range 52%–57%; Table 3). 82.2% and 87.0% of households owned at least one ITN in the ITN only arm and the ITN+IRS arm, respectively (all surveys combined), with weak evidence that the percentage of households that owned at least one ITN was lower in the ITN only arm, and that it decreased from survey A to survey C in both arms (Table 3). ITN usage in children was similar between study arms but declined from 50% in survey A to 36% in survey C.The primary outcome PfPR was lower in the ITN+IRS arm than in the ITN only arm in all three surveys in the intervention year (Table 4). For all three surveys combined, the overall OR was 0.43 (95% CI 0.19–0.97), with weak evidence that the intervention effect differed between surveys (interaction p\u200a=\u200a0.08). The strongest effect was observed in survey B (OR 0.33, 95% CI 0.15–0.75), which was conducted at the peak of malaria transmission after the long rains, 6 mo after the first IRS and 2 mo after the second IRS. The evidence for an effect was weaker in survey A (OR 0.51, 95% CI 0.24–1.09), conducted shortly after the first IRS round, and in survey C (OR 0.48, 95% CI 0.18–1.24), conducted several months after the main transmission season and 6 mo after last spray round. The range of cluster-specific estimates for PfPR was 0% to 92% in the ITN only arm and 0% to 68% in the ITN+IRS arm. The sensitivity analysis showed that excluding the cluster from the ITN only arm that had received IRS did not affect the results of the ITT analysis (Table S1). The overall OR for all three surveys combined was very similar after adjusting for baseline PfPR, OR\u200a=\u200a0.41, but the precision of the estimate was increased (95% CI 0.29–0.59, p<0.0001).10.1371/journal.pmed.1001630.t004Table 4\nPfPR in children 0.5–14 y old in the ITN only and ITN+IRS arms (intention to treat) in survey A, B, and C, Muleba District, Tanzania, 2012.SurveyArm\nPfPRaPercent [95% CI] (n)OR [95% CI], p-Value\nSurvey A\nITN only23.6 [15.4–34.2] (2,191)1.00ITN+IRS13.6 [8.3–21.4] (2,342)0.51 [0.24–1.09], p\u200a=\u200a0.082\nSurvey B\nITN only30.5 [20.2–43.4] (2,033)1.00ITN+IRS12.7 [7.4–21.0] (2,204)0.33 [0.15–0.75], p\u200a=\u200a0.009\nSurvey C\nITN only24.5 [14.2–38.9] (2,091)1.00ITN+IRS13.4 [7.3–23.4] (2,285)0.48 [0.18–1.24], p\u200a=\u200a0.127\nAll three surveys combined\nITN only26.1 [16.7–38.4] (6,315)1.00ITN+IRS13.3 [7.9–21.5] (6,831)0.43 [0.19–0.97], p\u200a=\u200a0.043b\nSurvey A\u200a=\u200a2 mo after first intervention spray. Survey B\u200a=\u200a6 mo after first intervention spray and 2 mo after second intervention spray. Survey C\u200a=\u200a10 mo after first intervention spray and 6 mo after second intervention spray.a\nPfPR from RDTs.bAdjusted for survey.Prevalence of moderate to severe anaemia in children under 5 y old, a secondary outcome, was lower in the ITN+IRS arm in all post-intervention surveys, but the difference was statistically significant only in survey B (Table 5). Mean haemoglobin was higher in children under 5 y old in the ITN+IRS arm than in the ITN only arm in all three surveys. The evidence for an effect was greatest in survey B (0.49 g/dl, 95% CI 0.10–0.89, p\u200a=\u200a0.016), with a non-significant result in survey A (0.28 g/dl, 95% CI −0.02 to 0.59, p\u200a=\u200a0.065) and survey C (0.36 g/dl, 95% CI −0.02 to 0.73, p\u200a=\u200a0.060).10.1371/journal.pmed.1001630.t005Table 5Anaemia and mean haemoglobin in children under 5+IRS arms (intention to treat), for survey A, B, and C, Muleba District, Tanzania, 2012.SurveyArmAnaemia Prevalencea\nMean Haemoglobin (g/dl)Percent [95% CI] (n)OR [95% CI], p-ValueMean [95% CI] (n)Difference [95% CI], p-Value\nSurvey A\nITN only6.0 [4.1–8.7] (815)1.0010.6 [10.4–10.8] (815)ITN+IRS3.9 [2.5–6.2] (864)0.64 [0.34–1.19], p\u200a=\u200a0.15510.9 [10.7–11.1] (864)0.28 [−0.02 to 0.59], p\u200a=\u200a0.065\nSurvey B\nITN only4.7 [2.6–8.6] (737)1.0010.9 [10.6–11.2] (737)ITN+IRS2.2 [1.3–3.6] (784)0.44 [0.20–1.01], p\u200a=\u200a0.05311.4 [11.2–11.6] (784)0.49 [0.10 to 0.89], p\u200a=\u200a0.016\nSurvey C\nITN only3.2 [1.8–5.7] (739)1.0010.8 [10.6–11.1] (739)ITN+IRS2.6 [1.6–4.4] (831)0.81 [0.37–1.77], p\u200a=\u200a0.59011.2 [11.0–11.4] (831)0.36 [−0.02 to 0.73], p\u200a=\u200a0.060\nAll three surveys combined\nITN only4.7 [3.2–6.9] (2,291)1.0010.8 [10.5–11.0] (2,291)ITN+IRS2.9 [2.0–4.3] (2,479)0.62 [0.34–1.10], p\u200a=\u200a0.102b\n11.2 [11.0–11.3] (2,479)0.37 [0.07 to 0.68], p\u200a=\u200a0.017b\nSurvey A\u200a=\u200a2 mo after first intervention spray. Survey B\u200a=\u200a6 mo after first intervention spray and 2 mo after second intervention spray. Survey C\u200a=\u200a10 mo after first intervention spray and 6 mo after second intervention spray.aPrevalence of moderate/severe anaemia (haemoglobin <8 g/dl).bAdjusted for survey.Mean EIR per month, a secondary outcome, was 0.22 in the ITN+IRS arm and 1.26 in the ITN only arm (rate ratio\u200a=\u200a0.17, 95% CI 0.03–1.08, p\u200a=\u200a0.059; Table 6).10.1371/journal.pmed.1001630.t006Table 6Mean number of An. gambiae mosquitoes per household, sporozoite rate, and EIR in the ITN only and ITN+IRS arms during the post-intervention period, Muleba District, Tanzania, 2011–2012.ArmMean or Percent [95% CI] (n)a\nEffect [95% CI], p-Value\nMean\nb\nAn. gambiae\n per house per night\nITN only1.7 [0.5–6.4] (1,892)ITN+IRS0.4 [0.1–1.4] (1,893)Rate ratio\u200a=\u200a0.23 [0.04–1.44], p\u200a=\u200a0.113\nSporozoite rate\nc\nITN only2.5 [2.1–3.1] (3,059)ITN+IRS1.8 [0.5–6.2] (717)OR\u200a=\u200a0.72 [0.21–2.53], p\u200a=\u200a0.600\nMean EIR/month\nd\nITN only1.3 [0.3–4.6]ITN+IRS0.2 [0.1–0.8]Rate ratio\u200a=\u200a0.17 [0.03–1.08], p\u200a=\u200a0.059aData are mean [95% CI] (number of houses) for mean An. gambiae per house per night and percent [95% CI] (number of An. gambiae) for sporozoite rate.bArithmetic mean.cProportion of mosquitoes positive for P. falciparum sporozoites.dNumber of infective bites per month.The between-cluster coefficient of variation (k) was 0.20, 0.28, and 0.26 in the three post-intervention surveys, respectively. For each survey, k was similar in the two arms.For all surveys, per-protocol analysis showed statistically significant evidence for a protective effect of the combined intervention on PfPR (survey A: OR 0.39, 95% CI 0.18–0.81; survey B: OR 0.21, 95% CI 0.09–0.49; and survey C: OR 0.27, 95% CI 0.10–0.73; Table 7).10.1371/journal.pmed.1001630.t007Table 7Per-protocol analysis of PfPR in children 0.5–14 y old and anaemia in children under 5 y old in surveys A, B, and C.SurveyArmPrevalencePercent [95% CI] (n)OR [95% CI], p-Value\nPf\nPR\na\nSurvey AITNb\n26.7 [17.5–38.6] (954)1.00ITN+IRSc\n12.3 [7.8–18.9] (1,142)0.39 [0.18–0.81], p\u200a=\u200a0.013Survey BITNb\n35.5 [23.2–50.2] (782)1.00ITN+IRSc\n10.2 [5.7–17.7] (892)0.21 [0.09–0.49], p\u200a=\u200a0.001Survey CITNb\n29.4 [16.7–46.4] (707)1.00ITN+IRSc\n10.1 [5.4–18.2] (770)0.27 [0.10–0.73], p\u200a=\u200a0.011\nAnaemia\nd\nSurvey AITNb\n5.9 [3.5–9.7] (390)1.00ITN+IRSc\n3.8 [1.8–7.5] (453)0.62 [0.25–1.55], p\u200a=\u200a0.301Survey BITNb\n5.4 [2.2–12.5] (295)1.00ITN+IRSc\n1.9 [0.8–4.1] (374)0.33 [0.10–1.12], p\u200a=\u200a0.076Survey CITNb\n4.0 [2.2–7.0] (303)1.00ITN+IRSc\n2.3 [1.0–5.0] (305)0.57 [0.21–1.55], p\u200a=\u200a0.264Muleba, Tanzania, 2012; analysis restricted to ITN users in both study arms. Survey A\u200a=\u200a2 mo after first intervention spray. Survey B\u200a=\u200a6 mo after first intervention spray and 2 mo after second intervention spray. Survey C\u200a=\u200a10 mo after first intervention spray and 6 mo after second intervention spray.a\nPfPR from RDTs.bITN used by the individual the night preceding the survey in the ITN only arm.cITN used by the individual the night preceding the survey, and household with IRS in the ITN+IRS arm. One cluster that was allocated to be in the ITN only arm but received IRS in the second spray round was excluded from this analysis.dPrevalence of moderate/severe anaemia (haemoglobin <8 g/dl).DiscussionThis is the first randomised trial to our knowledge that provides evidence that IRS, when used in combination with ITNs, can give significant added protection against malarial infection compared to ITN use alone. There was also some evidence that anaemia prevalence was lower in communities with the combination. Exposure to infectious mosquito bites was about one-sixth in communities with the combined intervention compared to those in the ITN only arm. Two rounds of IRS with bendiocarb were conducted to overcome the short residual activity of the insecticide [27],[36] and to ensure that there was active ingredient on the walls of sprayed homes throughout the transmission season.IRS coverage in the ITN+IRS arm was high at approximately 90% in both spray rounds, which would have optimised its effectiveness [37]. On the other hand, whilst 85% of households owned at least one ITN, use of ITNs was modest, declining to 36% by the end of the study. The low usage of ITNs means that the addition of IRS may have simply protected those who were not using an ITN, thus compensating for low ITN usage rather than offering additional protection to net users. This interpretation is contradicted by the results of a per-protocol analysis, which excluded those not using ITNs, showing strong evidence that ITN users whose houses were sprayed were additionally protected by IRS. The estimated reduction in PfPR associated with the combination of interventions was greater in the per-protocol analysis than in the ITT analysis in each survey. Per-protocol analysis excludes non-compliers (for IRS and ITN) and therefore may have been influenced by confounders. It is likely that the observed overall effect of the intervention combination was a result of both IRS protecting those not using ITNs, and IRS additionally protecting ITN users.A potential negative impact of the combination of interventions is that having their house sprayed may encourage some residents to stop sleeping under an ITN. This was not observed in this study; ITN usage was similar between the villages with and without IRS in each post-intervention survey.ITN usage and ownership was slightly higher at baseline in the ITN+IRS arm compared to the ITN only arm, but the 95% confidence intervals for these estimates overlapped. This non-significant difference could have led to a slight overestimation of the effect size. PfPR was slightly lower at baseline in the ITN+IRS arm compared to the ITN only arm, but the effect size did not change after adjusting for PfPR at baseline. This suggests that baseline PfPR was not confounding the relationship between study arm and PfPR (the outcome). In the baseline year, malaria prevalence was higher in June–July after the long rainy season than in February–March after the short rains. In the intervention year, the prevalence similarly increased in June–July (survey B) in the ITN only arm, but prevalence in the ITN+IRS arm remained low, suggesting IRS and ITNs in combination prevented the seasonal increase in infections.The added protective effect of IRS peaked in the second survey, at the height of transmission after the long rains. This was probably the optimal time for the insecticide to reduce the abundance of the mosquito population (N. Protopopoff, personal communication) and thus to observe the impact of IRS on the prevalence of malarial infections. The limited residual activity of bendiocarb IRS has been shown to reduce its protective effectiveness 3–5 mo after spraying, which probably accounts for the loss of added benefit seen in the third survey, which was 6 mo after the last spray round at the beginning of the short rains [27],[36]. Implementing IRS with long-lasting insecticide formulations might be necessary to maintain the effectiveness of the combination throughout the year. Alternatively, the time between IRS rounds could be reduced, but this would considerably raise the cost of the combined intervention [38].The secondary outcomes anaemia and EIR also pointed to added protection being provided by the combination of IRS and ITNs, but the evidence for these endpoints was weaker. The combination intervention was associated with higher haemoglobin levels in children under 5 y, particularly at the peak of the transmission season. The study had been powered to show a difference in the primary outcome (PfPR), and therefore may have been underpowered for these secondary outcomes. Nevertheless, the results for all outcomes are consistent.One of the limitations of this study is that clinical incidence of malaria could not be recorded in addition to infection prevalence because recording of confirmed malaria cases was unreliable because of stock-outs of RDTs at health facilities. Implementing both IRS and universal coverage of ITNs is obviously considerably more costly than ITNs alone. Estimating the cost-effectiveness of the combination compared to ITNs alone was beyond the scope of this particular research. Although IRS is known to be highly cost-effective [8],[39]–[43], the marginal cost per case averted through using IRS in combination with ITNs should ideally be assessed in future studies. This is particularly important in light of the funding gap that has been identified for meeting the demand for universal coverage of vector control for populations in malaria endemic regions [3].Previous studies have investigated the combined use of multiple vector control methods versus one method alone, but the results have been inconsistent [4],[44]–[47]. The only published trial data are from a 28-cluster, four-arm CRT carried out in Benin that compared (1) targeted coverage of LLINs (pregnant women and children only), (2) universal coverage of LLINs, (3) targeted coverage of LLINs combined with bendiocarb IRS, and (4) universal coverage of LLINs combined with bendiocarb-treated wall linings [10]. The study found no difference in malaria incidence, geometric mean parasite density, or mosquito abundance between any of the study arms. The lack of any evidence of an added benefit of the combined interventions over the use of LLINs alone has to be viewed against the modest sample size, and hence potentially low power of this trial [12], and the lack of a comparator arm with universal coverage of ITNs.There are a number of differences between the Benin trial and the current study that may have contributed to the discordant results. In the Benin trial, the interval between IRS rounds was 8 mo, whereas it was only 4 mo in the current study, as IRS was timed according to the seasonal peaks in cases, and taking account of its short residual duration on walls. The first two cross-sectional surveys for the current trial were timed to coincide with the seasonal peaks in cases and were only 2 mo after each IRS round, whereas in Benin the cases were recorded at 6-wk intervals for 18 mo, so that the measured effect of the additional IRS may include a period when the insecticide, which is known to have a short residual duration, was no longer effective. In the Benin trial, LLINs were given only to target groups in the reference arm and in the study arm with IRS, whereas in the current trial ITNs were distributed to all age groups.Large CRTs have recently been conducted in the Gambia [48],[49] and in Sudan [50] comparing villages with IRS and LLINs to villages with only LLINs, but the results have not yet been published.Evidence of an added benefit from the combination intervention compared to IRS or ITNs alone has been shown in a number of observational studies [4],[45],[47],[51]–[55]. For example, children 2–14 y old consistently received added personal protection from using nets in addition to IRS on the island of Bioko, Equatorial Guinea (OR 0.71, 95% CI 0.59–0.86), and in Zambezia, Mozambique (OR 0.63, 95% CI 0.50–0.79) [4],[36]. In Pakistan, nets provided added protection against P. vivax and P. falciparum in refugee camps where IRS was conducted [56]. However, other studies observed no additional benefit from the combination compared to one intervention alone [46],[57],[58].One interpretation of these divergent conclusions is that if the intervention present in both study arms is compromised or poorly implemented, the second method compensates for the deficiency of the first, providing apparent added protection that would otherwise not be seen. On the other hand, if the reference arm intervention is well implemented and efficacious in both study arms, there may be little or no scope for additional protection by a second intervention. ITN usage in the present trial was moderate, and hence the IRS protected many people who were not using a net in the ITN+IRS arm, whilst non-users in the ITN only arm remained unprotected. Any community or “mass effect” of ITNs on mosquito population size would have been limited because of the low community net usage. Therefore, the protective effect of ITNs in this study was possibly suboptimal. In Bioko, ITNs provided personal protection in the presence of IRS that was rendered only partially effective by moderate coverage (77%–79%) and use of an insecticide that did not outlast the long malaria season [36],[51]. Protopopoff et al. reported that in Burundi there was no additional reduction in infection prevalence in children from adding LLINs to IRS because high coverage (90%) of IRS had already reduced the sporozoite rate to a level where nets had no further impact [57]. In Sao Tome, where the IRS programme was poorly implemented, with low coverage and long intervals between spray rounds, there was an additional benefit from using ITNs and IRS compared to IRS alone [47]. However, on the neighbouring island of Principe, where IRS coverage was high (85%) and implemented on schedule, there was no added protection from ITNs in combination with IRS compared to IRS alone [46],[47].Insecticide resistance may be another reason why differences have been seen for the effectiveness of the combination of IRS and ITNs, resulting in either an apparent “added” effect of the second effective intervention, if the first was ineffective due to insecticide resistance, or no added effect if the second intervention was ineffective due to insecticide resistance. In the study area of this trial, there was evidence for high levels of resistance to pyrethroids in An. gambiae s.s. The epidemiological impact of pyrethroid resistance on the effectiveness of ITNs is currently not known [59]. However, if the effectiveness of the ITNs was compromised [24] because of insecticide resistance, this would have enhanced our estimate of the additional benefit of non-pyrethroid IRS. If pyrethroid-treated nets were to be rendered partially ineffective in the presence of resistance, there would be a compelling case for combining ITNs with non-pyrethroid IRS.An experimental hut trial in an area of Tanzania where the main vector is An. arabiensis found that if ITNs were used, the addition of IRS using insecticides with high irritancy such as dichlorodiphenyltrichloroethane (DDT) or lambda-cyhalothrin did not increase mosquito mortality or repel mosquitoes from the house [11]. However, the addition of IRS using pirimiphos-methyl, an organophosphate that has high toxicity and low irritancy, did increase mosquito mortality. These findings underscore that the interaction between the two interventions is complex and that the added protective effect will be dependent on the feeding and resting behaviours of particular malaria vectors, on the type of IRS insecticide used, on the susceptibility of local vectors to each of the insecticides in the combination, and on ITN usage [5]–[7],[11]. As a result, added protection may not be observed in all situations. A systematic review of all the trial results estimating the effectiveness of the combination of ITNs and IRS should be undertaken once the results of the trials in Sudan and the Gambia are available.Nevertheless, this trial provides encouraging evidence for an additional benefit from applying IRS in combination with ITNs compared to ITNs alone. To our knowledge it is the first CRT to do so. The added protection from the supplementary use of IRS may in the case of bendiocarb be limited to only a few months, raising the question of whether residual insecticides of short duration are cost-effective when used in combination with ITNs. This study was conducted as an effectiveness study and not an efficacy study. The LLINs were distributed by a national UCC and therefore represented a real-life malaria control programme, including the challenges faced in achieving high coverage and usage of ITNs.In conclusion, national malaria control programmes should consider implementing IRS in combination with ITNs if local ITN strategies alone are insufficiently effective and cannot be improved. A key consideration would be the additional cost of providing the combined intervention. Given the inconsistent trial evidence and the unproven generalisability of the findings of all studies that have investigated this question, it would be prudent for malaria control programmes implementing the two methods simultaneously to monitor the impact and cost-effectiveness of the combination to verify whether the additional resources have the desired effect.Supporting InformationChecklist S1\nCONSORT checklist.\n(DOCX)Click here for additional data file.Table S1\nPf\nPR in children 0.5–14 y old in the ITN only and ITN+IRS arms (intention to treat) excluding the cluster that violated the protocol, in survey A, B, and C, Muleba District, Tanzania, 2012.\n(DOCX)Click here for additional data file.The authors express their sincere thanks to the fieldworkers, clinical teams, and all the Pan African Malaria Vector Research Consortium staff at Muleba and Moshi for their hard work collecting the data. We acknowledge the assistance provided by staff at the Muleba District Medical Office, RTI International, and the hamlet and village leaders. We wish to thank all those who participated in the study. The London School of Hygiene and Tropical Medicine, Kilimanjaro Christian Medical College, and the National Institute for Medical Research in Tanzania are members of the Pan African Malaria Vector Research Consortium (http://www.pamverc.or.tz). P. A. W., N. P., M. R., and I. K. would like to thank other members of the Malaria Centre of the London School of Hygiene and Tropical Medicine for their advice and comments (http://malaria.lshtm.ac.uk/).References1Roll Back Malaria Partnership (2000) The Abuja Declaration and the plan of action. Geneva: World Health Organization.2World Health Organization Global Malaria Programme (2007) Insecticide-treated mosquito nets. Geneva: World Health Organization Global Malaria Programme.3World Health Organization (2013) World malaria report 2013. 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American Society of Tropical Medicine and Hygiene 61st Annual Meeting; 11–15 November 2012; Atlanta, Georgia, US.50Kafy H (2013) Combination of IRS with LLINs versus LLINS alone in Sudan: results of a very large randomised trial [abstract]. 6th MIM Pan-African Malaria Conference; 6–11 October 2013; Durban, South Africa.51\nKleinschmidtI, TorrezM, SchwabeC, BenaventeL, SeocharanI, et al (2007) Factors influencing the effectiveness of malaria control in Bioko Island, equatorial Guinea. Am J Trop Med Hyg\n76: 1027–1032.1755660652\nPardoG, DescalzoMA, MolinaL, CustodioE, LwangaM, et al (2006) Impact of different strategies to control Plasmodium infection and anaemia on the island of Bioko (Equatorial Guinea). Malar J\n5: 10.1646055853\nGravesPM, OsgoodDE, ThomsonMC, SerekeK, AraiaA, et al (2008) Effectiveness of malaria control during changing climate conditions in Eritrea, 1998–2003. 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Geneva: World Health Organization.AbbreviationsCRTcluster randomised controlled trialEIRentomological inoculation rateIRSindoor residual sprayingITNinsecticide-treated netITTintention to treatLLINlong-lasting insecticidal netORodds ratioPfPR\nPlasmodium falciparum prevalence ratePMIPresident's Malaria InitiativeRDTrapid diagnostic testUCCuniversal coverage campaignWHOWorld Health Organization", 'title': 'Indoor residual spraying in combination with insecticide-treated nets compared to insecticide-treated nets alone for protection against malaria: a cluster randomised trial in Tanzania.', 'date': '2014-04-17'}, '29655496': {'article_id': '29655496', 'content': "LancetLancetLancet (London, England)0140-67361474-547XElsevier296554965910376S0140-6736(18)30427-610.1016/S0140-6736(18)30427-6ArticleEffectiveness of a long-lasting piperonyl butoxide-treated insecticidal net and indoor residual spray interventions, separately and together, against malaria transmitted by pyrethroid-resistant mosquitoes: a cluster, randomised controlled, two-by-two factorial design trialProtopopoffNatachaPhDnatacha.protopopoff@lshtm.ac.uka*MoshaJacklin FPhDcLukoleEliudMScdCharlwoodJacques DPhDaWrightAlexandraMScaMwalimuCharles DMSceManjuranoAlphaxardPhDcMoshaFranklin WProfPhDdKisinzaWilliamPhDfKleinschmidtImmoProfPhDbgRowlandMarkProfPhDaaDepartment of Disease Control, London School of Hygiene & Tropical Medicine, London, UKbMRC Tropical Epidemiology Group, London School of Hygiene & Tropical Medicine, London, UKcNational Institute for Medical Research, Mwanza Medical Research Centre, Mwanza, TanzaniadPan-African Malaria Vector Research Consortium, Kilimanjaro Christian Medical University College, Moshi, TanzaniaeMinistry of Health Community Development Gender Elderly and Children, National Malaria Control Program, Dar es Salaam, TanzaniafNational Institute for Medical Research, Amani Medical Research Centre, Muheza, TanzaniagSchool of Pathology, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa*Correspondence to: Dr Natacha Protopopoff, Department of Disease Control, London School of Hygiene & Tropical Medicine, London WC1E 7HT, UK natacha.protopopoff@lshtm.ac.uk214201821420183911013015771588© 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license2018This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).SummaryBackgroundProgress in malaria control is under threat by wide-scale insecticide resistance in malaria vectors. Two recent vector control products have been developed: a long-lasting insecticidal net that incorporates a synergist piperonyl butoxide (PBO) and a long-lasting indoor residual spraying formulation of the insecticide pirimiphos-methyl. We evaluated the effectiveness of PBO long-lasting insecticidal nets versus standard long-lasting insecticidal nets as single interventions and in combination with the indoor residual spraying of pirimiphos-methyl.MethodsWe did a four-group cluster randomised controlled trial using a two-by-two factorial design of 48 clusters derived from 40 villages in Muleba (Kagera, Tanzania). We randomly assigned these clusters using restricted randomisation to four groups: standard long-lasting insecticidal nets, PBO long-lasting insecticidal nets, standard long-lasting insecticidal nets plus indoor residual spraying, or PBO long-lasting insecticidal nets plus indoor residual spraying. Both standard and PBO nets were distributed in 2015. Indoor residual spraying was applied only once in 2015. We masked the inhabitants of each cluster to the type of nets received, as well as field staff who took blood samples. Neither the investigators nor the participants were masked to indoor residual spraying. The primary outcome was the prevalence of malaria infection in children aged 6 months to 14 years assessed by cross-sectional surveys at 4, 9, 16, and 21 months after intervention. The endpoint for assessment of indoor residual spraying was 9 months and PBO long-lasting insecticidal nets was 21 months. This trial is registered with ClinicalTrials.gov, number NCT02288637.Findings7184 (68·0%) of 10\u2008560 households were selected for post-intervention survey, and 15\u2008469 (89·0%) of 17\u2008377 eligible children from the four surveys were included in the intention-to-treat analysis. Of the 878 households visited in the two indoor residual spraying groups, 827 (94%) had been sprayed. Reported use of long-lasting insecticidal nets, across all groups, was 15\u2008341 (77·3%) of 19\u2008852 residents after 1 year, decreasing to 12\u2008503 (59·2%) of 21\u2008105 in the second year. Malaria infection prevalence after 9 months was lower in the two groups that received PBO long-lasting insecticidal nets than in the two groups that received standard long-lasting insecticidal nets (531 [29%] of 1852 children vs 767 [42%] of 1809; odds ratio [OR] 0·37, 95% CI 0·21–0·65; p=0·0011). At the same timepoint, malaria prevalence in the two groups that received indoor residual spraying was lower than in groups that did not receive indoor residual spraying (508 [28%] of 1846 children vs 790 [44%] of 1815; OR 0·33, 95% CI 0·19–0·55; p<0·0001) and there was evidence of an interaction between PBO long-lasting insecticidal nets and indoor residual spraying (OR 2·43, 95% CI 1·19–4·97; p=0·0158), indicating redundancy when combined. The PBO long-lasting insecticidal net effect was sustained after 21 months with a lower malaria prevalence than the standard long-lasting insecticidal net (865 [45%] of 1930 children vs 1255 [62%] of 2034; OR 0·40, 0·20–0·81; p=0·0122).InterpretationThe PBO long-lasting insecticidal net and non-pyrethroid indoor residual spraying interventions showed improved control of malaria transmission compared with standard long-lasting insecticidal nets where pyrethroid resistance is prevalent and either intervention could be deployed to good effect. As a result, WHO has since recommended to increase coverage of PBO long-lasting insecticidal nets. Combining indoor residual spraying with pirimiphos-methyl and PBO long-lasting insecticidal nets provided no additional benefit compared with PBO long-lasting insecticidal nets alone or standard long-lasting insecticidal nets plus indoor residual spraying.FundingUK Department for International Development, Medical Research Council, and Wellcome Trust.Research in contextEvidence before this studyWe did two searches in PubMed with no language restrictions or specified dates. In the first search on long-lasting insecticidal nets treated with piperonyl butoxide (PBO), we used the search terms “malaria” and “long lasting insecticidal net” in combination with “piperonyl butoxide”, “Olyset Plus”, or “PermaNet 3.0”, which produced no references that were randomised controlled trials (RCTs). In a 2015 review of PBO long-lasting insecticidal nets, WHO concluded that although they appeared to have an increased efficacy the evidence was too inadequate to justify a switch from pyrethroid only to PBO nets across all settings. Because of the potential for an antagonistic effect between PBO and organophosphates, WHO also recommended that PBO nets should not be used in areas programmed for indoor residual spraying with pirimiphos-methyl capsule suspension.In the second search on combined vector control interventions, we included the search term “malaria” with one or more of the following: “long lasting insecticidal net” or “insecticide treated net”, “indoor residual spraying”, “vector control”, “pirimiphos methyl”, and “combined interventions”. We identified three other RCTs that have examined combined intervention of long-lasting insecticidal nets and indoor residual spraying. The Gambian RCT, which used DDT (dichlorodiphenyltrichloroethane) as the indoor residual spraying component showed no additional protection compared with long-lasting insecticidal nets alone. This finding could be explained by the high usage of nets or the properties of the sprayed insecticide used. In Benin, there was no advantage to combining indoor residual spraying and long-lasting insecticidal nets; however, suboptimal coverage of nets and the short residual effect of the spray used (bendiocarb) might have affected the effectiveness of the combination intervention. In an earlier Tanzanian study, where coverage of long-lasting insecticidal nets was moderate and pyrethroid resistance present, two rounds of indoor residual spraying with bendiocarb combined with long-lasting insecticidal nets were more effective than long-lasting insecticidal nets alone.Added value of this studyOur study is the first RCT to report that PBO-treated long-lasting insecticidal nets were more effective than standard pyrethroid long-lasting insecticidal nets against malaria infection and transmission. It also provides the strongest evidence to date of the negative effect of high-level pyrethroid resistance on the use and efficacy of standard nets. This study is also the first RCT to provide evidence for the effect of long-term malaria control of the first long-lasting organophosphate formulation to be developed specifically for indoor residual spraying. The RCT provides new evidence on the added value and risks of combining indoor residual spraying and long-lasting insecticidal nets, particularly PBO nets.Implications of all the available evidenceThis study provides justification for the increase in deployment and use of PBO long-lasting insecticidal nets. As a direct consequence of this trial, WHO revised its policy on long-lasting insecticidal nets in September, 2017, gave interim endorsement to pyrethroid-PBO nets as a new WHO class of vector control product, and recommended that PBO nets be deployed for prevention of malaria where vectors are resistant to pyrethroids provided that vector control coverage is not compromised. This endorsement would include many endemic areas in Africa where standard long-lasting insecticidal nets are currently used. The demonstration that long-lasting insecticidal nets with an appropriate change of active ingredient can continue to tackle transmission by pyrethroid-resistant vector populations will ensure the viability of this approach as well as justifies the continued investment and search for alternative insecticides for use on nets.Finally, the organophosphate indoor residual spraying formulation is the first long-lasting, non-pyrethroid insecticide to provide malaria control for at least 9 months over two transmission seasons in the same year. This finding justifies the scale up and use of indoor residual spraying in sub-Saharan Africa and the 12-year investment into long-lasting alternatives to pyrethroid and DDT for indoor spraying between private and public sector organisations.IntroductionLong-lasting insecticidal nets and indoor residual spraying are the cornerstones of malaria control in sub-Saharan Africa. Together with effective treatment, these interventions are estimated to have globally reduced malaria morbidity by 41% and mortality by 62% between 2000 and 2015.1 Despite this public health success, recent wide-scale selection of insecticide resistance in the mosquito vectors across Africa threatens to reverse the present gains.2 Development and evaluation of new strategies and tools are needed to address the threat of resistance and will accelerate progress towards elimination.The range of insecticides available for indoor residual spraying is limited. For long-lasting insecticidal nets, the range is particularly restricted because pyrethroids are the only class of insecticides recommended by WHO for nets. Evidence from indoor residual spraying programmes suggests that pyrethroid resistance can contribute to operational control failure—eg, in South Africa, control was only restored once the pyrethroid was replaced by an insecticide to which vectors were susceptible.3 By contrast, the negative effect of pyrethroid resistance on the effectiveness of long-lasting insecticidal nets has been less clear and harder to quantify than indoor residual spraying.4 Although entomological evidence suggests that these nets are becoming less effective at killing mosquitoes in household conditions when resistance develops,5, 6 the physical barrier provided by the net, especially when new and intact, might mitigate some of the loss in bioefficacy due to resistance.7 Cohort studies have shown that long-lasting insecticidal nets remain protective against malaria infection in areas of moderate insecticide resistance in Malawi8 and Kenya,9 whereas no reduction in incidence was observed after the distribution of these nets in Uganda.10Anticipating the possible failure of current control tools due to resistance, WHO has encouraged the industry to develop new types of long-lasting insecticidal nets and new insecticides for indoor residual spraying. One of these developments is a new long-lasting insecticidal net that uses piperonyl butoxide (PBO). PBO is a chemical synergist that acts by inhibiting enzymes involved in the natural defense mechanisms of insects, which results in pyrethroid not being detoxified in the insect and the pyrethroid on the long-lasting insecticidal net remaining potent against mosquitoes despite resistance. Such PBO-pyrethroid-treated long-lasting insecticidal nets appear to have similar or better efficacy against resistant mosquitoes under controlled household conditions than standard long-lasting insecticidal nets that do not have PBO.11, 12 In September, 2015, a WHO expert group reviewed the evidence for PBO long-lasting insecticidal nets to define their deployment. Despite awaiting for more conclusive evidence from community randomised controlled trials (RCTs) with epidemiological outcomes, WHO, nevertheless, has recommended a small rollout in specific situations.13Although the range of insecticide classes suitable for indoor residual spraying use is wider than long-lasting insecticidal nets, few insecticides are effective for more than a few months when sprayed onto walls and this limitation has been a constraint on their adoption and use. The organophosphate pirimiphos-methyl is an exception, and the recently developed long-lasting formulation, Actellic 300CS (Syngenta, Switzerland), is effective for up to 10 months when used for indoor residual spraying.14 It is now being deployed in several African countries instead of carbamates.15In attempts to accelerate malaria control progress, long-lasting insecticidal nets and indoor residual spraying have been deployed together in several countries.1 The advantage of combined intervention has, however, been the focus of considerable debate because both observational and RCTs have produced contradictory evidence. In The Gambia and Benin, no difference in malarial outcomes were reported when both control strategies were deployed together compared with long-lasting insecticidal nets alone,16, 17 whereas in Tanzania an increased effectiveness was observed when they were used in combination.18 On the basis of these data, the effect observed would seem to depend on the insecticide combination used, the vectors present, the coverage and quality of the intervention, and the level and type of insecticide resistance in the vectors.To develop an improved strategy for control of malaria transmitted by pyrethroid-resistant mosquito vectors, we aimed to compare the effectiveness of PBO long-lasting insecticidal nets with standard long-lasting insecticidal nets as single interventions and in combination with the long-lasting indoor residual spraying of pirimiphos-methyl.MethodsStudy design and participantsWe did a cluster RCT of four groups using a two-by-two factorial design. The RCT started on March 1, 2014. The post-intervention assessment period was initially planned for 18 months (from Jan 1, 2015, to June 30, 2016) and was subsequently extended on our request to the funding agency to 24 months (from Jan 1, 2014, to Dec 31, 2016) to enable further assessment of the PBO long-lasting insecticidal net (figure 1).Figure 1Study timetableRCT=randomised controlled trial.The study area was Muleba district of the Kagera region in northwest Tanzania, and comprised 40 villages. In 2011, malaria infection prevalence in children was 23%.18\nAnopheles gambiae and Anopheles arabiensis were the only vectors found in 2012. High levels of resistance to pyrethroids have been reported in A gambiae in the study area, and synergy bioassay tests done with PBO and pyrethroid together partially restored the toxicity of pyrethroids.19 All villages and hamlets with malaria prevalence more than 20% in 2011 were eligible for inclusion in the present trial. Our trial comprised 48 clusters, each divided into an inner core area, which was used for the measurement of study outcomes, and an outer buffer zone of at least 300 m to reduce spill-over effects between clusters.20 Core and buffer areas of each cluster received the same intervention. All households in the core area with children aged 6 months to 14 years were eligible for malaria cross-sectional survey and mosquito surveillance. We excluded children who were severely ill. Village meetings were held with village leaders, hamlet representatives, community health agents, and villagers to inform them about the trial.The trial was approved by the ethics review committees of the Kilimanjaro Christian Medical University College, the London School of Hygiene & Tropical Medicine, and the Tanzanian Medical Research Coordinating Committee (NIMR/HQ/R.8a/VolIX/1803). A trial steering committee reviewed progress. Written informed consent from parents or guardians was obtained for each survey and entomology collection.Randomisation and maskingWe used restricted randomisation to allocate the 48 clusters to the four study groups: standard long-lasting insecticidal nets, PBO long-lasting insecticidal nets, standard long-lasting insecticidal nets plus indoor residual spraying, and PBO long-lasting insecticidal nets plus indoor residual spraying. We limited potential imbalance using three restriction variables: malaria infection prevalence in children aged 6 months to 14 years, usage of long-lasting insecticidal nets, and socioeconomic status, as recorded in the baseline survey between September and October, 2014. Of the 200\u2008000 random allocations, 29\u2008478 met the restriction criteria of no more than 7% difference in mean malaria prevalence, 10% in mean usage of long-lasting insecticidal nets, and 10% of households in the lowest socioeconomic status tertile between study groups. After verifying that clusters were independently allocated to study groups, we randomly chose one of the eligible allocations.We masked the inhabitants of each cluster to the type of long-lasting insecticidal nets received. The two types of nets were of similar colour and shape, and only distinguishable by label codes and coloured thread inserted during manufacture. Additionally, we masked field staff, who took blood samples in the cross-sectional surveys, to the study groups the clusters were assigned to. It was not possible to mask either the investigators or the participants to the treatment allocation of indoor residual spraying.ProceduresWe used the following vector control products: Olyset Net (Sumitomo Chemicals, Japan) containing 2% permethrin (standard long-lasting insecticidal net), Olyset Plus (Sumitomo Chemicals, Japan) containing 2% permethrin and 1% PBO (PBO long-lasting insecticidal net), and Actellic 300CS containing microencapsulated pirimiphos-methyl (indoor residual spraying).We georeferenced all houses in the study using hand-held global positioning system units (Legend eTrex, Garmin, USA). The indoor residual spraying campaign was done once only in February, 2015, by the Research Triangle Institute funded by the President's Malaria Initiative. In the two groups assigned to indoor residual spraying intervention, Actellic 300CS was sprayed to the interior walls and ceilings of each dwelling at the recommended dosage of 1 g/m2. The residual decay of Actellic 300CS was monitored by a laboratory technician every 3 months on representative wall surfaces in several houses using WHO Cone bioassay tests (Universiti Sains Malaysia, Malaysia) and a reference strain of susceptible A gambiae. The permethrin and PBO contents of the long-lasting insecticidal nets were determined by high-performance liquid chromatography at yearly intervals for 2 years.Distribution of long-lasting insecticidal nets and health education communication on net usage were done in each cluster by the Tanzania Communication and Development Centre. On the basis of census data, each household received one net per two people. Altogether, 45\u2008000 standard long-lasting insecticidal nets and 45\u2008000 PBO long-lasting insecticidal nets were distributed in February, 2015. Nets already owned were not removed but householders were requested to use the study nets provided.Cross-sectional household and malaria infection prevalence surveys were done by project field assistants and nurses at baseline in September and October, 2014, and after intervention at the end of each malaria transmission season (June to July and November to December) in 2015 and 2016 (figure 1). During each survey, we randomly sampled 55 households with children aged 6 months to 14 years from the core area of each cluster using the census lists. We then selected up to three eligible children per house at random and recorded information about the number of residents, household assets, house structure, educational status, and use of malaria preventive measures (long-lasting insecticidal nets or other). The minimum target was 80 children per cluster. Enrolled children reported to the clinical team the next day and were tested for malaria using a rapid diagnostic test (CareStart Malaria HRP2/pLDH(pf/PAN) Combo, DiaSys, UK) and for haemoglobin concentration using HemoCue Hb 201+ (HemoCue AB, Sweden). Children diagnosed as malaria positive by the rapid diagnostic test were treated with artemether-lumefantrine according to national guidelines. Any child presenting with illness during the surveys was treated or referred to the nearest health facility if symptoms were severe.Mosquito surveillance was done from March, 2015, to December, 2016, in each cluster by a project field assistant for one night per month in seven randomly selected houses per cluster using CDC Miniature Light Trap Model 512 (John W Hock Company, USA) as a proxy for human biting rates.17 We morphologically identified the collected anophelines to species level21 and tested a subsample for Plasmodium falciparum circumsporozoite protein.22 PCR TaqMan assay23 was used to distinguish the two sibling species (A gambiae and A arabiensis) and to identify mutation in the voltage-gated sodium channel (Vgsc-1014F and Vgsc-1014S) associated with resistance to pyrethroids.24 Using wild caught A gambiae and Anopheles funestus of unknown age, the frequency of pyrethroid resistance was determined using 0·75% permethrin papers in WHO cylinder tests. We determined resistance intensity using CDC bottle bioassays and probit analysis to estimate the ratio of the permethrin concentration needed to kill 50% of wild mosquitoes relative to the susceptible strain.OutcomesThe primary outcome was the prevalence of Plasmodium spp infection measured by the rapid diagnostic test in children aged 6 months to 14 years assessed by the cross-sectional surveys. The trial was initially funded for 18 months after intervention. Although this period could have been chosen as the endpoint, it was not known for how long the PBO and pyrethroid active ingredients in the long-lasting insecticidal nets would last. This effect needed to be monitored every transmission season. We subsequently secured extension from the funding agency for 24 months. WHO then reset the policy agenda declaring that new types of long-lasting insecticidal nets (such as the PBO net) should be effective for at least two transmission seasons or 2 years. The primary endpoint for the indoor residual spraying was 1 year, based on reports of duration of residual activity. Because the two intervention products were being assessed separately and in combination, the main endpoint for assessment of the indoor residual spraying was 9 months and the PBO long-lasting insecticidal nets was 9 months and then 21 months.The secondary main outcome was malaria transmission or entomological inoculation rate, defined as the mean number of infective mosquito bites per household per month, during the first year and second year after intervention. Other secondary endpoints were the proportion of children with moderate-to-severe anaemia (defined as haemoglobin <8 g/dL), the sporozoite rate (the proportion of anopheline mosquitoes collected that were infected with malaria sporozoites), and anopheline population density.Statistical analysisThis study had 80% power25 to detect a relative reduction in prevalence of infection of at least 28% (prevalence ratio 0·72) for each of the two main effects (ie, indoor residual spraying vs no indoor residual spraying, and PBO long-lasting insecticidal nets vs no PBO long-lasting insecticidal nets) and a 40% difference between any of the individual groups, with 24 clusters of 80 individuals per cluster being tested in each of these comparisons, and assuming a mean prevalence of 20% in the reference groups and a coefficient of variation of 0·3 (based on data from the earlier study).18Statistical analysis was done using Stata (version 12). All statistical inferences allowed for within-cluster correlation of responses by use of a robust variance estimator to calculate SEs. No allowance was made for multiplicity of testing in the analyses. In the intention-to-treat analysis, logistic regression was used to estimate odds ratios (ORs) of the effect of each of the two interventions (PBO long-lasting insecticidal nets vs standard long-lasting insecticidal nets, and indoor residual spraying vs no indoor residual spraying) on prevalence of infection and prevalence of anaemia. We estimated interaction between the two main effects by including an appropriate term in the model. We also examined the effect of each intervention (PBO long-lasting insecticidal nets, combination of standard long-lasting insecticidal nets plus indoor residual spraying, and combination of PBO long-lasting insecticidal nets plus indoor residual spraying) compared with the control group (standard long-lasting insecticidal net). Effects were interpreted in relation to a postulated minimum difference of 28% for factorial analysis and 40% for the analysis of each intervention. Analysis of anaemia was restricted to children aged 6 months to 4 years. The per-protocol analysis is available in the appendix.Vector density and entomological inoculation rate were analysed with negative binomial regression, after adjusting for baseline. Entomological inoculation rate was estimated as the mean number of sporozoite-infected Anopheles per house per night26 and weighted to account for the proportion of collected Anopheles processed for sporozoites. The proportion of sporozoite-infected mosquitoes (the sporozoite rate) was compared using logistic regression.This trial is registered with ClinicalTrials.gov, number NCT02288637.Role of the funding sourceThe funder of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.ResultsThe study area comprised 29\u2008365 households and a population of 135\u2008900. Of the 10\u2008560 households selected for post-intervention survey, 7184 (68·0%) were included whereas 1127 (10·7%) were ineligible (no children younger than 15 years), 150 (1·4%) refused, 1543 (14·6%) were absent, and 556 (5·3%) were unvisited. Of the 17\u2008377 eligible children selected, 15\u2008492 (89·2%) attended for testing (figure 2). Pre-intervention household and demographic characteristics, as well as coverage and usage of long-lasting insecticidal nets were similar between study groups (table 1). Malaria infection prevalence was reported in 2499 (65%) of 3861 children at baseline, and any difference between groups were within the tolerances set for the constrained randomisation. The average indoor Anopheles density was 27·6 per house per night and the proportion of mosquitoes with sporozoites was 4·5%. Of the 13\u2008689 Anopheline mosquitoes collected, 13\u2008106 (95·7%) were A gambiae sensu lato and 510 (3·7%) were A funestus. Of the 990 A gambiae sensu lato identified to species, 946 (95·6%) were A gambiae sensu stricto and 44 (4·4%) were A arabiensis.Figure 2Trial profileLLIN=long-lasting insecticidal net. PBO=piperonyl butoxide. IRS=indoor residual spraying.Table 1Baseline characteristicsStandard LLINPBO LLINStandard LLIN plus IRSPBO LLIN plus IRSStudy cluster characteristicsTotal population in core and buffer areas33\u200882032\u200886138\u200808131\u2008138Population in core area15\u200894716\u200828216\u200835814\u2008845Household characteristicsMedian altitude of the households selected (range; N)1330 (1138–1654; 465)1275 (1138–1563; 500)1298 (1129–1486; 508)1338 (1152–1543; 510)Households in the lowest socioeconomic category146/464 (31%)166/534 (31%)198/528 (38%)163/467 (35%)Households with adequate long-lasting insecticidal nets174/545 (32%)223/582 (38%)230/580 (40%)211/561 (38%)Households with ≥1 long-lasting insecticidal nets356/545 (65%)410/582 (70%)402/581 (69%)378/561 (67%)Long-lasting insecticidal nets use in all age groups902/2996 (30%)810/3078 (26%)882/3197 (28%)810/3078 (26%)Children characteristicsMedian age, years (IQR; N)6 (3–10; 885)6 (3–9; 991)6 (3–10; 1017)6 (3–10; 967)Long-lasting insecticidal net use in selected children348/891 (39%)315/992 (32%)315/1018 (31%)307/970 (32%)Malaria infection prevalence600/885 (68%)606/991 (61%)678/1018 (67%)615/967 (64%)Anaemia prevalence in children <5 years*36/328 (11%)36/378 (10%)34/372 (9%)29/362 (8%)Median haemoglobin concentration in children <5 years, g/dL (IQR; N)10·4 (9·2–11·5; 328)10·6 (9·1–11·7; 378)10·6 (9·2–11·7; 372)10·6 (9·6–11·6; 362)Entomological characteristicsMean number of vectors found indoors per house per night (95% CI; N)17·0 (0–34·7; 129)37·0 (4·0–70·1; 119)11·8 (0–24·7; 117)43·6 (9·7–77·6; 129)Sporozoite rate39/809 (5%)59/1085 (5%)37/733 (5%)35/1161 (3%)Data are n/N (%), unless stated otherwise. Data for household, children, and entomological characteristics are only for the core area. LLIN=long-lasting insecticidal net. PBO=piperonyl butoxide. IRS=indoor residual spraying.*Anaemia was clinically diagnosed as <8 g/dL.Between baseline and the first cross-sectional survey 4 months after intervention, long-lasting insecticidal net ownership (≥one net per household) increased to 1690 (97·6%) of 1732 households, access (household with enough long-lasting insecticidal net per sleeping place) increased to 1550 (89·6%) of 1730, and long-lasting insecticidal net use increased to 7807 (76·9%) of 10\u2008152 (appendix). Long-lasting insecticidal net usage was similar between groups and between surveys during the first year. In the second year, 21 months after intervention, access decreased to 1291 (70·2%) of 1839 households and usage to 5905 (56·0%) of 10\u2008551 residents. Most long-lasting insecticidal nets observed were those deployed from this study. In the standard long-lasting insecticidal net (Olyset Net), permethrin concentration at 0 months of use was 21·4 g/kg and 21·5 g/kg after 12 months of use and decreased to 16·7 g/kg after 21 months of use. For the PBO long-lasting insecticidal net (Olyset Plus), permethrin concentration at 0 months of use was 20·9 g/kg, which decreased to 14·7 g/kg after 12 months and to 12·2 g/kg after 21 months, while PBO concentration on Olyset Plus also decreased from 9·5 g/kg at 0 months to 2·9 g/kg after 12 months and to 1·6 g/kg after 21 months of use.827 (94%) of 878 households selected for the survey received indoor residual spraying in the two groups assigned to this intervention. The insecticide residues on sprayed walls decayed gradually over the year; mosquito mortality in WHO cone bioassays was 99% (566 of 570 exposed mosquitoes died, 95% CI 97·9–100) shortly after spraying, 82% (356 of 432, 75·4–89·5) after 9 months, and 59% (495 of 840, 51·4–66·4) after 12 months.In the intention-to-treat factorial analysis for the prevalence of malaria infection, the effect of indoor residual spraying versus no indoor residual spraying was evident at 4 months (OR 0·50, 95% CI 0·31–0·82; p=0·0071) whereas there was no evidence of a difference between PBO long-lasting insecticidal nets and standard long-lasting insecticidal nets (0·68, 0·39–1·18; p=0·1630; table 2). A clear effect was observed 9 months after intervention for indoor residual spraying versus no indoor spraying (OR 0·33, 95% CI 0·19–0·55; p<0·0001) and PBO long-lasting insecticidal nets versus standard nets (OR 0·37, 0·21–0·65; p=0·0011). During the second year, the prevalence of malaria infection in the PBO long-lasting insecticidal net groups remained less than in the standard long-lasting insecticidal net groups (OR 0·47, 95% CI 0·26–0·87; p=0·0173 after 16 months of intervention; and 0·40, 0·20–0·81; p=0·0122 after 21 months of intervention), whereas the effect of the single round of indoor residual spraying applied previously waned over time (OR 0·59, 95% CI 0·34–1·04 after 16 months; and 0·58, 0·29–1·14 after 21 months; table 2). The only significant interaction was at 9 months (OR 2·43, 95% CI 1·19–4·97; p=0·0158), suggesting that at this point in time the combined effect of indoor residual spraying and PBO long-lasting insecticidal net was less than the additive effect of each of the two effects alone.Table 2ITT analysis of malaria infection prevalence by main effect and for each individual intervention at 4, 9, 16, and 21 months after interventionn/N (%)OR (95% CI)p valueSurvey A, 2015, 4 months after interventionMain effect comparison (factorial analysis)No PBO LLIN*936/1991 (47%)1 (ref)..PBO LLIN†798/1926 (41%)0·68‡ (0·39–1·18)0·1630No IRS§998/1968 (51%)1 (ref)..IRS¶736/1949 (38%)0·50‡ (0·31–0·82)0·0071Interaction coefficient..1·37 (0·66–2·86)0·3825Individual group comparisonStandard LLIN553/997 (55%)1 (ref)..PBO LLIN445/971 (46%)0·68‖ (0·39–1·18)0·1630Standard LLIN plus IRS383/994 (39%)0·50‖ (0·31–0·82)0·0071PBO LLIN plus IRS353/955 (37%)0·47‖ (0·28–0·79)0·0048Survey B, 2015, 9 months after interventionMain effect comparison (factorial analysis)No PBO LLIN*767/1809 (42%)1 (ref)..PBO LLIN†531/1852 (29%)0·37 (0·21–0·65)0·0011No IRS§790/1815 (44%)1 (ref)..IRS¶508/1846 (28%)0·33 (0·19–0·55)<0·0001Interaction coefficient..2·43 (1·19–4·97)0·0158Individual group comparisonStandard LLIN515/932 (55%)1 (ref)..PBO LLIN275/883 (31%)0·37 (0·21–0·65)0·0011Standard LLIN plus IRS252/877 (29%)0·33 (0·19–0·55)<0·0001PBO LLIN plus IRS256/969 (26%)0·29 (0·17–0·49)0·0001Survey C, 2016, 16 months after interventionMain effect comparison (factorial analysis)No PBO LLIN*941/2017 (47%)1 (ref)..PBO LLIN†611/1910 (32%)0·47 (0·26–0·87)0·0173No IRS§890/2018 (44%)1 (ref)..IRS¶662/1909 (35%)0·59‡ (0·34–1·04)0·0652Interaction coefficient..1·30 (0·59-2·86)0·5045Individual group comparisonStandard LLIN548/1034 (53%)1 (ref)..PBO LLIN342/984 (35%)0·47‖ (0·26–0·87)0·0173Standard LLIN plus IRS393/983 (40%)0·59‖ (0·34–1·04)0·0652PBO LLIN plus IRS269/926 (29%)0·36 (0·20–0·66)0·0014Survey D, 2016, 21 months after interventionMain effect comparison (factorial analysis)No PBO LLIN*1255/2034 (62%)1 (ref)..PBO LLIN†865/1930 (45%)0·40‡ (0·20–0·81)0·0122No IRS§1150/2002 (57%)1 (ref)..IRS¶970/1962 (49%)0·58‡ (0·29–1·14)0·1130Interaction coefficient..1·59 (0·62–4·07)0·3282Individual group comparisonStandard LLIN710/1044 (68%)1 (ref)..PBO LLIN440/958 (46%)0·40‖ (0·20–0·81)0·0122Standard LLIN plus IRS545/990 (55%)0·58‖ (0·29–1·14)0·1130PBO LLIN plus IRS425/972 (44%)0·37‖ (0·19–0·73)0·0056ORs for the factorial analysis compared the two main intervention effects (no PBO LLIN vs PBO LLIN, and no IRS vs IRS) and their interaction, and compared each of the intervention to the standard LLIN in the individual group analysis. OR was unadjusted for baseline plasmodium infection prevalence. Plasmodium infection prevalence is reported for children aged 6 months to 14 years. OR=odds ratio. LLIN=long-lasting insecticidal net. PBO=piperonyl butoxide. IRS=indoor residual spraying. ITT=intention to treat.*Standard LLIN and standard LLIN plus IRS.†PBO LLIN and PBO LLIN plus IRS.‡Reduction in prevalence is less than the 28% difference defined a priori for the main effect.§Standard LLIN and PBO LLIN.¶Standard LLIN plus IRS and PBO LLIN plus IRS.‖Reduction in prevalence is less than the 40% defined a priori for the individual arm comparison.In the analysis of the individual group comparisons, the difference in malaria infection prevalence between the reference group (standard long-lasting insecticidal net) and the PBO long-lasting insecticidal net group or the combination of the standard net plus indoor residual spraying group was greater than that observed in the factorial analysis at every timepoint between PBO nets and non-PBO nets or between indoor residual spraying and no indoor spraying (table 2). The individual group comparison also provides information about the effect of the PBO long-lasting insecticidal net plus indoor residual spraying intervention.Prevalence of severe-to-moderate anaemia was lower for the groups receiving PBO long-lasting insecticidal net compared with their standard long-lasting insecticidal net reference groups, and was also lower in the groups receiving indoor residual spraying than in the non-indoor residual spraying reference groups in the surveys after 9 months and 16 months intervention (table 3). Results of the per-protocol analyses of malaria infection and anaemia were similar to that of the intention-to-treat analyses (appendix).Table 3ITT analysis of anaemia prevalence by main effect and for each individual intervention at 4, 9, 16 and 21 months after interventionn/N (%)OR (95% CI)p valueSurvey A, 2015, 4 months after interventionMain effect comparison (factorial analysis)No PBO LLIN*28/664 (4%)1 (ref)..PBO LLIN†15/675 (2%)0·39 (0·11–1·30)0·1221No IRS‡23/665 (3%)1 (ref)..IRS§20/674 (3%)0·69 (0·24–1·98)0·4792Interaction coefficient..1·75 (0·37–8·14)0·4696Individual group comparisonStandard LLIN16/320 (5%)1 (ref)..PBO LLIN7/345 (2%)0·39 (0·11–1·30)0·1221Standard LLIN plus IRS12/344 (3%)0·69 (0·24–1·98)0·4792PBO LLIN plus IRS8/330 (2%)0·47 (0·18–1·25)0·1268Survey B, 2015, 9 months after interventionMain effect comparison (factorial analysis)No PBO LLIN*20/580 (3%)1 (ref)..PBO LLIN†13/603 (2%)0·31 (0·11–0·88)0·0292No IRS‡23/584 (4%)1 (ref)..IRS§10/599 (2%)0·16 (0·04–0·69)0·0149Interaction coefficient..7·51 (1·09–51·69)0·0408Individual group comparisonStandard LLIN17/281 (6%)1 (ref)..PBO LLIN6/303 (2%)0·31 (0·11–0·88)0·0292Standard LLIN plus IRS3/299 (1%)0·16 (0·04–0·69)0·0149PBO LLIN plus IRS7/300 (2%)0·37 (0·11–1·22)0·1004Survey C, 2016, 16 months after interventionMain effect comparison (factorial analysis)No PBO LLIN*20/577 (3%)1 (ref)..PBO LLIN†7/574 (1%)0·23 (0·08–0·65)0·0068No IRS‡20/571 (4%)1 (ref)..IRS§7/580 (1%)0·22 (0·08–0·64)0·0064Interaction coefficient..3·46 (0·48–24·80)0·2108Individual group comparisonStandard LLIN16/279 (6%)1 (ref)..PBO LLIN4/292 (1%)0·23 (0·08–0·65)0·0068Standard LLIN plus IRS4/298 (1%)0·22 (0·08–0·64)0·0064PBO LLIN plus IRS3/282 (1%)0·18 (0·05–0·84)0·0301Survey D, 2016, 21 months after interventionMain effect comparison (factorial analysis)No PBO LLIN*19/586 (3%)1 (ref)..PBO LLIN†24/582 (4%)1·67 (0·49–5·75)0·4080No IRS‡19/564 (3%)1 (ref)..IRS§24/604 (4%)1·55 (0·36–6·58)0·5468Interaction coefficient..0·63 (0·12–3·43)0·5881Individual group comparisonStandard LLIN7/276 (3%)1 (ref)..PBO LLIN12/288 (4%)1·67 (0·49–5·75)0·4080Standard LLIN plus IRS12/310 (4%)1·55 (0·36–6·58)0·5468PBO LLIN plus IRS12/294 (4%)1·64 (0·47–5·65)0·4287ORs for the factorial analysis compared the two main intervention effects (no PBO LLIN vs PBO LLIN, and no IRS vs IRS) and their interaction, and compared each of the intervention to the standard LLIN in the individual group analysis. OR was unadjusted for baseline anaemia prevalence. Prevalence of moderate-to-severe anaemia reported in children younger than 5 years with haemoglobin concentrations <8 g/dL. OR=odds ratio. LLIN=long-lasting insecticidal net. PBO=piperonyl butoxide. IRS=indoor residual spraying. ITT=intention to treat.*Standard LLIN and standard LLIN plus IRS.†PBO LLIN and PBO LLIN plus IRS.‡Standard LLIN and PBO LLIN.§Standard LLIN plus IRS and PBO LLIN plus IRS.A total of 16\u2008371 vector mosquitoes were collected in 5756 indoor light-trap collections over the 2 years. In the first year, vector densities, sporozoite rates, and entomological inoculation rates were lower in the PBO long-lasting insecticidal net groups than in the standard long-lasting insecticidal net groups (table 4), but only entomological inoculation rate was significantly lower in the indoor residual spraying groups than in the non-indoor residual spraying groups. In the second year, the entomological inoculation rate in the PBO long-lasting insecticidal groups remained lower than in the standard long-lasting insecticidal net groups but the effect of indoor residual spraying on entomological inoculation rate had largely diminished by this time compared with the entomological inoculation rates of 2015.Table 4Entomological outcomes by intervention (PBO LLIN vs no PBO LLIN, and IRS vs no IRS) in 2015 and 2016Vector density per night per householdSporozoite rateEIR per month per household*NMean (SD)DR (95% CI)p valuen/N (%)OR (95% CI)p valueNMean (SD)DR (95% CI)p valueYear 1: 2015No PBO LLIN†8962·61 (8·97)1 (ref)..20/952 (2%)1 (ref)..8620·90 (5·42)1 (ref)..PBO LLIN‡9611·85 (7·12)0·33 (0·16–0·69)0·00382/648 (<1%)0·25 (0·07–0·88)0·03179110·13 (2·.07)0·13 (0·03–0·53)0·0055No IRS§9392·34 (8·18)1 (ref)..21/988 (2%)1 (ref)..9011·01 (5·85)1 (ref)..IRS¶9182·09 (7·96)0·63 (0·27–1·43)0·26521/612 (<1%)0·15 (0·02–1·02)0·05198720·25 (0·89)0·03 (0·00–0·24)0·0014Interaction coefficient....1·35 (0·44–4·18)0·5940..NANA....NANAYear 2: 2016No PBO LLIN†19463·60 (16·86)1 (ref)..80/2236 (4%)1 (ref)..17931·15 (6·53)1 (ref)..PBO LLIN‡19532·68 (11·33)0·40 (0·20–0·80)0·010127/1931 (1%)0·38 (0·15–0·92)0·033118450·39 (3·91)0·33 (0·13–0·83)0·0189No IRS§19422·82 (9·34)1 (ref)..64/2207 (3%)1 (ref)..18011·00 (6·04)1 (ref)..IRS¶19573·46 (18.01)0·93 (0·47–1·85)0·830943/1960 (2%)0·81 (0·37–1·78)0·589018370·58 (4·87)0·48 (0·25–0·94)0·0340Interaction coefficient....1·00 (0·36–2·75)0·9970..1·13 (0·35–3·63)0·8308....1·38 (0·47–4·08)0·5532DR for vector density and EIR and OR for sporozoite rates are adjusted for their respective baseline value. EIR=entomological inoculation rate. DR=density ratio. OR=odds ratio. LLIN=long-lasting insecticidal net. PBO=piperonyl butoxide. IRS=indoor residual spraying. NA=not applicable.*The mean and DR of the EIR are weighted to account for the proportion of mosquitoes sampled to be tested for sporozoites. Interaction not estimated in year 1 for sporozoite and EIR outcomes, because sporozoite rate was null in the PBO LLIN plus IRS group.†Standard LLIN and standard LLIN plus IRS.‡PBO LLIN and PBO LLIN plus IRS.§Standard LLIN and PBO LLIN.¶Standard LLIN plus IRS and PBO LLIN plus IRS.The mortality of mosquitoes exposed to permethrin for resistance determination in the WHO cylinder tests was 8·8% (95% CI 5·3–12·3; n/N=54/613) for A gambiae sensu lato and 54·5% (36·8–76·2; n/N=59/108) for A funestus. The lethal concentration required to kill 50% of the wild A gambiae sensu lato was 38-times higher and of wild A funestus was 34-times higher than for the susceptible reference mosquitoes. The Vgsc gene mutation was found in all tested A gambiae with co-occurrence of Vgsc-1014F and Vgsc-1014S in 22 (9%) of 234 A gambiae mosquitoes. No mutation was found in the 247 A arabiensis tested.DiscussionThis trial showed that long-lasting insecticidal nets incorporating the synergist PBO (Olyset Plus) were more effective than the standard pyrethroid long-lasting insecticidal net (Olyset Net) in reducing malaria infection prevalence in an area of high usage of these nets and high pyrethroid resistance in the primary vectors. The additional effect of the PBO long-lasting insecticidal nets on malaria prevalence was evident at the end of the first year with a 44% protective efficacy and at the end of the second year with a 33% protective efficacy compared with the standard long-lasting insecticidal nets. These findings were supported by the entomological outcomes, which showed a significant reduction in malaria transmission, with entomological inoculation rates being reduced by 87% during the first year and 67% during the second year in areas receiving PBO long-lasting insecticidal nets compared with standard long-lasting insecticidal nets. At 9 months, the addition of pirimiphos-methyl indoor residual spraying to the standard long-lasting insecticidal nets provided similar protection against malaria (44% protective efficacy) relative to the standard nets alone, whereas the addition of indoor residual spraying to PBO long-lasting insecticidal nets did not significantly improve protection based on the interaction observed when both indoor spraying and PBO long-lasting insecticidal nets effect were at their strongest. The impact of indoor residual spraying on the entomological inoculation rates was more than 95% in the first year. This effect on malaria transmission occurred shortly after implementation of indoor residual spraying whereas the effect of PBO long-lasting insecticidal nets took longer. This rapid impact of indoor residual spraying is one reason why this intervention is sometimes more favoured than long-lasting insecticidal net distribution during malaria epidemics, although there has been a paucity of evidence to justify this advice.27 Our cluster RCT would support this recommendation, provided high indoor residual spraying coverage can be quickly achieved. Residual insecticidal activity of pirimiphos-methyl on the sprayed walls was observed up to 12 months after a single round of spraying. Following the decay in residual activity during the second year when no spraying was done, the effect of indoor residual spraying on entomological inoculation rates diminished and malaria prevalence increased but not to the level observed in the standard long-lasting insecticidal net control group, which had not received indoor residual spraying in year 1. A sustained effect on malaria transmission would require recurrent annual campaigns of indoor residual spraying.This trial is the first to provide evidence to suggest that incorporation of the synergist PBO to long-lasting insecticidal nets provides improved community protection compared with standard pyrethroid-only nets against malaria transmission by pyrethroid-resistant vector populations. Previous small-scale experimental hut studies of PBO long-lasting insecticidal nets measured entomological outcomes such as mosquito mortality and biting rates. In Benin, these studies showed that Olyset Plus was more effective than standard Olyset Net against pyrethroid-resistant A gambiae, both before and after multiple washing of the nets.12 In Tanzania where A gambiae was still susceptible to pyrethroids, the differential effect between Olyset Plus and standard Olyset Net was less evident.28 Parallel studies with a different type of PBO long-lasting insecticidal net (PermaNet 3.0) showed improved outcomes with the unwashed PBO net compared with the standard long-lasting insecticidal net, but in some studies the efficacy was lost after several washes.29 Although these small-scale studies11, 12, 28, 29 indicate the potential of PBO nets, they could not capture the full effect of this new class of net on transmission, which is only understood at high coverage levels and in community randomised trials because of the additional community protection that arises from the reduction in mosquito life-span and population density, often called the vectorial mass effect.27 With the relatively high coverage and usage of long-lasting insecticidal nets achieved in the present trial (77% usage in the first year and 60% in the second year), we were able to observe a mass effect of the PBO nets on transmission, with concomitant reductions in mosquito density, sporozoite rate, and entomological inoculation rates.Despite the 83% loss in PBO content after 21 months, the PBO and permethrin retained on the net remained highly effective against malaria infection and entomological inoculation rates throughout. By contrast, the loss of residual activity of the single round of indoor residual spraying of Actellic 300CS led to resumption of transmission and to increasing entomological inoculation rates and malaria prevalence in the second year. The PBO nets will be monitored during a third year to assess whether effectiveness is maintained at low PBO content. There was also a 42% loss of permethrin content in Olyset Plus and 22% in Olyset Net over the two years. The differential release rate of permethrin in the two nets has been observed in other studies, and it has been suggested in an earlier WHO review of Olyset Plus that the more effective performance of the PBO net is due to the higher release rate and surface concentration of permethrin in this net compared with Olyset Net.28 Although this argument cannot be completely refuted by our data, the A gambiae and A funestus vectors in the Muleba area are highly resistant to pyrethroid and any difference in surface permethrin between Olyset Plus and Olyset Net in our trial is unlikely to result in differential mortality rate. A study has shown that under household conditions a 20-times increase in the surface content of permethrin on hand-treated nets causes no increase in mortality to free-flying pyrethroid-resistant A gambiae.30 Furthermore, synergy tests with PBO showed that pyrethroid-resistant A gambiae from our study area are killed by a permethrin concentration they would normally survive if it were not mixed with PBO.19The more effective performance of PBO long-lasting insecticidal nets compared with standard long-lasting insecticidal nets in reducing the prevalence of malaria infection, together with no change in prevalence following the initial distribution and high usage of standard nets, suggests that insecticide resistance of the magnitude reported is compromising the effectiveness of standard pyrethroid nets in northwest Tanzania. A recent study in neighbouring Uganda reported no change in incidence of malaria before and after the distribution of standard long-lasting insecticidal nets.10 Other studies have reported the failure of these nets to reduce entomological indicators after the standard long-lasting insecticidal nets developed holes.5, 6 From our study design, it is not clear whether the standard nets still provide some degree of protection. Although a previous study in Muleba done in 2012 showed that users of standard long-lasting insecticidal nets were slightly better protected (OR 0·83) against malaria infection prevalence than non-users of nets,31 this finding should be contrasted with the much larger effect of PBO long-lasting insecticidal nets versus standard nets (OR 0·37) in the present study. In areas with more moderate levels of pyrethroid resistance, standard nets still provide personal protection. A study in Malawi, for example, showed that standard nets reduced malaria incidence by 30% in children in an area where pyrethroid-resistant A funestus was the main vector.8 In Kenya, the use of standard nets provided 45% protection against the incidence of malaria infection as compared with those not using long-lasting insecticidal nets, but incidence still remained high in net users.9 The strength or intensity of resistance in the local primary vector species might be the factor defining the level of protection to be derived from standard long-lasting insecticidal nets.Our study provides further insight into the question of whether indoor residual spraying and long-lasting insecticidal nets should be combined to accelerate the control of malaria. In a previous cluster RCT in Muleba, where conditions of high pyrethroid resistance and moderate usage of long-lasting insecticidal nets (50%), indoor residual spraying with the carbamate bendiocarb provided an added benefit (OR 0·43).18 In the present study, a single round of indoor residual spraying with the long-lasting pirimiphos-methyl capsule suspension in combination with standard nets was sufficient to give long-term additional protection over two transmission seasons (OR 0·33), whereas the bendiocarb required two rounds to achieve an effect of similar size, owing to its shorter residual activity on walls.The combination of indoor residual spraying of pirimiphos-methyl and PBO long-last insecticidal nets have been suggested to be antagonistic.13 This concern arose because pirimiphos-methyl requires oxidation by cytochrome P450 enzymes within the mosquito before it becomes toxic. Uptake of PBO from previous contact with Olyset Plus nets might potentially inhibit this activation process. Although the present cluster RCT neither confirmed nor disproved any antagonistic effect, it showed there was limited benefit to be gained from adding this indoor residual spraying product to PBO nets. Whether another indoor residual spraying insecticide, which does not require activation by cytochrome P450s, would prove an effective partner to PBO long-lasting insecticidal nets is not known. The present cluster RCT also implies that where indoor spraying with pirimiphos-methyl is being applied annually, the substitution of PBO nets for standard nets would provide little or no additional benefit. Considering the focal coverage of indoor residual spraying compared with the much wider coverage of long-lasting insecticidal nets in Africa, an important question from a public health standpoint is which strategy should be adopted in areas where standard long-lasting insecticidal nets might be losing effectiveness because of high intensity of pyrethroid resistance in the local vector? The substitution of PBO long-lasting insecticidal nets in such areas would provide a substantial benefit, similar to that which annual indoor residual spraying campaigns might provide.This trial has several potential limitations. Buffer areas of 300 m were small compared with what has been used in other trials,17, 18 which might not have totally prevented contamination. However, any spill-over would have lessened rather than increased the effect size between intervention groups. Additionally, the community was not masked to the indoor residual spraying allocation, which might have led to reduced child attendance at clinic sessions. However, such bias has not been observed and attendance was similar across all intervention groups. Furthermore, we used vector density in CDC light trap collections as a proxy to estimate entomological inoculation rate, rather than vector biting rate in human landing catches. The light trap approach is becoming more common in trials for pragmatic and ethical reasons; and although it could have led to error in the estimation of transmission intensity, it would not have affected the relative difference in entomological inoculation rates observed between the study groups. Finally, our trial was not powered to detect interactions.In conclusion, this trial shows the residual efficacy of indoor residual spraying with pirimiphos-methyl for malaria control of over 1 year, and provides strong evidence for increasing the coverage of PBO long-lasting insecticidal nets over standard long-lasting insecticidal nets of pyrethroid to meet the increasing challenge of pyrethroid resistance and to improve personal and community protection from malaria, particularly in areas of intense pyrethroid resistance. As a consequence of the trial, WHO has made this policy recommendation.32References1WHOWorld malaria report 20162016World Health OrganizationGeneva2RansonHN'GuessanRLinesJMoirouxNNkuniZCorbelVPyrethroid resistance in African anopheline mosquitoes: what are the implications for malaria control?Trends Parasitol2720119198208437453BarnesKIDurrheimDNLittleFEffect of artemether-lumefantrine policy and improved vector control on malaria burden in KwaZulu-Natal, South AfricaPLoS Med22005e330161877984KleinschmidtIMnzavaAPKafyHTDesign of a study to determine the impact of insecticide resistance on malaria vector control: a multi-country investigationMalar J142015282261946485AsidiAN'GuessanRAkogbetoMCurtisCRowlandMLoss of household protection from use of insecticide-treated nets against pyrethroid-resistant mosquitoes, BeninEmerg Infect Dis18201211011106227099306OchomoEOBayohNMWalkerEDThe efficacy of long-lasting nets with declining physical integrity may be compromised in areas with high levels of pyrethroid resistanceMalar J122013368241567157VianaMHughesAMatthiopoulosJRansonHFergusonHMDelayed mortality effects cut the malaria transmission potential of insecticide-resistant mosquitoesProc Natl Acad Sci USA113201689758980274027408LindbladeKAMwandamaDMzilahowaTA cohort study of the effectiveness of insecticide-treated bed nets to prevent malaria in an area of moderate pyrethroid resistance, MalawiMalar J14201531256279879OchomoEChahiluMCookJInsecticide-treated nets and protection against insecticide-resistant malaria vectors in western KenyaEmerg Infect Dis2320177587642841829310KatureebeAZinszerKArinaitweEMeasures of malaria burden after long-lasting insecticidal net distribution and indoor residual spraying at three sites in Uganda: a prospective observational studyPLoS Med132016e10021672782488511CorbelVChabiJDabireRKField efficacy of a new mosaic long-lasting mosquito net (PermaNet 3.0) against pyrethroid-resistant malaria vectors: a multi centre study in western and central AfricaMalar J920101132042347912PennetierCBouraimaAChandreFEfficacy of Olyset Plus, a new long-lasting insecticidal net incorporating permethrin and piperonyl-butoxide against multi-resistant malaria vectorsPLoS One82013e751342411602913WHOConditions for use of long-lasting insecticidal nets treated with a pyrethroid and piperonyl butoxide2015World Health OrganizationGeneva14RowlandMBokoPOdjoAAsidiAAkogbetoMN'GuessanRA new long-lasting indoor residual formulation of the organophosphate insecticide pirimiphos methyl for prolonged control of pyrethroid-resistant mosquitoes: an experimental hut trial in BeninPLoS One82013e695162393603315OxboroughRMTrends in US President's Malaria Initiative-funded indoor residual spray coverage and insecticide choice in sub-Saharan Africa (2008–2015): urgent need for affordable, long-lasting insecticidesMalar J1520161462695721016CorbelVAkogbetoMDamienGBCombination of malaria vector control interventions in pyrethroid resistance area in Benin: a cluster randomised controlled trialLancet Infect Dis1220126176262268253617PinderMJawaraMJarjuLBEfficacy of indoor residual spraying with dichlorodiphenyltrichloroethane against malaria in Gambian communities with high usage of long-lasting insecticidal mosquito nets: a cluster-randomised controlled trialLancet3852015143614462549884718WestPAProtopopoffNWrightAIndoor residual spraying in combination with insecticide-treated nets compared to insecticide-treated nets alone for protection against malaria: a cluster randomised trial in TanzaniaPLoS Med112014e10016302473637019MatowoJKitauJKaayaRTrends in the selection of insecticide resistance in Anopheles gambiae s.l. mosquitoes in northwest Tanzania during a community randomized trial of longlasting insecticidal nets and indoor residual sprayingMed Vet Entomol29201551592553775420HawleyWAPhillips-HowardPAter KuileFOCommunity-wide effects of permethrin-treated bed nets on child mortality and malaria morbidity in western KenyaAm J Trop Med Hyg68suppl 420031211271274949521GilliesMTCoetzeeMA supplement to the Anophelinae of Africa south of the Sahara (Afrotropical region)1987South African Institute for Medical ResearchJohannesburg22WirtzRAZavalaFCharoenvitYComparative testing of monoclonal antibodies against Plasmodium falciparum sporozoites for ELISA developmentBull World Health Organ6519873945355587923BassCWilliamsonMSFieldLMDevelopment of a multiplex real-time PCR assay for identification of members of the Anopheles gambiae species complexActa Trop107200850531849000024BassCNikouDDonnellyMJDetection of knockdown resistance (kdr) mutations in Anopheles gambiae: a comparison of two new high-throughput assays with existing methodsMalar J620071111769732525HayesRJMoultonLHCluster randomised trials2009Chapman and Hall/CRCNew York26DrakeleyCSchellenbergDKihondaJAn estimation of the entomological inoculation rate for Ifakara: a semi-urban area in a region of intense malaria transmission in TanzaniaTrop Med Int Health820037677741295066227PluessBTanserFCLengelerCSharpBLIndoor residual spraying for preventing malariaCochrane Database Syst Rev42010CD006657.28WHOReport of the fifteenth WHOPES working group meeting: WHO/HQ, Geneva, 18–22 June 20122012World Health OrganizationGeneva29WHOReport of the twelfth WHOPES working group meeting, WHO/HQ, Geneva 8–11 December 20082009World Health OrganizationGeneva30CorbelVChandreFBrenguesCDosage-dependent effects of permethrin-treated nets on the behaviour of Anopheles gambiae and the selection of pyrethroid resistanceMalar J32004221524251331WestPAProtopopoffNWrightAEnhanced protection against malaria by indoor residual spraying in addition to insecticide treated nets: is it dependent on transmission intensity or net usage?PLoS One102015e01156612581137932WHOConditions for deployment of mosquito nets treated with a pyrethroid and piperonyl butoxide2017World Health OrganizationGenevaSupplementary MaterialSupplementary appendixAcknowledgmentsThis study was funded by the Joint Global Health Trials Scheme of the UK Department for International Development, Medical Research Council, and Wellcome Trust (MR/L004437/). We thank colleagues and staff at the Kilimanjaro Christian Medical University College in Muleba and Moshi, and those at the National Institute of Medical Research in Muheza and Mwanza who were involved in the project. We acknowledge the assistance provided by staff at the Muleba District Medical Office, at both the village and hamlet level. Additionally, we thank the study trial steering committee members (John Gimnig, Jan Kolaczinski, and Mark Paine). We thank USAID/President's Malaria Initiative and RTI International for funding and implementing the indoor residual spraying operation in the study area, and the Tanzania Communication and Development Center for communications and implementation of the distribution campaign of the long-lasting insecticidal nets. We thank Hanafy Ismail (Liverpool School of Tropical Medicine, Liverpool, UK) for chemical analysis of the long-lasting insecticidal net samples and Philippa West (The London School of Hygiene & Tropical Medicine, London, UK) for the constrained randomisation. Finally, we thank all the participating children and their parents.ContributorsNP, IK, and MR conceived and designed the study. CDM, FWM, and WK advised on interventions, study communities, and coordination with local and national authorities. NP, JFM, EL, JDC, AW, and AM implemented the study. NP and JFM analysed the data. NP, JFM, IK, and MR interpreted the data. NP and JFM wrote the first draft of the manuscript. IK and MR critically revised the manuscript for important content. MR led the coordination with international policy authorities. EL, JDC, AW, CDM, AM, FWM, and WK revised the manuscript. All authors read and approved the final version of the manuscript.Declaration of interestsWe declare no competing interests.", 'title': 'Effectiveness of a long-lasting piperonyl butoxide-treated insecticidal net and indoor residual spray interventions, separately and together, against malaria transmitted by pyrethroid-resistant mosquitoes: a cluster, randomised controlled, two-by-two factorial design trial.', 'date': '2018-04-16'}}
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Public Health, Epidemiology & Health Systems
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80
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Is malaria incidence higher, lower, or the same when comparing pyrethroid‐like indoor residual spraying (IRS) plus insecticide‐treated nets (ITNs) to insecticide‐treated nets (ITNs) alone?
|
no difference
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moderate
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no
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['25498847', '29229808']
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{'25498847': {'article_id': '25498847', 'content': 'Although many malaria control programmes in sub-Saharan Africa use indoor residual spraying with long-lasting insecticidal nets (LLINs), the two studies assessing the benefit of the combination of these two interventions gave conflicting results. We aimed to assess whether the addition of indoor residual spraying to LLINs provided a significantly different level of protection against clinical malaria in children or against house entry by vector mosquitoes.\nIn this two-arm cluster, randomised, controlled efficacy trial we randomly allocated clusters of Gambian villages using a computerised algorithm to LLINs alone (n=35) or indoor residual spraying with dichlorodiphenyltrichloroethane plus LLINs (n=35). In each cluster, 65-213 children, aged 6 months to 14 years, were surveyed at the start of the 2010 transmission season and followed in 2010 and 2011 by passive case detection for clinical malaria. Exposure to parasite transmission was assessed by collection of vector mosquitoes with both light and exit traps indoors. Primary endpoints were the incidence of clinical malaria assessed by passive case detection and number of Anopheles gambiae sensu lato mosquitoes collected per light trap per night. Intervention teams had no role in data collection and the data collection teams were not informed of the spray status of villages. The trial is registered at the ISRCTN registry, number ISRCTN01738840.\nLLIN coverage in 2011 was 3510 (93%) of 3777 children in the indoor residual spraying plus LLIN group and 3622 (95.5%) of 3791 in the LLIN group. In 2010, 7845 children were enrolled, 7829 completed passive case detection, and 7697 (98%) had complete clinical and covariate data. In 2011, 7009 children remained in the study, 648 more were enrolled, 7657 completed passive case detection, and 7545 (98.5%) had complete data. Indoor residual spraying coverage per cluster was more than 80% for both years in the indoor residual spraying plus LLIN group. Incidence of clinical malaria was 0.047 per child-month at risk in the LLIN group and 0.044 per child-month at risk in the indoor residual spraying plus LLIN group in 2010, and 0.032 per child-month at risk in the LLIN group and 0.034 per child-month at risk in the indoor residual spraying plus LLIN group in 2011. The incident rate ratio was 1.08 (95% CI 0.80-1.46) controlling for confounders and cluster by mixed-effect negative binomial regression on all malaria attacks for both years. No significant difference was recorded in the density of vector mosquitoes caught in light traps in houses over the two transmission seasons; the mean number of A gambiae sensu lato mosquitoes per trap per night was 6.7 (4.0-10.1) in the LLIN group and 4.5 (2.4-7.4) in the indoor residual spraying plus LLIN group (p=0.281 in the random-effects linear regression model).\nWe identified no significant difference in clinical malaria or vector density between study groups. In this area with high LLIN coverage, moderate seasonal transmission, and susceptible vectors, indoor residual spraying did not provide additional benefit.\nUK Medical Research Council.', 'title': 'Efficacy of indoor residual spraying with dichlorodiphenyltrichloroethane against malaria in Gambian communities with high usage of long-lasting insecticidal mosquito nets: a cluster-randomised controlled trial.', 'date': '2014-12-17'}, '29229808': {'article_id': '29229808', 'content': 'Proc Natl Acad Sci U S AProc. Natl. Acad. Sci. U.S.ApnaspnasPNASProceedings of the National Academy of Sciences of the United States of America0027-84241091-6490National Academy of Sciences29229808574819420171381410.1073/pnas.1713814114PNAS PlusBiological SciencesMedical SciencesPNAS PlusImpact of insecticide resistance in Anopheles arabiensis on malaria incidence and prevalence in Sudan and the costs of mitigationInsecticide resistance impact on malariaKafyHmooda Totoab1IsmailBashir Adambc1MnzavaAbraham PeterdLinesJonathaneAbdinMogahid Shiekh EldinfgEltaherJihad SuliemanhBanagaAnuar OsmaniWestPhilippajBradleyJohnjCookJackiejThomasBrentkSubramaniamKrishanthikHemingwayJanetk2KnoxTessa BellamydMalikElfatih M.lYukichJoshua O.mDonnellyMartin Jameskn2KleinschmidtImmojo2aVector Unit, Ministry of Health, Khartoum, Sudan;bSchool of Biological Sciences, Universiti Sains Malaysia, 11800 Pulau Penang, Malaysia;cState Malaria Control Programme, Khartoum, Sudan;dMalaria Programme, World Health Organization, 1202 Geneva, Switzerland;eDepartment of Disease Control, London School of Hygiene and Tropical Medicine (LSHTM), London WC1E 7HT, United Kingdom;fKilimanjaro Christian Medical University College, Moshi, Tanzania;gDepartment of Information, Ministry of Health, Khartoum, Sudan;hMalaria Research and Training Centre, Sennar, Sudan;iState Malaria Control Programme, Gedarif, Sudan;jDepartment of Infectious Disease Epidemiology, LSHTM, London WC1E 7HT, United Kingdom;kDepartment of Vector Biology, Liverpool School of Tropical Medicine, Liverpool L35QA, United Kingdom;lMinistry of Health, Khartoum, Sudan;mCenter for Applied Malaria Research and Evaluation, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112;nWellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, United Kingdom;oSchool of Pathology, University of Witwatersrand, Braamfontein 2000, Johannesburg, South Africa2To whom correspondence may be addressed. Email: janet.hemingway@lstmed.ac.uk, martin.donnelly@lstmed.ac.uk, or Immo.Kleinschidmt@LSHTM.ac.uk.Contributed by Janet Hemingway, October 2, 2017 (sent for review November 12, 2016; reviewed by Christen Fornadel and Kimberly Lindblade)Author contributions: A.P.M., J.L., J.H., T.B.K., M.J.D., and I.K. designed research; H.T.K., B.A.I., M.S.E.A., J.S.E., A.O.B., B.T., K.S., E.M.M., and M.J.D. performed research; H.T.K., M.S.E.A., J.S.E., B.T., K.S., and M.J.D. contributed new reagents/analytic tools; P.W., J.B., J.C., E.M.M., J.O.Y., and I.K. analyzed data; and J.H., M.J.D., and I.K. wrote the paper.Reviewers: C.F., United States Agency for International Development; and K.L., Centers for Disease Control.1H.T.K. and B.A.I. contributed equally to this work.26122017111220171112201711452E11267E11275Copyright © 2017 the Author(s). Published by PNAS.2017This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).SignificanceEmerging insecticide resistance in malaria vectors could presage a catastrophic rebound in malaria morbidity and mortality. In areas of moderate levels of resistance to pyrethroids, long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) with a carbamate insecticide were significantly more effective than IRS with pyrethroid insecticide. The impact on the effectiveness of LLINs could not be quantified. The incremental cost of using a carbamate insecticide to which vectors are susceptible was US $0.65 per person protected per year, which is considered acceptable by international standards. While the WHO recommends that different interventions, where possible, should use different insecticide classes, these data alone should not be used as the basis for a policy change in vector control interventions.Insecticide-based interventions have contributed to ∼78% of the reduction in the malaria burden in sub-Saharan Africa since 2000. Insecticide resistance in malaria vectors could presage a catastrophic rebound in disease incidence and mortality. A major impediment to the implementation of insecticide resistance management strategies is that evidence of the impact of resistance on malaria disease burden is limited. A cluster randomized trial was conducted in Sudan with pyrethroid-resistant and carbamate-susceptible malaria vectors. Clusters were randomly allocated to receive either long-lasting insecticidal nets (LLINs) alone or LLINs in combination with indoor residual spraying (IRS) with a pyrethroid (deltamethrin) insecticide in the first year and a carbamate (bendiocarb) insecticide in the two subsequent years. Malaria incidence was monitored for 3 y through active case detection in cohorts of children aged 1 to <10 y. When deltamethrin was used for IRS, incidence rates in the LLIN + IRS arm and the LLIN-only arm were similar, with the IRS providing no additional protection [incidence rate ratio (IRR) = 1.0 (95% confidence interval [CI]: 0.36–3.0; P = 0.96)]. When bendiocarb was used for IRS, there was some evidence of additional protection [interaction IRR = 0.55 (95% CI: 0.40–0.76; P < 0.001)]. In conclusion, pyrethroid resistance may have had an impact on pyrethroid-based IRS. The study was not designed to assess whether resistance had an impact on LLINs. These data alone should not be used as the basis for any policy change in vector control interventions.malariapyrethroidresistanceinsecticideAnophelesBill and Melinda Gates Foundation (Bill & Melinda Gates Foundation)10000086548499.01United Nations (UN)100004420GEF ID:2546To date, the 21st century has seen an unprecedented reduction in the global burden of malaria. While still unacceptably high, disease incidence in sub-Saharan Africa has decreased by 42% from an average of 427 cases per 1,000 persons at risk in 2,000 to 246 cases per 1,000 persons at risk in 2015; infection prevalence with Plasmodium falciparum in children aged 2–10 y has halved from 33 to 16% over the same period (1). This has resulted in an estimated 1.2 billion fewer malaria cases and 6.2 million fewer malaria deaths. Recent estimates show that the widespread deployment of insecticide-based interventions has been, overwhelmingly, the driver of the reduction in malaria in Africa (2). Of the 663 million clinical cases estimated to have been averted due to malaria control interventions since 2000, 78% were attributable to insecticide-treated nets or indoor residual spraying (IRS). These two interventions have been massively scaled up since 2000 (1).Emerging insecticide resistance in the anopheline malaria vectors could presage a catastrophic rebound in disease incidence. At present, there are only four insecticide classes available to malaria control programs; pyrethroids, organochlorines, carbamates, and organophosphates, with pyrethroids being the only class currently recommended by the WHO for use on long-lasting insecticidal nets (LLINs). Pyrethroids and the organochlorine dichlorodiphenyltrichloroethane (DDT) share the same target site, the voltage-gated sodium channel, while carbamates and organophosphates are acetylcholinesterase inhibitors. Resistance to pyrethroids is extensive throughout sub-Saharan Africa, while resistance to the three nonpyrethroid chemical classes used for IRS is simultaneously emerging in many regions (3–5). Resistance arises mainly from a combination of mutations within mosquitoes at the target site of the insecticide and enhanced detoxification/excretion of the insecticide.While conclusive evidence that resistance is directly impacting epidemiological indicators of malaria is scanty, by the time such data are available, it may well be too late. To address the problem, the WHO developed the Global Plan for Insecticide Resistance Management in malaria vectors (GPIRM), which was designed to forestall a disastrous increase in malaria burden (6). Unfortunately, most malarious countries have yet to amend their vector control strategies to align with the GPIRM despite widespread resistance to pyrethroids (7). While this is partially due to the absence of compelling data on the impact of insecticide resistance, it also reflects the lack of viable alternatives to LLINs and current insecticides.A five-country study was established to provide quantitative estimates of the impact of resistance on malaria burden (8). One study was conducted in Galabat, Sudan. In Sudan, almost the entire population lives in areas with low to moderate transmission. Malaria transmission is seasonal and unstable. Countrywide, the majority of the population (80%), including urban populations, live in areas with <1% P. falciparum infection risk in children aged 2–10 y, while the remaining 20% of the population, residing mainly in the south of the country, experience meso- to hyperendemic risk of infection (9). Reported malaria cases were reduced from an estimated 7.5 million in 1990 (10) to 1.2 million in 2014. P. falciparum accounts for 95% of the malaria burden (9, 10), with Anopheles arabiensis being the main malaria vector (11).In Sudan, artemisinin-based combination therapy has been used for malaria treatment since 2004, with artesunate plus sulfadoxine/pyrimethamine as first-line treatment, artemether/lumefantrine as second-line therapy, and quinine for the treatment of complicated malaria (10). Malaria diagnosis is based on microscopy and rapid diagnostic tests (RDTs) (10). Between 2013 and 2015, 13 million LLINs were distributed, resulting in overall coverage of 92% of households with one LLIN per two persons in 2015 according to Ministry of Health reports. Therefore, the emergence of insecticide resistance (12, 13) is a major concern as it could severely compromise the effectiveness of vector control in Sudan.Galabat, Gedarif State, was considered suitable for this study since malaria is highly seasonal and more intense there than in many other parts of Sudan, and it had no previous history of IRS. Human settlements also facilitate the formation of well-separated clusters. Twenty-six villages were selected as study clusters and received universal coverage of LLINs. Thirteen of these clusters were randomly selected to receive IRS in addition to LLINs. In 2012, deltamethrin was used for IRS, which was replaced by bendiocarb in 2013 and 2014. The protective effect of bendiocarb, to which there was no resistance, could therefore be compared with the effect of deltamethrin, to which there was insecticide resistance, with the LLIN-only clusters acting as controls. For ethical reasons, it was not feasible to assess the impact of insecticide resistance on the overall effectiveness of LLINs since this would require a neutral arm with no vector control.This study aimed to quantify:i)The impact of switching to a nonpyrethroid IRS insecticide on the incidence and prevalence of malaria infection in an area of moderate pyrethroid resistanceii)The impact of phenotypic and genotypic insecticide resistance on the incidence and prevalence of malaria infectioniii)The impact of the addition of nonpyrethroid IRS insecticide on the evolution of pyrethroid resistance in an area of universal LLIN coverageiv)The cost of using nonpyrethoid IRS in addition to LLIN coverage to mitigate the negative consequences of pyrethroid resistance on the incidence of malaria infectionResultsIntervention Coverage.Following a census to determine the number of households and population size of the study area, 72,714 LLINs (PermaNet 2.0; Vestergaard) were distributed in the 26 clusters in April 2011 to protect 139,566 individuals based upon a universal coverage approach of one net for two people. Nets were replaced in June 2014 with 72,098 new LLINs for 122,647 people. An annual intervention assessment survey showed that household net ownership was 99.6% in 2012, 82.1% in 2013, and 98.6% in 2014. LLIN usage, defined as the proportion of affirmative responses to the question “Did this child sleep under an LLIN last night?”, was generally high and very similar in study arms (Table 1), but varied by season throughout the year (data not tabulated). IRS was conducted in August and again in late December of each year. In 2012, both spray rounds utilized deltamethrin (25 mg of active ingredient per square meter; Chema Industries), while in 2013 and 2014, bendiocarb (Ficam 80% WP; Bayer; 200 mg of active ingredient per square meter) was sprayed. IRS spray coverage was 99%, 82%, and 83% in the years 2012, 2013, and 2014, respectively, as determined by annual cross-sectional surveys. The IRS coverage reported in the LLIN arm is from the householder questionnaires. It is possible that this was from private spraying, but more likely that it represents householder misreporting.Table 1.LLIN usage, IRS coverage, insecticide resistance, prevalence of infection, and malaria incidence in cohort children by study arm and study yearLLIN-only armLLIN + IRS armVariable201220132014201220132014LLIN usage, % (child nights)79 (73,375)74 (75,040)82 (78,918)79 (73,738)75 (74,612)82 (78,888)IRS coverage, % (N)9 [1–45] (1,320)1 [0–2] (1,954)4 [1–27] (2,195)99 [96–100] (1,314)82 [75–87] (1,816)83 [68–91] (2,032)Mean age, y5.1 [4.9–5.4]5.4 [5.2–5.5]6.2 [6.1–6.3]5.2 [5.0–5.4]5.5 [5.4–5.7]6.3 [6.1–6.4]Malaria cases117155981268265Malaria incidence*45 [24–87]52 [26–101]33 [14–78]47 [20–110]27 [15–50]21 [10–43]Prevalence of infection, % (N)7 [3–14] (1,272)5 [2–10] (1,791)5 [3–9] (1,961)10 [6–16] (1,246)4 [2–7] (1,654)3 [2–5] (1,880)Deltamethrin mortality (clusters), % (references)65 [49–81] (6)90 [85–95] (6)56 [48–64] (11)60 [44–76] (5)84 [71–96] (6)68 [61–75] (13)95% CIs are shown in brackets.*Cases per 1,000 child-years.During the 3-y period from June 1, 2012–May 31, 2015, there were 643 episodes of malaria in 7,529 cohort children who were followed up cumulatively for 17,284 person-years. The mean age of cohort children was similar in the two study arms in each year, but rose gradually from 5.2 y in the first study year to 6.25 y in the third year (Table 1).Incidence of Malaria and Prevalence of Malaria Infection by Study Arm and by IRS Insecticide.Mean overall incidence was 37.2 per 1,000 person-years [95% confidence interval (CI): 24.3–56.9], declining from 49.9 per 1,000 person-years in year 1, to 36.1 per 1,000 person-years in year 2, to 26.8 per 1,000 person-years in year 3.Mean incidence in the LLIN + IRS study arm was 47.2 per 1,000 person-years when deltamethrin was used (2012), but was almost halved to an average of 24.6 per 1,000 person-years during the 2 y when bendiocarb was used (2013 and 2014) (Table 2). Over the same period in the LLIN-only arm, incidence remained virtually unchanged, from 44.4 per 1,000 person-years in year 1 to 42.1 per 1,000 person-years in years 2–3. Comparing incidence between study arms, the incidence rate ratio (IRR) for LLIN + deltamethrin compared with LLIN alone (2012) was 1.0 (95% CI: 0.36–2.97; P = 0.96); for LLIN + bendiocarb versus LLINs alone (2013), it was 0.60 (95% CI: 0.39–0.91; P = 0.017), while for 2014 (LLIN + bendiocarb versus LLIN), it was 0.69 (95% CI: 0.31–1.50; P = 0.35). For the two bendiocarb years combined, the IRR for IRS + LLIN versus. LLIN alone was 0.65 (95% CI: 0.44–0.96; P = 0.032). There was strong evidence that the change in insecticide modified the effect of IRS + LLIN versus LLIN alone: The IRR for comparing the effect of IRS + LLIN in 2013 and 2014 (bendiocarb) versus LLIN alone with the effect of IRS + LLIN in 2012 (deltamethrin) versus LLIN alone was 0.51 (95% CI: 0.35–0.73; P < 0.001) and 0.62 (95% CI: 0.42–0.93; P = 0.020), respectively (overall interaction P = 0.001; Table 2). The interaction IRR comparing the effect of IRS + LLIN in 2013–2014 combined (bendiocarb) versus LLIN alone with the effect of IRS + LLIN in 2012 (deltamethrin) versus LLIN alone was 0.55 (95% CI: 0.40–0.76; P < 0.001).Table 2.Effect of year, study arm, and IRS insecticide on malaria incidence, Galabat, Sudan, 2012–2014Effects by individual study yearsEffects comparing 2013/2014 (bendiocarb) with 2012 (deltamethrin)YearStudy armCasesMean incidence (range)Unadjusted rate ratio (95% CI)Adjusted rate ratio* (95% CI)†Bendiocarb effect‡PeriodStudy armMean incidenceAdjusted rate ratio* (95% CI)‡Bendiocarb effect‡2012LLIN11745 (24–87)1112012LLIN45 (4–87)1LLIN + Delta12647 (20–110)1.0 (0.36–2.95); P = 0.961.0 (0.36–2.97); P = 0.96LLIN + Delta47 (20–110)1.0 (0.36–2.97); P = 0.9612013LLIN15552 (26–101)110.51 (0.35–0.73); P < 0.0012013/2014LLIN42 (21–85)1LLIN + Bend8227 (15–50)0.53 (0.21–1.32); P = 0.170.60 (0.39–0.91); P = 0.0172014LLIN9833 (14–78)110.62 (0.42–0.93); P = 0.020LLIN + Bend25 (13–47)0.65 (0.44–0.96); P = 0.0320.55 (0.40–0.76); P < 0.001LLIN + Bend6521 (10–43)0.62 (0.20–1.95); P = 0.420.69 (0.31–1.50); P = 0.347*Adjusted for age at time of visit and, for 2013 and 2014, the rate in 2012.†Test to determine if the effect of IRS was different between years (P = 0.001).‡Test comparing the effect of bendiocarb IRS and deltamethrin IRS (P < 0.001).In a sensitivity analysis to test the robustness of the results to the possibility of undue influence exerted by participants who had multiple episodes of malaria, follow-up was restricted to the 550 first episodes observed (i.e., censoring follow-up after the first positive test result). This analysis produced very similar findings to those obtained from the full dataset (results not tabulated).In the three cross-sectional prevalence surveys that were conducted from September to October of each of the three study years, 2,518, 3,445, and 3,841 children were tested by RDTs, of whom 214 (8.5%), 146 (4.2%), and 162 (4.2%) tested positive in 2012, 2013, and 2014, respectively. Analogous results were recorded to those comparing malaria incidence (Table 3). In the IRS + LLIN study arm, mean prevalence of infection fell from 10.4% when deltamethrin was used for IRS (2012) to 3.4% when bendiocarb was used (years 2013/2014) (P = 0.002). Over the same period, mean prevalence in the LLIN-only arm declined more moderately and nonsignificantly from 6.7 to 5.0% (P = 0.41). Comparing prevalence between study arms, the odds ratio (OR) for LLIN + deltamethrin versus LLIN alone in 2012 was 2.11 (95% CI: 0.36–2.97; P = 0.96); for LLIN + bendiocarb versus LLINs alone (2013), it was 1.39 (95% CI: 0.32–6.14; P = 0.66), while for 2014, it was 0.37 (95% CI: 0.18–0.77; P = 0.007). For the two bendiocarb years combined, the OR for LLIN + IRS versus LLIN alone was 0.61 (95% CI: 0.29–1.27; P = 0.19). There was strong evidence that the change in insecticide modified the effect of IRS with an overall interaction of P = 0.001 for interaction tests applied to individual years (left-hand side of Table 3) and P < 0.001 for interaction tests applied to 2012 versus 2013/2014 combined (right-hand side of Table 3). The interaction OR for comparing the effect of IRS + LLIN in 2013 and 2014 (bendiocarb years) versus LLIN alone with the effect of IRS + LLIN in 2012 (deltamethrin) with LLIN alone was 0.55 (95% CI: 0.35–0.87; P = 0.01) and 0.30 (95% CI: 0.19–0.47; P < 0.001), respectively. The interaction OR comparing the effect of IRS + LLIN in 2013–2014 combined (versus LLIN alone) with the effect of IRS + LLIN in 2012 (deltamethrin) (versus LLIN alone) was 0.40 (95% CI: 0.27–0.59; P < 0.001).Table 3.Effect of year, study arm, and IRS insecticide on malaria prevalence, Galabat, Sudan, 2012–2014Effects by individual study yearsEffects comparing 2013/2014 (bendiocarb) with 2012 (deltamethrin)YearStudy armPrevalence, % (N)Unadjusted ORAdjusted OR*Bendiocarb effect†PeriodStudy armMean prevalence, %Adjusted OR*Bendiocarb effect‡2012LLIN7 [3–14] (1,272)112012 DeltaLLIN7 [3–14] (1,272)1LLIN + IRS10 [6–16] (1,246)1.61 [0.60–4.35]; P = 0.332.11 [0.85–5.22]; P = 0.11LLIN + IRS10 [6–16] (1,246)2.11 [0.85–5.22]; P = 0.1112013LLIN5 [2–10] (1,791]112013–2014 BendiocarbLLIN5 [2.8–8.6] (3,752)1LLIN + IRS4 [2–7] (1,654)0.86 [0.31–2.42]; P = 0.771.39 [0.32–6.14]; P = 0.660.55 [0.35–0.87]; P = 0.012014LLIN5 [3–9] (1,961)11LLIN +I RS3.4 [2.1–5.4] (3,534)0.61 [0.29–1.27]; P = 0.190.40 [0.27–0.59]; P < 0.001LLIN + IRS3 [2–5] (1,880)0.54 [0.26–1.13]; P = 0.0980.37 [0.18–0.77]; P = 0.0070.30 [0.19–0.47]; P < 0.00195% CIs are shown in brackets. Delta, deltamethrin.*Adjusted for age, study arm, and study period.†Overall likelihood ratio test, P < 0.0001 (test to determine if effect of IRS was different between years).‡Overall likelihood ratio test, P < 0.0001 (test comparing the effect of bendiocarb IRS and deltamethrin IRS).Association Between Resistance and Incidence and Prevalence of Malaria Infection.During the course of the study, 4,680 female An. arabiensis mosquitoes were phenotyped for deltamethrin susceptibility using WHO discriminating dose tests (14), with evidence of resistance to deltamethrin in both study arms (Fig. 1). The mean percentage mortality in the LLIN arm (65.0%, 95% CI: 44.6–85.3) was not significantly different (t = 0.425; df, 9; P = 0.68) from that of the LLIN + IRS arm (60%, 95% CI: 38.2–82.2) during year 1. The assay for the Vgsc-1014F mutation was successfully conducted in 1,847 of 1,872 specimens (Fig. 1). There was a subsequent decrease in allelic frequency (two-way ANOVA, P < 0.001), but no evidence of an association between allelic frequency and the study arm (two-way ANOVA, P > 0.05; Fig. 1). There was no evidence of nonnormality of the mortality or the allele frequency data.Fig. 1.Change in deltamethrin mortality (Upper) and Vgsc-1014F (Lower) across study years and between single (LLIN) and dual (LLIN + IRS) intervention arms. Box whisker plots show the median (bold line) and interquartile range (boxes). Phenotypic data were available from six LLIN and five LLIN + IRS clusters in 2012, six LLIN and six LLIN + IRS clusters in 2013, and 11 LLIN and 13 LLIN + IRS clusters in 2014. Genotypic data were available for all 26 clusters for all years. In 2014, there was significantly (P = 0.038) higher mortality (less resistance) in the LLIN + IRS arm (n = 13; mortality = 68%; 95% CI: 60.0–76.0) compared with the LLIN-only arm (n = 11; mortality = 56.1%; 95% CI: 47.1–64.9).The association between cluster- and year-specific bioassay survivorship (phenotypic resistance) and cluster- and year-specific malaria incidence in cohort children was assessed using multiple variable Poisson regression models, adjusting for study arm and study year. Unadjusted and adjusted IRRs show no association between malaria incidence in cohort children and deltamethrin bioassay survivorship in mosquitoes from corresponding clusters (Fig. 2 and Table 4). To estimate any effect that resistance in a particular year and a particular cluster may have had on the prevalence of infection as determined by annual cross-sectional surveys, logistic regression was carried out, again adjusting for study arm and study year. Unadjusted and adjusted ORs showed no evidence of any association between resistance as measured through bioassay survivorship and infection prevalence (Table 3).Fig. 2.Cluster-specific malaria case incidence and cluster-specific malaria infection prevalence plotted against cluster-specific phenotypic resistance (bioassay mortality after standard exposure to deltamethrin) and against cluster-specific Vgsc-1014F allele frequency for 2012, 2013, and 2014 in Galabat, Sudan.Table 4.Association between malaria prevalence and malaria incidence with genotypic and phenotypic resistance, respectively, from 2012–2014Resistance statusUnadjusted OR/ rate ratio (95% CI)Adjusted OR/rate ratio* (95% CI)Malaria prevalence\u2003L1014F linear, per 1% mutation1.009 (0.99–1.03); P = 0.350.992 (0.97–1.02); P = 0.51\u2003Deltamethrin linear, per 1% survivorship0.999 (0.970–1.029); P = 0.911.007 (0.98–1.04); P = 0.67Malaria incidence\u2003L1014F linear, per 1% mutation1.462 (0.411–5.196); P = 0.560.415 (0.065–2.665); P = 0.35\u2003Deltamethrin linear, per 1% survivorship0.995 (0.959–1.032); P = 0.780.991 (0.947–1.037); P = 0.70*Adjusted for variations in year and study arm. Note that for phenotype data, there is interyear variation in the number of clusters.Similar analysis was carried out to investigate whether malaria incidence and infection prevalence were associated with Vgsc-1014F frequency, measured in mosquito specimens collected in corresponding clusters and years. There was no evidence of any association between malaria incidence or infection prevalence on the one hand and Vgsc-1014F frequency on the other (Fig. 2 and Table 4).Subgroup analysis was carried out restricted to the combined data from the LLIN-only arm for all 3 y and to the LLIN + IRS arm for the year in which deltamethrin was sprayed. There was again no association between malaria incidence and Vgsc-1014F frequency (P = 0.59), between infection prevalence and Vgsc-1014F frequency (P = 0.39), between malaria incidence and bioassay survivorship (P = 0.85), and between infection prevalence and bioassay survivorship (P = 0.98).Association Between the Addition of Nonpyrethroid IRS Insecticide and the Evolution of Insecticide Resistance to Pyrethroids in an Area of Universal LLIN Coverage.It was only possible to conduct resistance phenotyping in 11 and 12 clusters in 2012 and 2013, respectively; this figure rose to 24 in 2014. In 2012 as well as in 2013 (the first year of bendiocarb spraying), there was no significant difference in mosquito deltamethrin susceptibility between intervention arms. However, in 2014, there was significantly higher mortality (less resistance) in the LLIN + IRS arm (n = 13; mortality = 68%; 95% CI: 60–76) compared with the LLIN arm (n = 11; mortality = 56%; 95% CI: 47–65) (P = 0.038) (Fig. 1). In all clusters across all years, An. arabiensis populations were susceptible to bendiocarb.Cost and Cost-Effectiveness.The cost of protection with LLIN only in Galabat was estimated to be US $2.16 per person-year, while the cost of protection per person-year with LLIN + IRS (deltamethrin) was estimated to be US $4.36. The cost per person-year of protection with LLIN + IRS (bendiocarb) was estimated to be US $5.01. These cost estimates translate into an incremental cost of switching from IRS with deltamethrin to IRS with bendiocarb in this study of US $0.65 per person-year. With the year 1 incidence of 49.9 episodes per 1,000 person-years, this translates to an incremental cost per case averted of US $29. Assuming a case fatality rate for malaria of 0.005, the incremental cost per death averted was approximately US $6,400 and an incremental cost per disability adjusted life year (DALY) averted of US $195. These results are well within accepted standards for highly cost-effective interventions for Sudan established by the WHO (15). Sensitivity analysis indicated that changes to discount rate, prices of LLINs, or allocation of shared costs did not affect the incremental costs of the insecticide switch and that reduction of the cost of bendiocarb to the cost of deltamethrin would have resulted in nearly identical costs per person protected, indicating that there were only minor differences in delivery costs for the intervention with bendiocarb. Sudan is an area with low malaria incidence, and it is likely that in other areas with a higher incidence and more severe pyrethroid resistance, such a switch is likely to be associated with even greater cost-effectiveness.DiscussionAssociation Between Malaria Incidence/Prevalence and Switching Active Ingredients.Malaria incidence was similar and malaria prevalence was higher in the study arm in which deltamethrin IRS was sprayed in addition to LLIN use, compared with LLINs alone. The higher prevalence in the LLIN + IRS arm was likely to be the result of an imperfect balance in the two study arms. In the following 2 y when IRS with bendiocarb replaced deltamethrin, there was a significant reduction in the LLIN + IRS arm compared with the year in which deltamethrin was used, while incidence and prevalence remained stable in the clusters that only had LLINs. Compared with the LLIN-only arm, incidence was significantly lower in the IRS + LLIN arm in the 2 y in which bendiocarb was used [IRR = 0.65 (95% CI: 0.44–0.96; P = 0.032)], and this effect differed significantly from the effect of IRS + LLIN with deltamethrin [interaction IRR = 0.55 (95% CI: 0.40–0.76; P < 0.001)]. Prevalence of infection was only lower in the IRS + LLIN arm compared with the LLIN-only arm of the study in 2014; however, again, there was very strong evidence that bendiocarb significantly modified the effect of IRS when comparing the OR between study arms during the years in which bendiocarb was used with the OR between study arms when deltamethrin was used [interaction OR = 0.40 (95% CI: 0.27–0.59; P < 0.001)]. Deltamethrin has been shown to be effective when used for IRS in a variety of settings (16–19). While we cannot completely discount differential longevity of the deltamethrin and bendiocarb IRS formulations used in Sudan, the expectation from previous studies is that the deltamethrin formulation would have a marginally longer residual life than the bendiocarb formulation. We conclude that the presence of pyrethroid resistance is a plausible explanation for the loss of effectiveness of deltamethrin IRS, resulting in substantially suboptimal malaria control. To date, there are few studies assessing the impact of insecticide resistance as the design of such studies is problematic because (i) the exposure of interest, resistance to an insecticide in the local vector, cannot be randomly allocated and (ii) it is unethical to knowingly protect a human population with IRS using an insecticide that is unlikely to be effective if alternatives are available. Evidence of the impact of insecticide resistance on IRS has thus far always been generated by retrospective studies (20, 21). Our data, when considered with two retrospective studies from South Africa and Uganda, where the primary vectors were Anopheles funestus and Anopheles gambiae, respectively, provide further evidence that pyrethroid resistance is highly likely to be compromising the effectiveness of IRS.The impact of resistance in KwaZulu-Natal, South Africa, was more marked than that observed in the current study, with a near 10-fold increase in annual malaria cases witnessed from 1995 to 2000 following a switch from DDT to deltamethrin (21). Insecticide susceptibility tests later showed that there was resistance to pyrethroids in An. funestus, a vector that had previously been driven to near extinction in KwaZulu-Natal but that resurged following the change to pyrethroid IRS (22). Subsequent reversion back to IRS with DDT in 2000 was followed by a rapid decline in cases that was maintained in subsequent years (23). In a study by Kigozi et al. (20) in Uganda, routinely collected malaria health facility data were compared temporally in relation to the insecticide used in IRS: five rounds of IRS spraying DDT (n = 1), pyrethroid (n = 1), or bendiocarb (n = 3). There was known resistance to both pyrethroids and DDT, but not to bendiocarb, in the area. Small decreases in the odds of malaria infection were observed following both DDT and pyrethroid spraying, with the decrease in malaria infection being much greater following the bendiocarb spray round.The strength of the study described here was the ability to compare the change in incidence in the IRS clusters with changes in incidence in 13 contemporaneous control group clusters, which had been randomly selected and which were similar in most respects to the intervention group. The reduction in both malaria incidence and prevalence after the introduction of the carbamate insecticide may therefore be attributable to this change in insecticide. Since IRS with deltamethrin and IRS with bendiocarb are effective insecticides in settings with susceptible vectors (17, 18, 24, 25), the lack of impact of the deltamethrin IRS may be due to the presence of deltamethrin resistance in the study area. As would be expected from earlier studies (26, 27), despite resistance, some protection against malaria was provided in both study arms by high coverage with LLINs.The IRS with bendiocarb in this study provided very similar protection in addition to LLINs to that estimated in a recent cluster randomized trial in Tanzania (28). This study serves as reminder of the potential consequences of using failing insecticides, particularly if no other preventive measures are in place, and the need for insecticide policy to be informed by appropriate susceptibility testing (6).Association Between Resistance and Malaria Incidence/Infection Prevalence.There was no evidence of an association between malaria rates and insecticide resistance measured phenotypically or genotypically for target-site resistance (as Vgsc-1014F frequency). An association between malaria burden and pyrethroid insecticide resistance was expected in clusters with pyrethroid-treated LLINs only or in clusters receiving LLINs and IRS with pyrethroid. The study lacked power to detect such an association due to a number of factors: (i) the range in pyrethroid resistance in the study area may have been too small; (ii) the effect of insecticide resistance on the effectiveness of LLINs may be relatively modest in settings of moderate pyrethroid resistance; (iii) bioassay data were not available in all clusters in each study year; and (iv) bioassay survivorship is an imprecise measure of the strength of resistance (29), despite its wide use for detecting the presence of resistance in a mosquito population. Our analysis of malaria incidence and prevalence in relation to insecticide resistance relied on detecting a dose–response association between the two variables; if the latter is inadequately quantified through bioassay survivorship or Vgsc-1014F frequency, then such a trend is unlikely to be significant.Previous studies have shown that insecticide-treated nets still provide protection against malaria infection even in settings of vector resistance to pyrethroids. A meta-analysis using entomological data (26) concluded that insecticide treated nets are a more effective form of vector control than untreated nets despite insecticide resistance. A study in Malawi found that children sleeping under LLINs suffered significantly fewer malaria episodes than their counterparts who did not sleep under nets in an area where the predominant malaria vector species, An. funestus and An. arabiensis, showed moderate to high levels of pyrethroid resistance (27).Cost and Cost-Effectiveness.The current study also demonstrated the relative cost-effectiveness of switching active ingredients to mitigate the potential effects of insecticide resistance on malaria incidence. It is, to date, the only study of which we are aware that does so using direct field evidence. Even in a relatively low transmission area, such as Galabat, a switch to the marginally more expensive bendiocarb insecticide is justified.Insecticide Combination and the Evolution of Resistance.A positive finding was modest evidence of retardation in the speed of evolution of insecticide resistance when two active ingredients with differing modes of actions were used in the LLIN + IRS arm. This is important for malaria control program managers as they struggle to develop plans for the monitoring and management of insecticide resistance in line with WHO GPIRM recommendations (6). Curiously, across our study site, there was a significant decrease in the Vgsc-1014F resistance marker frequency. While there are a number of instances of kdr markers sweeping rapidly to fixation (30–32), the obverse trend shown here has not been reported elsewhere. There are numerous studies showing that in An. arabiensis, Vgsc-1014F is a strong predictor of pyrethroid resistance (33), so this may suggest a decline in its importance in conferring a resistant phenotype due to the emergence of additional resistance mechanism(s).Limitations.For ethical reasons, it was not possible to conduct a trial with a neutral control arm; therefore, the effectiveness of the IRS alone could not be directly assessed. A trial randomizing clusters to the two insecticides would have provided a more direct contemporaneous comparison of deltamethrin to bendiocarb. Instead, the opportunity of comparing each insecticide against the same LLIN-alone control arm arose when insecticide needed to be switched due to the presence of pyrethroid resistance in the area. This design lacks the strength of evidence provided by a direct comparison; however, this shortcoming was compensated for, at least in part, by the contemporaneous comparison with the randomly selected LLIN-only clusters to control for temporal change in malaria transmission. The evidence of a change in the effect of IRS coinciding with the switch to bendiocarb was statistically very strong.ConclusionIn summary this trial has shown the following: (i) loss of effectiveness of pyrethroid IRS is likely to be associated with pyrethroid resistance in malaria vectors; (ii) IRS effectiveness can be restored by switching to an insecticide to which vectors are fully susceptible for an incremental cost that is considered attractive by international standards; and (iii) modest retardation to the speed of pyrethroid resistance development may be achieved with appropriate combinations of LLINs and nonpyrethroid IRS, compared with using LLINs alone.Materials and MethodsStudy Site.Galabat is located ∼80 km from Gedarif town and borders Ethiopia. A baseline household census estimated that the area comprised ∼119,000 households in 197 villages with a total of 600,000 inhabitants who are predominantly dependent on rain-fed agriculture. Climatically, the area is within the dry savannah region, with annual rainfall ranging between 700 mm and 1,200 mm and concentrated in a short rainy season from June to September. Average daily temperatures range between 31 °C and 44 °C (34). Malaria transmission is seasonal from September to November, with P. falciparum prevalence between 1% and 10% in 2- to 10-y-old children (9). An. arabiensis is the main vector of malaria in the area, with An. funestus implicated as having a minor role in malaria transmission (34). Before this study, LLINs were the only form of vector control in Galabat.Treatment for malaria in the area is provided by 101 public sector health facilities, including 7 referral hospitals, 24 health centers, 70 health units, and 20 villages with home-based management of malaria. Diagnosis of suspected cases is based on RDTs at the majority of health and home-based management facilities, while microscopy is used at 20 facilities in the area.Study Design.The Galabat study is loosely linked to a larger multicountry study on the implications of insecticide resistance that has been described previously (8). The opportunity to compare the two insecticides arose when deltamethrin IRS had to be replaced with bendiocarb IRS. The original objective of the Galabat trial was to investigate whether IRS in combination with LLINs provided additional protection against malaria compared with LLINs alone. With 13 clusters per arm and 200 children per cluster followed up for 3 y, the trial had 80% power to observe a 38% reduction in malaria incidence or more in the LLIN + IRS arm compared with the LLIN-only arm, assuming a mean incidence of 30 per 1,000 person-years and a coefficient of variation of 0.3 between study clusters. Twenty-six villages were selected from a total of 197 to form clusters, each consisting of at least 500 households, and with the distance between the edges of adjoining clusters being at least 3 km (Fig. 3). In 2010, a baseline malaria indicator survey testing for P. falciparum infection using malaria RDTs (SD BIOLINE-Malaria Ag P.f/P.v.; Standard Diagnostics, Inc.) was carried out on a sample of 100 children <10 y of age in each of the 26 clusters. At the same time, pyrethrum spray catches were made in houses, from which a sample of 24 An. arabiensis mosquitoes from each cluster was screened for the pyrethroid resistance-associated mutations in the voltage-gated sodium channels Vgsc-1014F and Vgsc-1014S using established molecular diagnostic techniques (33).Fig. 3.Map of the study area in Galabat, southeastern Sudan. Triangles denote clusters with LLIN only, and circles denote clusters with LLIN + IRS.LLINs with a deltamethrin concentration of 55 mg of active ingredient per square meter (PermaNet 2.0) were distributed in April 2011 in all 26 study clusters to reach levels required for universal coverage, defined as one net for every two people. The LLINs were replaced with new nets of the same type in all clusters in June 2014. In 2012, clusters were randomly allocated to two study arms using restricted randomization (35, 36) to ensure that the two study arms were balanced on a number of criteria, including baseline frequency of the Vgsc-1014F mutation, baseline prevalence of infection, baseline use of LLINs, and access to health facilities. One study arm (n = 13 clusters) retained universal coverage of LLINs only, while the second arm (n = 13 clusters) received two rounds of IRS in addition to LLINs. The first round of IRS was in August of each year to cover the main transmission season (September to November), with the second round in late December. In 2012, deltamethrin insecticide (Wettable Powder 25%) was used in both IRS rounds; in 2013 and 2014, bendiocarb (Ficam WP 80%) was sprayed. Bendiocarb, a carbamate, is an acetylcholinesterase antagonist, as opposed to deltamethrin, which targets the mosquito Vgsc. While LLINs target mosquitoes that are seeking a blood meal, IRS targets mosquitoes that rest indoors either before or after blood-feeding. Quality assurance of both IRS and LLIN interventions was conducted following WHO guidelines (14) using a susceptible laboratory strain of An. arabiensis raised in the insectaries of the Sennar Malaria Research and Training Centre.Insecticide Resistance.Over the course of the study, two estimates of insecticide resistance were made yearly in each cluster: One, termed phenotypic resistance, was reliant upon collecting live mosquitoes and ascertaining their susceptibility to standard dosages of deltamethrin and bendiocarb; the other, termed genotypic resistance, involved screening for Vgsc-1014F (reviewed in ref. 33). Anopheles larvae and pupae were collected annually (2012–2014) during the rainy season. All larvae and pupae were reared to adults in a field insectary until used for insecticide susceptibility tests. Pyrethrum spray catches were also performed to collect adult Anopheles mosquitoes. Phenotypic assays for deltamethrin and bendiocarb were performed following the standard WHO discriminating dose tests (14, 37). All susceptibility tests were conducted under laboratory conditions at temperatures ranging from 24.8 to 27.1 °C and relative humidity ranging from 75.4 to 79.8%.An. gambiae complex species, the main vector, were identified to species status, with An. arabiensis the only species observed, using a standard PCR assay (38). Twenty-four An. arabiensis females per cluster were selected at random for Vgsc-1014F genotyping to estimate a cluster-specific resistance marker frequency (39).Active Case Detection.In each cluster, a community health worker (CHW) was appointed, and ∼200 children aged between 6 mo and <10 y were recruited into cohorts after explaining the study procedures to caregivers and after obtaining written informed consent. Older children were asked to assent to recruitment. CHWs visited cohort members weekly during the peak of the malaria season (September to November) and fortnightly during the remainder of the year, for a total of 30 annual visits. Cohort children who were reported to be febrile at the time of a visit had their temperature taken. Children who had a confirmed fever at the time of the visit, or a reported fever during the period since the last visit, were referred to the local health facility to be tested for malaria parasites, or were tested by the CHW using an RDT when no local facility was available. Local health facilities used either RDTs or microscopy to test for malaria parasites. If caregivers, upon questioning, reported that a child had visited the health facility for a febrile illness during the period since the last visit, the CHW visited the health facility to determine if the child had a blood test that confirmed a diagnosis of malaria. Each visit by a CHW and each clinic attendance resulting in a definitive diagnosis of malaria were recorded in the cohort register, which was collected at regular intervals for entry into an MS Access database at a central location. A study coordinator carried out regular supervisory visits to CHWs to verify the quality of data collection. Upon reaching the age of 10 y, cohort children were replaced by younger children from the same household or from another household if no younger sibling was available.Prevalence of Infection.Once each year, during September to October, cohort children were tested for P. falciparum infection using RDTs (SD BIOLINE-Malaria Ag P.f/P.v.), irrespective of symptoms. A random sample of 50% of cohort members was selected in 2012, while all cohort children who were present at the time of the survey were screened in 2013 and 2014. Any child who tested positive was referred to the local health facility for treatment.Statistical Analysis.Malaria case incidence was estimated as the number of cases per child-year of follow-up. IRRs were calculated comparing incidence between study arms for each study year, and for the 2 y combined during which bendiocarb IRS was used. Effect modification (interaction) between study arm and study year was investigated to determine the differential effect of IRS + LLINs with bendiocarb compared with IRS + LLINs with deltamethrin versus LLINs alone. Multiple variable Poisson regression was used to adjust the effect of study arm for age of child at time of visit and, for 2013 and 2014, for incidence rate in 2012. To assess whether malaria incidence was associated with insecticide resistance, IRRs were calculated per 1% change in cluster-specific vector susceptibility (mosquito mortality) and per 1% change in cluster specific Vgsc-1014F allele frequency. For this analysis, year and cluster-specific insecticide resistance measurements were linked to year and cluster-specific incidence.For cross-sectional prevalence of infection data, analogous analyses were carried out using logistic regression to estimate ORs.Multiple episodes of malaria in the same child were rare; any consecutive positive test results were counted as one episode since the second positive test result could be either a false-positive result from RDTs that measure parasite protein retained from an already cleared infection or the result of a treatment failure. To test the robustness of these results against the possibility of undue influence exerted by participants who had multiple episodes of malaria, the analysis was repeated but restricted to the 550 first-time episodes that were observed in the same cohort over the same period ( i.e., excluding children from further follow-up after their first positive test result). To calculate appropriate SEs of estimated means, a robust variance estimator using the first-order Taylor-series linearization method was used to account for variation between clusters (40, 41). Poisson regression and logistic regression were performed using random effects models.To compare the differences in mean mortalities and Vgsc-1014F allele frequencies between the two intervention arms, t tests were used, while ANOVA was used to compare the differences between years. The Shapiro–Wilks test was used to assess whether mortality and allele frequency data deviated from the normal distribution.Cost Data Collection Tools and Indicators.A microcosting (ingredients approach) activities-based framework was applied to the development of cost-collection tools. Key-informant interviews and record reviews were conducted to identify all of the activities and resources needed that were expected to be utilized during the course of the trial. Care was taken to exclude activities that were specifically related to research and not necessary for the provision or performance of the intervention; these included enhanced case finding and enhanced vector surveillance beyond what was necessary for routine use of IRS or LLINs. A standardized instrument for the collection of resource quantities and prices was developed for use at the national (central), state, and locality levels. The instrument was employed by staff of the Federal Ministry of Health Integrated Vector Management Unit to collect information on resource usage at each level of the health system.Analysis of Cost Data.Resource use was quantified and valued in Sudanese pounds (SDG) in the year during which the resource use occurred. Costs were converted to US dollars using the prevailing average exchange rate for the period. All costs were valued in 2011 US dollars, after adjusting for inflation using the consumer price index for Sudan. Prices derived from the WHO-CHOICE (choosing interventions that are cost effective) database (15) were converted from international dollars using a purchasing power parity (PPP)-to-local currency ratio (1 international dollar to 1.28 SDG) for 2009.In all cases, economic costs are presented, which are also known as opportunity costs. Economic costs represent the value of a given resource in its next most appropriate use. As such, capital costs, including vehicles, buildings, LLINs, and spray equipment, were annualized and discounted using assumed lifetimes and a social discount rate of 3%.Cost Outcomes Sensitivity Analysis.Two types of outcome were measured: a process measure, numbers of persons living in clusters with vector control per year (or person-years of protection), and the effectiveness of the interventions in terms of incident cases of malaria prevented.Because most cost models and assessments are dependent on assumptions about quantities of resources used, prices of resources, and allocation of shared costs, it is necessary to conduct a sensitivity analysis to attempt to determine the robustness of the cost assessment to various assumptions made during development of the model. A one-way sensitivity analysis was conducted to determine the robustness of the cost model to various assumptions made during the assessment. Parameters, which were varied, included discount rate, prices of LLINs and insecticides used, allocation of shared costs, numbers of persons protected by the interventions, and baseline malaria incidence.Ethics.The study was approved by the Ethics Committees of the London School of Hygiene and Tropical Medicine (approval no. 5825) and Federal Ministry of Health, Sudan (approval no.116-12-09). The study was registered on ClinicalTrials.com (registration no. NCT01713517).This project was supported financially by the United Nations Environment Programme/Global Environment Facility project: Demonstration of Sustainable Alternatives to DDT and Strengthening of National Vector Control Capabilities in the Middle East and North Africa (GEF ID 2546), and by the Bill and Melinda Gates Foundation (Grant 48499.01). This research forms part of a multicountry study coordinated by the WHO Global Malaria Programme. Additional technical support was provided by the WHO Regional Office for the Eastern Mediterranean and the WHO country office in Sudan.The authors declare no conflict of interest.1World Health Organization2015World Malaria Report 2015WHOGeneva2BhattS2015The effect of malaria control on Plasmodium falciparum in Africa between 2000 and 2015Nature526207211263750083MitchellSN2012Identification and validation of a gene causing cross-resistance between insecticide classes in Anopheles gambiae from GhanaProc Natl Acad Sci USA10961476152224607954MitchellSN2014Metabolic and target-site mechanisms combine to confer strong DDT resistance in Anopheles gambiaePLoS One9e92662246757975EdiCVAKoudouBGJonesCMWeetmanDRansonH2012Multiple-insecticide resistance in Anopheles gambiae mosquitoes, Southern Côte d’IvoireEmerg Infect Dis1815081511229324786World Health Organization-GMP2012Global Plan for Insecticide Resistance Management in Malaria VectorsWHOGeneva7RansonHLissendenN2016Insecticide resistance in African Anopheles mosquitoes: A worsening situation that needs urgent action to maintain malaria controlTrends Parasitol32187196268267848KleinschmidtI2015Design of a study to determine the impact of insecticide resistance on malaria vector control: A multi-country investigationMalar J14282261946489NoorAM2012Malaria risk mapping for control in the republic of SudanAm J Trop Med Hyg87101210212303340010MalikEM2006From chloroquine to artemisinin-based combination therapy: The Sudanese experienceMalar J5651687974211PetrarcaV2000Cytogenetics of the Anopheles gambiae complex in Sudan, with special reference to An. arabiensis: Relationships with East and West African populationsMed Vet Entomol141491641087285912AbdallaH2008Insecticide susceptibility and vector status of natural populations of Anopheles arabiensis from SudanTrans R Soc Trop Med Hyg1022632711805405613HimeidanYEChenHChandreFDonnellyMJYanG2007Short report: Permethrin and DDT resistance in the malaria vector Anopheles arabiensis from eastern SudanAm J Trop Med Hyg77106610681816552314World Health Organization2012Test Procedures for Insecticide Resistance Monitoring in Malaria Vector MosquitoesWHOGeneva15World Health Organization2003Making Choices in Health: WHO Guide to Cost-Effectiveness AnalysisWHOGeneva16BradleyJ2016A cluster randomized trial comparing deltamethrin and bendiocarb as insecticides for indoor residual spraying to control malaria on Bioko Island, Equatorial GuineaMalar J153782744866717RatovonjatoJ2014Entomological and parasitological impacts of indoor residual spraying with DDT, alphacypermethrin and deltamethrin in the western foothill area of MadagascarMalar J13212442324618HamainzaB2016Incremental impact upon malaria transmission of supplementing pyrethroid-impregnated long-lasting insecticidal nets with indoor residual spraying using pyrethroids or the organophosphate, pirimiphos methylMalar J151002689301219KleinschmidtI2006Reduction in infection with Plasmodium falciparum one year after the introduction of malaria control interventions on Bioko Island, Equatorial GuineaAm J Trop Med Hyg749729781676050620KigoziR2012Indoor residual spraying of insecticide and malaria morbidity in a high transmission intensity area of UgandaPLoS One7e428572288012321MaharajRMthembuDJSharpBL2005Impact of DDT re-introduction on malaria transmission in KwaZulu-NatalS Afr Med J958718741634488522HargreavesK2000Anopheles funestus resistant to pyrethroid insecticides in South AfricaMed Vet Entomol141811891087286223MaharajR2013Epidemiology of malaria in South Africa: From control to eliminationS Afr Med J1037797832407963324KleinschmidtI2007Factors influencing the effectiveness of malaria control in Bioko Island, Equatorial GuineaAm J Trop Med Hyg76102710321755660625SharpBL2007Seven years of regional malaria control collaboration–Mozambique, South Africa, and SwazilandAm J Trop Med Hyg7642471725522726StrodeCDoneganSGarnerPEnayatiAAHemingwayJ2014The impact of pyrethroid resistance on the efficacy of insecticide-treated bed nets against African anopheline mosquitoes: Systematic review and meta-analysisPLoS Med11e10016192464279127LindbladeKA2015A cohort study of the effectiveness of insecticide-treated bed nets to prevent malaria in an area of moderate pyrethroid resistance, MalawiMalar J14312562798728WestPA2014Indoor residual spraying in combination with insecticide-treated nets compared to insecticide-treated nets alone for protection against malaria: A cluster randomised trial in TanzaniaPLoS Med11e10016302473637029BagiJ2015When a discriminating dose assay is not enough: Measuring the intensity of insecticide resistance in malaria vectorsMalar J142102598589630ClarksonCS2014Adaptive introgression between anopheles sibling species eliminates a major genomic island but not reproductive isolationNat Commun542482496364931MathiasDK2011Spatial and temporal variation in the kdr allele L1014S in Anopheles gambiae s.s. and phenotypic variability in susceptibility to insecticides in Western KenyaMalar J10102123578332NorrisLC2015Adaptive introgression in an African malaria mosquito coincident with the increased usage of insecticide-treated bed netsProc Natl Acad Sci USA1128158202556152533DonnellyMJIsaacsATWeetmanD2016Identification, validation, and application of molecular diagnostics for insecticide resistance in malaria vectorsTrends Parasitol321972062675086434HamadAA2002A marked seasonality of malaria transmission in two rural sites in eastern SudanActa Trop8371821206279535HayesRJMoultonLH2009IntroductionCluster Randomised Trials, Interdisciplinary StatisticsChapman and Hall/CRCBoca Raton, FL336SismanidisC2008Restricted randomization of ZAMSTAR: A 2 x 2 factorial cluster randomized trialClin Trials53163271869784637World Health Organization1998Test procedures for insecticide resistance monitoring in malaria vectors, bio-efficacy and persistence of insecticides on treated surfaces (WHO, Geneva), Technical Report WHO/CDS/CPC/MAL/98.1238ScottJABrogdonWGCollinsFH1993Identification of single specimens of the Anopheles gambiae complex by the polymerase chain reactionAm J Trop Med Hyg49520529821428339BassC2007Detection of knockdown resistance (kdr) mutations in Anopheles gambiae: A comparison of two new high-throughput assays with existing methodsMalar J61111769732540RaoJNScottAJ1992A simple method for the analysis of clustered binary dataBiometrics48577585163798041Stata Corporation2013Stata Survey Data Reference Manual: Release 14Stata PressCollege Station, TX', 'title': 'Impact of insecticide resistance in ', 'date': '2017-12-13'}}
| 1
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Public Health, Epidemiology & Health Systems
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81
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Is malaria parasite prevalence higher, lower, or the same when comparing pyrethroid‐like indoor residual spraying (IRS) plus insecticide‐treated nets (ITNs) to insecticide‐treated nets (ITNs) alone?
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no difference
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moderate
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no
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['25498847', '29229808', '21565149']
| 31,120,132
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{'25498847': {'article_id': '25498847', 'content': 'Although many malaria control programmes in sub-Saharan Africa use indoor residual spraying with long-lasting insecticidal nets (LLINs), the two studies assessing the benefit of the combination of these two interventions gave conflicting results. We aimed to assess whether the addition of indoor residual spraying to LLINs provided a significantly different level of protection against clinical malaria in children or against house entry by vector mosquitoes.\nIn this two-arm cluster, randomised, controlled efficacy trial we randomly allocated clusters of Gambian villages using a computerised algorithm to LLINs alone (n=35) or indoor residual spraying with dichlorodiphenyltrichloroethane plus LLINs (n=35). In each cluster, 65-213 children, aged 6 months to 14 years, were surveyed at the start of the 2010 transmission season and followed in 2010 and 2011 by passive case detection for clinical malaria. Exposure to parasite transmission was assessed by collection of vector mosquitoes with both light and exit traps indoors. Primary endpoints were the incidence of clinical malaria assessed by passive case detection and number of Anopheles gambiae sensu lato mosquitoes collected per light trap per night. Intervention teams had no role in data collection and the data collection teams were not informed of the spray status of villages. The trial is registered at the ISRCTN registry, number ISRCTN01738840.\nLLIN coverage in 2011 was 3510 (93%) of 3777 children in the indoor residual spraying plus LLIN group and 3622 (95.5%) of 3791 in the LLIN group. In 2010, 7845 children were enrolled, 7829 completed passive case detection, and 7697 (98%) had complete clinical and covariate data. In 2011, 7009 children remained in the study, 648 more were enrolled, 7657 completed passive case detection, and 7545 (98.5%) had complete data. Indoor residual spraying coverage per cluster was more than 80% for both years in the indoor residual spraying plus LLIN group. Incidence of clinical malaria was 0.047 per child-month at risk in the LLIN group and 0.044 per child-month at risk in the indoor residual spraying plus LLIN group in 2010, and 0.032 per child-month at risk in the LLIN group and 0.034 per child-month at risk in the indoor residual spraying plus LLIN group in 2011. The incident rate ratio was 1.08 (95% CI 0.80-1.46) controlling for confounders and cluster by mixed-effect negative binomial regression on all malaria attacks for both years. No significant difference was recorded in the density of vector mosquitoes caught in light traps in houses over the two transmission seasons; the mean number of A gambiae sensu lato mosquitoes per trap per night was 6.7 (4.0-10.1) in the LLIN group and 4.5 (2.4-7.4) in the indoor residual spraying plus LLIN group (p=0.281 in the random-effects linear regression model).\nWe identified no significant difference in clinical malaria or vector density between study groups. In this area with high LLIN coverage, moderate seasonal transmission, and susceptible vectors, indoor residual spraying did not provide additional benefit.\nUK Medical Research Council.', 'title': 'Efficacy of indoor residual spraying with dichlorodiphenyltrichloroethane against malaria in Gambian communities with high usage of long-lasting insecticidal mosquito nets: a cluster-randomised controlled trial.', 'date': '2014-12-17'}, '29229808': {'article_id': '29229808', 'content': 'Proc Natl Acad Sci U S AProc. Natl. Acad. Sci. U.S.ApnaspnasPNASProceedings of the National Academy of Sciences of the United States of America0027-84241091-6490National Academy of Sciences29229808574819420171381410.1073/pnas.1713814114PNAS PlusBiological SciencesMedical SciencesPNAS PlusImpact of insecticide resistance in Anopheles arabiensis on malaria incidence and prevalence in Sudan and the costs of mitigationInsecticide resistance impact on malariaKafyHmooda Totoab1IsmailBashir Adambc1MnzavaAbraham PeterdLinesJonathaneAbdinMogahid Shiekh EldinfgEltaherJihad SuliemanhBanagaAnuar OsmaniWestPhilippajBradleyJohnjCookJackiejThomasBrentkSubramaniamKrishanthikHemingwayJanetk2KnoxTessa BellamydMalikElfatih M.lYukichJoshua O.mDonnellyMartin Jameskn2KleinschmidtImmojo2aVector Unit, Ministry of Health, Khartoum, Sudan;bSchool of Biological Sciences, Universiti Sains Malaysia, 11800 Pulau Penang, Malaysia;cState Malaria Control Programme, Khartoum, Sudan;dMalaria Programme, World Health Organization, 1202 Geneva, Switzerland;eDepartment of Disease Control, London School of Hygiene and Tropical Medicine (LSHTM), London WC1E 7HT, United Kingdom;fKilimanjaro Christian Medical University College, Moshi, Tanzania;gDepartment of Information, Ministry of Health, Khartoum, Sudan;hMalaria Research and Training Centre, Sennar, Sudan;iState Malaria Control Programme, Gedarif, Sudan;jDepartment of Infectious Disease Epidemiology, LSHTM, London WC1E 7HT, United Kingdom;kDepartment of Vector Biology, Liverpool School of Tropical Medicine, Liverpool L35QA, United Kingdom;lMinistry of Health, Khartoum, Sudan;mCenter for Applied Malaria Research and Evaluation, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112;nWellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, United Kingdom;oSchool of Pathology, University of Witwatersrand, Braamfontein 2000, Johannesburg, South Africa2To whom correspondence may be addressed. Email: janet.hemingway@lstmed.ac.uk, martin.donnelly@lstmed.ac.uk, or Immo.Kleinschidmt@LSHTM.ac.uk.Contributed by Janet Hemingway, October 2, 2017 (sent for review November 12, 2016; reviewed by Christen Fornadel and Kimberly Lindblade)Author contributions: A.P.M., J.L., J.H., T.B.K., M.J.D., and I.K. designed research; H.T.K., B.A.I., M.S.E.A., J.S.E., A.O.B., B.T., K.S., E.M.M., and M.J.D. performed research; H.T.K., M.S.E.A., J.S.E., B.T., K.S., and M.J.D. contributed new reagents/analytic tools; P.W., J.B., J.C., E.M.M., J.O.Y., and I.K. analyzed data; and J.H., M.J.D., and I.K. wrote the paper.Reviewers: C.F., United States Agency for International Development; and K.L., Centers for Disease Control.1H.T.K. and B.A.I. contributed equally to this work.26122017111220171112201711452E11267E11275Copyright © 2017 the Author(s). Published by PNAS.2017This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).SignificanceEmerging insecticide resistance in malaria vectors could presage a catastrophic rebound in malaria morbidity and mortality. In areas of moderate levels of resistance to pyrethroids, long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) with a carbamate insecticide were significantly more effective than IRS with pyrethroid insecticide. The impact on the effectiveness of LLINs could not be quantified. The incremental cost of using a carbamate insecticide to which vectors are susceptible was US $0.65 per person protected per year, which is considered acceptable by international standards. While the WHO recommends that different interventions, where possible, should use different insecticide classes, these data alone should not be used as the basis for a policy change in vector control interventions.Insecticide-based interventions have contributed to ∼78% of the reduction in the malaria burden in sub-Saharan Africa since 2000. Insecticide resistance in malaria vectors could presage a catastrophic rebound in disease incidence and mortality. A major impediment to the implementation of insecticide resistance management strategies is that evidence of the impact of resistance on malaria disease burden is limited. A cluster randomized trial was conducted in Sudan with pyrethroid-resistant and carbamate-susceptible malaria vectors. Clusters were randomly allocated to receive either long-lasting insecticidal nets (LLINs) alone or LLINs in combination with indoor residual spraying (IRS) with a pyrethroid (deltamethrin) insecticide in the first year and a carbamate (bendiocarb) insecticide in the two subsequent years. Malaria incidence was monitored for 3 y through active case detection in cohorts of children aged 1 to <10 y. When deltamethrin was used for IRS, incidence rates in the LLIN + IRS arm and the LLIN-only arm were similar, with the IRS providing no additional protection [incidence rate ratio (IRR) = 1.0 (95% confidence interval [CI]: 0.36–3.0; P = 0.96)]. When bendiocarb was used for IRS, there was some evidence of additional protection [interaction IRR = 0.55 (95% CI: 0.40–0.76; P < 0.001)]. In conclusion, pyrethroid resistance may have had an impact on pyrethroid-based IRS. The study was not designed to assess whether resistance had an impact on LLINs. These data alone should not be used as the basis for any policy change in vector control interventions.malariapyrethroidresistanceinsecticideAnophelesBill and Melinda Gates Foundation (Bill & Melinda Gates Foundation)10000086548499.01United Nations (UN)100004420GEF ID:2546To date, the 21st century has seen an unprecedented reduction in the global burden of malaria. While still unacceptably high, disease incidence in sub-Saharan Africa has decreased by 42% from an average of 427 cases per 1,000 persons at risk in 2,000 to 246 cases per 1,000 persons at risk in 2015; infection prevalence with Plasmodium falciparum in children aged 2–10 y has halved from 33 to 16% over the same period (1). This has resulted in an estimated 1.2 billion fewer malaria cases and 6.2 million fewer malaria deaths. Recent estimates show that the widespread deployment of insecticide-based interventions has been, overwhelmingly, the driver of the reduction in malaria in Africa (2). Of the 663 million clinical cases estimated to have been averted due to malaria control interventions since 2000, 78% were attributable to insecticide-treated nets or indoor residual spraying (IRS). These two interventions have been massively scaled up since 2000 (1).Emerging insecticide resistance in the anopheline malaria vectors could presage a catastrophic rebound in disease incidence. At present, there are only four insecticide classes available to malaria control programs; pyrethroids, organochlorines, carbamates, and organophosphates, with pyrethroids being the only class currently recommended by the WHO for use on long-lasting insecticidal nets (LLINs). Pyrethroids and the organochlorine dichlorodiphenyltrichloroethane (DDT) share the same target site, the voltage-gated sodium channel, while carbamates and organophosphates are acetylcholinesterase inhibitors. Resistance to pyrethroids is extensive throughout sub-Saharan Africa, while resistance to the three nonpyrethroid chemical classes used for IRS is simultaneously emerging in many regions (3–5). Resistance arises mainly from a combination of mutations within mosquitoes at the target site of the insecticide and enhanced detoxification/excretion of the insecticide.While conclusive evidence that resistance is directly impacting epidemiological indicators of malaria is scanty, by the time such data are available, it may well be too late. To address the problem, the WHO developed the Global Plan for Insecticide Resistance Management in malaria vectors (GPIRM), which was designed to forestall a disastrous increase in malaria burden (6). Unfortunately, most malarious countries have yet to amend their vector control strategies to align with the GPIRM despite widespread resistance to pyrethroids (7). While this is partially due to the absence of compelling data on the impact of insecticide resistance, it also reflects the lack of viable alternatives to LLINs and current insecticides.A five-country study was established to provide quantitative estimates of the impact of resistance on malaria burden (8). One study was conducted in Galabat, Sudan. In Sudan, almost the entire population lives in areas with low to moderate transmission. Malaria transmission is seasonal and unstable. Countrywide, the majority of the population (80%), including urban populations, live in areas with <1% P. falciparum infection risk in children aged 2–10 y, while the remaining 20% of the population, residing mainly in the south of the country, experience meso- to hyperendemic risk of infection (9). Reported malaria cases were reduced from an estimated 7.5 million in 1990 (10) to 1.2 million in 2014. P. falciparum accounts for 95% of the malaria burden (9, 10), with Anopheles arabiensis being the main malaria vector (11).In Sudan, artemisinin-based combination therapy has been used for malaria treatment since 2004, with artesunate plus sulfadoxine/pyrimethamine as first-line treatment, artemether/lumefantrine as second-line therapy, and quinine for the treatment of complicated malaria (10). Malaria diagnosis is based on microscopy and rapid diagnostic tests (RDTs) (10). Between 2013 and 2015, 13 million LLINs were distributed, resulting in overall coverage of 92% of households with one LLIN per two persons in 2015 according to Ministry of Health reports. Therefore, the emergence of insecticide resistance (12, 13) is a major concern as it could severely compromise the effectiveness of vector control in Sudan.Galabat, Gedarif State, was considered suitable for this study since malaria is highly seasonal and more intense there than in many other parts of Sudan, and it had no previous history of IRS. Human settlements also facilitate the formation of well-separated clusters. Twenty-six villages were selected as study clusters and received universal coverage of LLINs. Thirteen of these clusters were randomly selected to receive IRS in addition to LLINs. In 2012, deltamethrin was used for IRS, which was replaced by bendiocarb in 2013 and 2014. The protective effect of bendiocarb, to which there was no resistance, could therefore be compared with the effect of deltamethrin, to which there was insecticide resistance, with the LLIN-only clusters acting as controls. For ethical reasons, it was not feasible to assess the impact of insecticide resistance on the overall effectiveness of LLINs since this would require a neutral arm with no vector control.This study aimed to quantify:i)The impact of switching to a nonpyrethroid IRS insecticide on the incidence and prevalence of malaria infection in an area of moderate pyrethroid resistanceii)The impact of phenotypic and genotypic insecticide resistance on the incidence and prevalence of malaria infectioniii)The impact of the addition of nonpyrethroid IRS insecticide on the evolution of pyrethroid resistance in an area of universal LLIN coverageiv)The cost of using nonpyrethoid IRS in addition to LLIN coverage to mitigate the negative consequences of pyrethroid resistance on the incidence of malaria infectionResultsIntervention Coverage.Following a census to determine the number of households and population size of the study area, 72,714 LLINs (PermaNet 2.0; Vestergaard) were distributed in the 26 clusters in April 2011 to protect 139,566 individuals based upon a universal coverage approach of one net for two people. Nets were replaced in June 2014 with 72,098 new LLINs for 122,647 people. An annual intervention assessment survey showed that household net ownership was 99.6% in 2012, 82.1% in 2013, and 98.6% in 2014. LLIN usage, defined as the proportion of affirmative responses to the question “Did this child sleep under an LLIN last night?”, was generally high and very similar in study arms (Table 1), but varied by season throughout the year (data not tabulated). IRS was conducted in August and again in late December of each year. In 2012, both spray rounds utilized deltamethrin (25 mg of active ingredient per square meter; Chema Industries), while in 2013 and 2014, bendiocarb (Ficam 80% WP; Bayer; 200 mg of active ingredient per square meter) was sprayed. IRS spray coverage was 99%, 82%, and 83% in the years 2012, 2013, and 2014, respectively, as determined by annual cross-sectional surveys. The IRS coverage reported in the LLIN arm is from the householder questionnaires. It is possible that this was from private spraying, but more likely that it represents householder misreporting.Table 1.LLIN usage, IRS coverage, insecticide resistance, prevalence of infection, and malaria incidence in cohort children by study arm and study yearLLIN-only armLLIN + IRS armVariable201220132014201220132014LLIN usage, % (child nights)79 (73,375)74 (75,040)82 (78,918)79 (73,738)75 (74,612)82 (78,888)IRS coverage, % (N)9 [1–45] (1,320)1 [0–2] (1,954)4 [1–27] (2,195)99 [96–100] (1,314)82 [75–87] (1,816)83 [68–91] (2,032)Mean age, y5.1 [4.9–5.4]5.4 [5.2–5.5]6.2 [6.1–6.3]5.2 [5.0–5.4]5.5 [5.4–5.7]6.3 [6.1–6.4]Malaria cases117155981268265Malaria incidence*45 [24–87]52 [26–101]33 [14–78]47 [20–110]27 [15–50]21 [10–43]Prevalence of infection, % (N)7 [3–14] (1,272)5 [2–10] (1,791)5 [3–9] (1,961)10 [6–16] (1,246)4 [2–7] (1,654)3 [2–5] (1,880)Deltamethrin mortality (clusters), % (references)65 [49–81] (6)90 [85–95] (6)56 [48–64] (11)60 [44–76] (5)84 [71–96] (6)68 [61–75] (13)95% CIs are shown in brackets.*Cases per 1,000 child-years.During the 3-y period from June 1, 2012–May 31, 2015, there were 643 episodes of malaria in 7,529 cohort children who were followed up cumulatively for 17,284 person-years. The mean age of cohort children was similar in the two study arms in each year, but rose gradually from 5.2 y in the first study year to 6.25 y in the third year (Table 1).Incidence of Malaria and Prevalence of Malaria Infection by Study Arm and by IRS Insecticide.Mean overall incidence was 37.2 per 1,000 person-years [95% confidence interval (CI): 24.3–56.9], declining from 49.9 per 1,000 person-years in year 1, to 36.1 per 1,000 person-years in year 2, to 26.8 per 1,000 person-years in year 3.Mean incidence in the LLIN + IRS study arm was 47.2 per 1,000 person-years when deltamethrin was used (2012), but was almost halved to an average of 24.6 per 1,000 person-years during the 2 y when bendiocarb was used (2013 and 2014) (Table 2). Over the same period in the LLIN-only arm, incidence remained virtually unchanged, from 44.4 per 1,000 person-years in year 1 to 42.1 per 1,000 person-years in years 2–3. Comparing incidence between study arms, the incidence rate ratio (IRR) for LLIN + deltamethrin compared with LLIN alone (2012) was 1.0 (95% CI: 0.36–2.97; P = 0.96); for LLIN + bendiocarb versus LLINs alone (2013), it was 0.60 (95% CI: 0.39–0.91; P = 0.017), while for 2014 (LLIN + bendiocarb versus LLIN), it was 0.69 (95% CI: 0.31–1.50; P = 0.35). For the two bendiocarb years combined, the IRR for IRS + LLIN versus. LLIN alone was 0.65 (95% CI: 0.44–0.96; P = 0.032). There was strong evidence that the change in insecticide modified the effect of IRS + LLIN versus LLIN alone: The IRR for comparing the effect of IRS + LLIN in 2013 and 2014 (bendiocarb) versus LLIN alone with the effect of IRS + LLIN in 2012 (deltamethrin) versus LLIN alone was 0.51 (95% CI: 0.35–0.73; P < 0.001) and 0.62 (95% CI: 0.42–0.93; P = 0.020), respectively (overall interaction P = 0.001; Table 2). The interaction IRR comparing the effect of IRS + LLIN in 2013–2014 combined (bendiocarb) versus LLIN alone with the effect of IRS + LLIN in 2012 (deltamethrin) versus LLIN alone was 0.55 (95% CI: 0.40–0.76; P < 0.001).Table 2.Effect of year, study arm, and IRS insecticide on malaria incidence, Galabat, Sudan, 2012–2014Effects by individual study yearsEffects comparing 2013/2014 (bendiocarb) with 2012 (deltamethrin)YearStudy armCasesMean incidence (range)Unadjusted rate ratio (95% CI)Adjusted rate ratio* (95% CI)†Bendiocarb effect‡PeriodStudy armMean incidenceAdjusted rate ratio* (95% CI)‡Bendiocarb effect‡2012LLIN11745 (24–87)1112012LLIN45 (4–87)1LLIN + Delta12647 (20–110)1.0 (0.36–2.95); P = 0.961.0 (0.36–2.97); P = 0.96LLIN + Delta47 (20–110)1.0 (0.36–2.97); P = 0.9612013LLIN15552 (26–101)110.51 (0.35–0.73); P < 0.0012013/2014LLIN42 (21–85)1LLIN + Bend8227 (15–50)0.53 (0.21–1.32); P = 0.170.60 (0.39–0.91); P = 0.0172014LLIN9833 (14–78)110.62 (0.42–0.93); P = 0.020LLIN + Bend25 (13–47)0.65 (0.44–0.96); P = 0.0320.55 (0.40–0.76); P < 0.001LLIN + Bend6521 (10–43)0.62 (0.20–1.95); P = 0.420.69 (0.31–1.50); P = 0.347*Adjusted for age at time of visit and, for 2013 and 2014, the rate in 2012.†Test to determine if the effect of IRS was different between years (P = 0.001).‡Test comparing the effect of bendiocarb IRS and deltamethrin IRS (P < 0.001).In a sensitivity analysis to test the robustness of the results to the possibility of undue influence exerted by participants who had multiple episodes of malaria, follow-up was restricted to the 550 first episodes observed (i.e., censoring follow-up after the first positive test result). This analysis produced very similar findings to those obtained from the full dataset (results not tabulated).In the three cross-sectional prevalence surveys that were conducted from September to October of each of the three study years, 2,518, 3,445, and 3,841 children were tested by RDTs, of whom 214 (8.5%), 146 (4.2%), and 162 (4.2%) tested positive in 2012, 2013, and 2014, respectively. Analogous results were recorded to those comparing malaria incidence (Table 3). In the IRS + LLIN study arm, mean prevalence of infection fell from 10.4% when deltamethrin was used for IRS (2012) to 3.4% when bendiocarb was used (years 2013/2014) (P = 0.002). Over the same period, mean prevalence in the LLIN-only arm declined more moderately and nonsignificantly from 6.7 to 5.0% (P = 0.41). Comparing prevalence between study arms, the odds ratio (OR) for LLIN + deltamethrin versus LLIN alone in 2012 was 2.11 (95% CI: 0.36–2.97; P = 0.96); for LLIN + bendiocarb versus LLINs alone (2013), it was 1.39 (95% CI: 0.32–6.14; P = 0.66), while for 2014, it was 0.37 (95% CI: 0.18–0.77; P = 0.007). For the two bendiocarb years combined, the OR for LLIN + IRS versus LLIN alone was 0.61 (95% CI: 0.29–1.27; P = 0.19). There was strong evidence that the change in insecticide modified the effect of IRS with an overall interaction of P = 0.001 for interaction tests applied to individual years (left-hand side of Table 3) and P < 0.001 for interaction tests applied to 2012 versus 2013/2014 combined (right-hand side of Table 3). The interaction OR for comparing the effect of IRS + LLIN in 2013 and 2014 (bendiocarb years) versus LLIN alone with the effect of IRS + LLIN in 2012 (deltamethrin) with LLIN alone was 0.55 (95% CI: 0.35–0.87; P = 0.01) and 0.30 (95% CI: 0.19–0.47; P < 0.001), respectively. The interaction OR comparing the effect of IRS + LLIN in 2013–2014 combined (versus LLIN alone) with the effect of IRS + LLIN in 2012 (deltamethrin) (versus LLIN alone) was 0.40 (95% CI: 0.27–0.59; P < 0.001).Table 3.Effect of year, study arm, and IRS insecticide on malaria prevalence, Galabat, Sudan, 2012–2014Effects by individual study yearsEffects comparing 2013/2014 (bendiocarb) with 2012 (deltamethrin)YearStudy armPrevalence, % (N)Unadjusted ORAdjusted OR*Bendiocarb effect†PeriodStudy armMean prevalence, %Adjusted OR*Bendiocarb effect‡2012LLIN7 [3–14] (1,272)112012 DeltaLLIN7 [3–14] (1,272)1LLIN + IRS10 [6–16] (1,246)1.61 [0.60–4.35]; P = 0.332.11 [0.85–5.22]; P = 0.11LLIN + IRS10 [6–16] (1,246)2.11 [0.85–5.22]; P = 0.1112013LLIN5 [2–10] (1,791]112013–2014 BendiocarbLLIN5 [2.8–8.6] (3,752)1LLIN + IRS4 [2–7] (1,654)0.86 [0.31–2.42]; P = 0.771.39 [0.32–6.14]; P = 0.660.55 [0.35–0.87]; P = 0.012014LLIN5 [3–9] (1,961)11LLIN +I RS3.4 [2.1–5.4] (3,534)0.61 [0.29–1.27]; P = 0.190.40 [0.27–0.59]; P < 0.001LLIN + IRS3 [2–5] (1,880)0.54 [0.26–1.13]; P = 0.0980.37 [0.18–0.77]; P = 0.0070.30 [0.19–0.47]; P < 0.00195% CIs are shown in brackets. Delta, deltamethrin.*Adjusted for age, study arm, and study period.†Overall likelihood ratio test, P < 0.0001 (test to determine if effect of IRS was different between years).‡Overall likelihood ratio test, P < 0.0001 (test comparing the effect of bendiocarb IRS and deltamethrin IRS).Association Between Resistance and Incidence and Prevalence of Malaria Infection.During the course of the study, 4,680 female An. arabiensis mosquitoes were phenotyped for deltamethrin susceptibility using WHO discriminating dose tests (14), with evidence of resistance to deltamethrin in both study arms (Fig. 1). The mean percentage mortality in the LLIN arm (65.0%, 95% CI: 44.6–85.3) was not significantly different (t = 0.425; df, 9; P = 0.68) from that of the LLIN + IRS arm (60%, 95% CI: 38.2–82.2) during year 1. The assay for the Vgsc-1014F mutation was successfully conducted in 1,847 of 1,872 specimens (Fig. 1). There was a subsequent decrease in allelic frequency (two-way ANOVA, P < 0.001), but no evidence of an association between allelic frequency and the study arm (two-way ANOVA, P > 0.05; Fig. 1). There was no evidence of nonnormality of the mortality or the allele frequency data.Fig. 1.Change in deltamethrin mortality (Upper) and Vgsc-1014F (Lower) across study years and between single (LLIN) and dual (LLIN + IRS) intervention arms. Box whisker plots show the median (bold line) and interquartile range (boxes). Phenotypic data were available from six LLIN and five LLIN + IRS clusters in 2012, six LLIN and six LLIN + IRS clusters in 2013, and 11 LLIN and 13 LLIN + IRS clusters in 2014. Genotypic data were available for all 26 clusters for all years. In 2014, there was significantly (P = 0.038) higher mortality (less resistance) in the LLIN + IRS arm (n = 13; mortality = 68%; 95% CI: 60.0–76.0) compared with the LLIN-only arm (n = 11; mortality = 56.1%; 95% CI: 47.1–64.9).The association between cluster- and year-specific bioassay survivorship (phenotypic resistance) and cluster- and year-specific malaria incidence in cohort children was assessed using multiple variable Poisson regression models, adjusting for study arm and study year. Unadjusted and adjusted IRRs show no association between malaria incidence in cohort children and deltamethrin bioassay survivorship in mosquitoes from corresponding clusters (Fig. 2 and Table 4). To estimate any effect that resistance in a particular year and a particular cluster may have had on the prevalence of infection as determined by annual cross-sectional surveys, logistic regression was carried out, again adjusting for study arm and study year. Unadjusted and adjusted ORs showed no evidence of any association between resistance as measured through bioassay survivorship and infection prevalence (Table 3).Fig. 2.Cluster-specific malaria case incidence and cluster-specific malaria infection prevalence plotted against cluster-specific phenotypic resistance (bioassay mortality after standard exposure to deltamethrin) and against cluster-specific Vgsc-1014F allele frequency for 2012, 2013, and 2014 in Galabat, Sudan.Table 4.Association between malaria prevalence and malaria incidence with genotypic and phenotypic resistance, respectively, from 2012–2014Resistance statusUnadjusted OR/ rate ratio (95% CI)Adjusted OR/rate ratio* (95% CI)Malaria prevalence\u2003L1014F linear, per 1% mutation1.009 (0.99–1.03); P = 0.350.992 (0.97–1.02); P = 0.51\u2003Deltamethrin linear, per 1% survivorship0.999 (0.970–1.029); P = 0.911.007 (0.98–1.04); P = 0.67Malaria incidence\u2003L1014F linear, per 1% mutation1.462 (0.411–5.196); P = 0.560.415 (0.065–2.665); P = 0.35\u2003Deltamethrin linear, per 1% survivorship0.995 (0.959–1.032); P = 0.780.991 (0.947–1.037); P = 0.70*Adjusted for variations in year and study arm. Note that for phenotype data, there is interyear variation in the number of clusters.Similar analysis was carried out to investigate whether malaria incidence and infection prevalence were associated with Vgsc-1014F frequency, measured in mosquito specimens collected in corresponding clusters and years. There was no evidence of any association between malaria incidence or infection prevalence on the one hand and Vgsc-1014F frequency on the other (Fig. 2 and Table 4).Subgroup analysis was carried out restricted to the combined data from the LLIN-only arm for all 3 y and to the LLIN + IRS arm for the year in which deltamethrin was sprayed. There was again no association between malaria incidence and Vgsc-1014F frequency (P = 0.59), between infection prevalence and Vgsc-1014F frequency (P = 0.39), between malaria incidence and bioassay survivorship (P = 0.85), and between infection prevalence and bioassay survivorship (P = 0.98).Association Between the Addition of Nonpyrethroid IRS Insecticide and the Evolution of Insecticide Resistance to Pyrethroids in an Area of Universal LLIN Coverage.It was only possible to conduct resistance phenotyping in 11 and 12 clusters in 2012 and 2013, respectively; this figure rose to 24 in 2014. In 2012 as well as in 2013 (the first year of bendiocarb spraying), there was no significant difference in mosquito deltamethrin susceptibility between intervention arms. However, in 2014, there was significantly higher mortality (less resistance) in the LLIN + IRS arm (n = 13; mortality = 68%; 95% CI: 60–76) compared with the LLIN arm (n = 11; mortality = 56%; 95% CI: 47–65) (P = 0.038) (Fig. 1). In all clusters across all years, An. arabiensis populations were susceptible to bendiocarb.Cost and Cost-Effectiveness.The cost of protection with LLIN only in Galabat was estimated to be US $2.16 per person-year, while the cost of protection per person-year with LLIN + IRS (deltamethrin) was estimated to be US $4.36. The cost per person-year of protection with LLIN + IRS (bendiocarb) was estimated to be US $5.01. These cost estimates translate into an incremental cost of switching from IRS with deltamethrin to IRS with bendiocarb in this study of US $0.65 per person-year. With the year 1 incidence of 49.9 episodes per 1,000 person-years, this translates to an incremental cost per case averted of US $29. Assuming a case fatality rate for malaria of 0.005, the incremental cost per death averted was approximately US $6,400 and an incremental cost per disability adjusted life year (DALY) averted of US $195. These results are well within accepted standards for highly cost-effective interventions for Sudan established by the WHO (15). Sensitivity analysis indicated that changes to discount rate, prices of LLINs, or allocation of shared costs did not affect the incremental costs of the insecticide switch and that reduction of the cost of bendiocarb to the cost of deltamethrin would have resulted in nearly identical costs per person protected, indicating that there were only minor differences in delivery costs for the intervention with bendiocarb. Sudan is an area with low malaria incidence, and it is likely that in other areas with a higher incidence and more severe pyrethroid resistance, such a switch is likely to be associated with even greater cost-effectiveness.DiscussionAssociation Between Malaria Incidence/Prevalence and Switching Active Ingredients.Malaria incidence was similar and malaria prevalence was higher in the study arm in which deltamethrin IRS was sprayed in addition to LLIN use, compared with LLINs alone. The higher prevalence in the LLIN + IRS arm was likely to be the result of an imperfect balance in the two study arms. In the following 2 y when IRS with bendiocarb replaced deltamethrin, there was a significant reduction in the LLIN + IRS arm compared with the year in which deltamethrin was used, while incidence and prevalence remained stable in the clusters that only had LLINs. Compared with the LLIN-only arm, incidence was significantly lower in the IRS + LLIN arm in the 2 y in which bendiocarb was used [IRR = 0.65 (95% CI: 0.44–0.96; P = 0.032)], and this effect differed significantly from the effect of IRS + LLIN with deltamethrin [interaction IRR = 0.55 (95% CI: 0.40–0.76; P < 0.001)]. Prevalence of infection was only lower in the IRS + LLIN arm compared with the LLIN-only arm of the study in 2014; however, again, there was very strong evidence that bendiocarb significantly modified the effect of IRS when comparing the OR between study arms during the years in which bendiocarb was used with the OR between study arms when deltamethrin was used [interaction OR = 0.40 (95% CI: 0.27–0.59; P < 0.001)]. Deltamethrin has been shown to be effective when used for IRS in a variety of settings (16–19). While we cannot completely discount differential longevity of the deltamethrin and bendiocarb IRS formulations used in Sudan, the expectation from previous studies is that the deltamethrin formulation would have a marginally longer residual life than the bendiocarb formulation. We conclude that the presence of pyrethroid resistance is a plausible explanation for the loss of effectiveness of deltamethrin IRS, resulting in substantially suboptimal malaria control. To date, there are few studies assessing the impact of insecticide resistance as the design of such studies is problematic because (i) the exposure of interest, resistance to an insecticide in the local vector, cannot be randomly allocated and (ii) it is unethical to knowingly protect a human population with IRS using an insecticide that is unlikely to be effective if alternatives are available. Evidence of the impact of insecticide resistance on IRS has thus far always been generated by retrospective studies (20, 21). Our data, when considered with two retrospective studies from South Africa and Uganda, where the primary vectors were Anopheles funestus and Anopheles gambiae, respectively, provide further evidence that pyrethroid resistance is highly likely to be compromising the effectiveness of IRS.The impact of resistance in KwaZulu-Natal, South Africa, was more marked than that observed in the current study, with a near 10-fold increase in annual malaria cases witnessed from 1995 to 2000 following a switch from DDT to deltamethrin (21). Insecticide susceptibility tests later showed that there was resistance to pyrethroids in An. funestus, a vector that had previously been driven to near extinction in KwaZulu-Natal but that resurged following the change to pyrethroid IRS (22). Subsequent reversion back to IRS with DDT in 2000 was followed by a rapid decline in cases that was maintained in subsequent years (23). In a study by Kigozi et al. (20) in Uganda, routinely collected malaria health facility data were compared temporally in relation to the insecticide used in IRS: five rounds of IRS spraying DDT (n = 1), pyrethroid (n = 1), or bendiocarb (n = 3). There was known resistance to both pyrethroids and DDT, but not to bendiocarb, in the area. Small decreases in the odds of malaria infection were observed following both DDT and pyrethroid spraying, with the decrease in malaria infection being much greater following the bendiocarb spray round.The strength of the study described here was the ability to compare the change in incidence in the IRS clusters with changes in incidence in 13 contemporaneous control group clusters, which had been randomly selected and which were similar in most respects to the intervention group. The reduction in both malaria incidence and prevalence after the introduction of the carbamate insecticide may therefore be attributable to this change in insecticide. Since IRS with deltamethrin and IRS with bendiocarb are effective insecticides in settings with susceptible vectors (17, 18, 24, 25), the lack of impact of the deltamethrin IRS may be due to the presence of deltamethrin resistance in the study area. As would be expected from earlier studies (26, 27), despite resistance, some protection against malaria was provided in both study arms by high coverage with LLINs.The IRS with bendiocarb in this study provided very similar protection in addition to LLINs to that estimated in a recent cluster randomized trial in Tanzania (28). This study serves as reminder of the potential consequences of using failing insecticides, particularly if no other preventive measures are in place, and the need for insecticide policy to be informed by appropriate susceptibility testing (6).Association Between Resistance and Malaria Incidence/Infection Prevalence.There was no evidence of an association between malaria rates and insecticide resistance measured phenotypically or genotypically for target-site resistance (as Vgsc-1014F frequency). An association between malaria burden and pyrethroid insecticide resistance was expected in clusters with pyrethroid-treated LLINs only or in clusters receiving LLINs and IRS with pyrethroid. The study lacked power to detect such an association due to a number of factors: (i) the range in pyrethroid resistance in the study area may have been too small; (ii) the effect of insecticide resistance on the effectiveness of LLINs may be relatively modest in settings of moderate pyrethroid resistance; (iii) bioassay data were not available in all clusters in each study year; and (iv) bioassay survivorship is an imprecise measure of the strength of resistance (29), despite its wide use for detecting the presence of resistance in a mosquito population. Our analysis of malaria incidence and prevalence in relation to insecticide resistance relied on detecting a dose–response association between the two variables; if the latter is inadequately quantified through bioassay survivorship or Vgsc-1014F frequency, then such a trend is unlikely to be significant.Previous studies have shown that insecticide-treated nets still provide protection against malaria infection even in settings of vector resistance to pyrethroids. A meta-analysis using entomological data (26) concluded that insecticide treated nets are a more effective form of vector control than untreated nets despite insecticide resistance. A study in Malawi found that children sleeping under LLINs suffered significantly fewer malaria episodes than their counterparts who did not sleep under nets in an area where the predominant malaria vector species, An. funestus and An. arabiensis, showed moderate to high levels of pyrethroid resistance (27).Cost and Cost-Effectiveness.The current study also demonstrated the relative cost-effectiveness of switching active ingredients to mitigate the potential effects of insecticide resistance on malaria incidence. It is, to date, the only study of which we are aware that does so using direct field evidence. Even in a relatively low transmission area, such as Galabat, a switch to the marginally more expensive bendiocarb insecticide is justified.Insecticide Combination and the Evolution of Resistance.A positive finding was modest evidence of retardation in the speed of evolution of insecticide resistance when two active ingredients with differing modes of actions were used in the LLIN + IRS arm. This is important for malaria control program managers as they struggle to develop plans for the monitoring and management of insecticide resistance in line with WHO GPIRM recommendations (6). Curiously, across our study site, there was a significant decrease in the Vgsc-1014F resistance marker frequency. While there are a number of instances of kdr markers sweeping rapidly to fixation (30–32), the obverse trend shown here has not been reported elsewhere. There are numerous studies showing that in An. arabiensis, Vgsc-1014F is a strong predictor of pyrethroid resistance (33), so this may suggest a decline in its importance in conferring a resistant phenotype due to the emergence of additional resistance mechanism(s).Limitations.For ethical reasons, it was not possible to conduct a trial with a neutral control arm; therefore, the effectiveness of the IRS alone could not be directly assessed. A trial randomizing clusters to the two insecticides would have provided a more direct contemporaneous comparison of deltamethrin to bendiocarb. Instead, the opportunity of comparing each insecticide against the same LLIN-alone control arm arose when insecticide needed to be switched due to the presence of pyrethroid resistance in the area. This design lacks the strength of evidence provided by a direct comparison; however, this shortcoming was compensated for, at least in part, by the contemporaneous comparison with the randomly selected LLIN-only clusters to control for temporal change in malaria transmission. The evidence of a change in the effect of IRS coinciding with the switch to bendiocarb was statistically very strong.ConclusionIn summary this trial has shown the following: (i) loss of effectiveness of pyrethroid IRS is likely to be associated with pyrethroid resistance in malaria vectors; (ii) IRS effectiveness can be restored by switching to an insecticide to which vectors are fully susceptible for an incremental cost that is considered attractive by international standards; and (iii) modest retardation to the speed of pyrethroid resistance development may be achieved with appropriate combinations of LLINs and nonpyrethroid IRS, compared with using LLINs alone.Materials and MethodsStudy Site.Galabat is located ∼80 km from Gedarif town and borders Ethiopia. A baseline household census estimated that the area comprised ∼119,000 households in 197 villages with a total of 600,000 inhabitants who are predominantly dependent on rain-fed agriculture. Climatically, the area is within the dry savannah region, with annual rainfall ranging between 700 mm and 1,200 mm and concentrated in a short rainy season from June to September. Average daily temperatures range between 31 °C and 44 °C (34). Malaria transmission is seasonal from September to November, with P. falciparum prevalence between 1% and 10% in 2- to 10-y-old children (9). An. arabiensis is the main vector of malaria in the area, with An. funestus implicated as having a minor role in malaria transmission (34). Before this study, LLINs were the only form of vector control in Galabat.Treatment for malaria in the area is provided by 101 public sector health facilities, including 7 referral hospitals, 24 health centers, 70 health units, and 20 villages with home-based management of malaria. Diagnosis of suspected cases is based on RDTs at the majority of health and home-based management facilities, while microscopy is used at 20 facilities in the area.Study Design.The Galabat study is loosely linked to a larger multicountry study on the implications of insecticide resistance that has been described previously (8). The opportunity to compare the two insecticides arose when deltamethrin IRS had to be replaced with bendiocarb IRS. The original objective of the Galabat trial was to investigate whether IRS in combination with LLINs provided additional protection against malaria compared with LLINs alone. With 13 clusters per arm and 200 children per cluster followed up for 3 y, the trial had 80% power to observe a 38% reduction in malaria incidence or more in the LLIN + IRS arm compared with the LLIN-only arm, assuming a mean incidence of 30 per 1,000 person-years and a coefficient of variation of 0.3 between study clusters. Twenty-six villages were selected from a total of 197 to form clusters, each consisting of at least 500 households, and with the distance between the edges of adjoining clusters being at least 3 km (Fig. 3). In 2010, a baseline malaria indicator survey testing for P. falciparum infection using malaria RDTs (SD BIOLINE-Malaria Ag P.f/P.v.; Standard Diagnostics, Inc.) was carried out on a sample of 100 children <10 y of age in each of the 26 clusters. At the same time, pyrethrum spray catches were made in houses, from which a sample of 24 An. arabiensis mosquitoes from each cluster was screened for the pyrethroid resistance-associated mutations in the voltage-gated sodium channels Vgsc-1014F and Vgsc-1014S using established molecular diagnostic techniques (33).Fig. 3.Map of the study area in Galabat, southeastern Sudan. Triangles denote clusters with LLIN only, and circles denote clusters with LLIN + IRS.LLINs with a deltamethrin concentration of 55 mg of active ingredient per square meter (PermaNet 2.0) were distributed in April 2011 in all 26 study clusters to reach levels required for universal coverage, defined as one net for every two people. The LLINs were replaced with new nets of the same type in all clusters in June 2014. In 2012, clusters were randomly allocated to two study arms using restricted randomization (35, 36) to ensure that the two study arms were balanced on a number of criteria, including baseline frequency of the Vgsc-1014F mutation, baseline prevalence of infection, baseline use of LLINs, and access to health facilities. One study arm (n = 13 clusters) retained universal coverage of LLINs only, while the second arm (n = 13 clusters) received two rounds of IRS in addition to LLINs. The first round of IRS was in August of each year to cover the main transmission season (September to November), with the second round in late December. In 2012, deltamethrin insecticide (Wettable Powder 25%) was used in both IRS rounds; in 2013 and 2014, bendiocarb (Ficam WP 80%) was sprayed. Bendiocarb, a carbamate, is an acetylcholinesterase antagonist, as opposed to deltamethrin, which targets the mosquito Vgsc. While LLINs target mosquitoes that are seeking a blood meal, IRS targets mosquitoes that rest indoors either before or after blood-feeding. Quality assurance of both IRS and LLIN interventions was conducted following WHO guidelines (14) using a susceptible laboratory strain of An. arabiensis raised in the insectaries of the Sennar Malaria Research and Training Centre.Insecticide Resistance.Over the course of the study, two estimates of insecticide resistance were made yearly in each cluster: One, termed phenotypic resistance, was reliant upon collecting live mosquitoes and ascertaining their susceptibility to standard dosages of deltamethrin and bendiocarb; the other, termed genotypic resistance, involved screening for Vgsc-1014F (reviewed in ref. 33). Anopheles larvae and pupae were collected annually (2012–2014) during the rainy season. All larvae and pupae were reared to adults in a field insectary until used for insecticide susceptibility tests. Pyrethrum spray catches were also performed to collect adult Anopheles mosquitoes. Phenotypic assays for deltamethrin and bendiocarb were performed following the standard WHO discriminating dose tests (14, 37). All susceptibility tests were conducted under laboratory conditions at temperatures ranging from 24.8 to 27.1 °C and relative humidity ranging from 75.4 to 79.8%.An. gambiae complex species, the main vector, were identified to species status, with An. arabiensis the only species observed, using a standard PCR assay (38). Twenty-four An. arabiensis females per cluster were selected at random for Vgsc-1014F genotyping to estimate a cluster-specific resistance marker frequency (39).Active Case Detection.In each cluster, a community health worker (CHW) was appointed, and ∼200 children aged between 6 mo and <10 y were recruited into cohorts after explaining the study procedures to caregivers and after obtaining written informed consent. Older children were asked to assent to recruitment. CHWs visited cohort members weekly during the peak of the malaria season (September to November) and fortnightly during the remainder of the year, for a total of 30 annual visits. Cohort children who were reported to be febrile at the time of a visit had their temperature taken. Children who had a confirmed fever at the time of the visit, or a reported fever during the period since the last visit, were referred to the local health facility to be tested for malaria parasites, or were tested by the CHW using an RDT when no local facility was available. Local health facilities used either RDTs or microscopy to test for malaria parasites. If caregivers, upon questioning, reported that a child had visited the health facility for a febrile illness during the period since the last visit, the CHW visited the health facility to determine if the child had a blood test that confirmed a diagnosis of malaria. Each visit by a CHW and each clinic attendance resulting in a definitive diagnosis of malaria were recorded in the cohort register, which was collected at regular intervals for entry into an MS Access database at a central location. A study coordinator carried out regular supervisory visits to CHWs to verify the quality of data collection. Upon reaching the age of 10 y, cohort children were replaced by younger children from the same household or from another household if no younger sibling was available.Prevalence of Infection.Once each year, during September to October, cohort children were tested for P. falciparum infection using RDTs (SD BIOLINE-Malaria Ag P.f/P.v.), irrespective of symptoms. A random sample of 50% of cohort members was selected in 2012, while all cohort children who were present at the time of the survey were screened in 2013 and 2014. Any child who tested positive was referred to the local health facility for treatment.Statistical Analysis.Malaria case incidence was estimated as the number of cases per child-year of follow-up. IRRs were calculated comparing incidence between study arms for each study year, and for the 2 y combined during which bendiocarb IRS was used. Effect modification (interaction) between study arm and study year was investigated to determine the differential effect of IRS + LLINs with bendiocarb compared with IRS + LLINs with deltamethrin versus LLINs alone. Multiple variable Poisson regression was used to adjust the effect of study arm for age of child at time of visit and, for 2013 and 2014, for incidence rate in 2012. To assess whether malaria incidence was associated with insecticide resistance, IRRs were calculated per 1% change in cluster-specific vector susceptibility (mosquito mortality) and per 1% change in cluster specific Vgsc-1014F allele frequency. For this analysis, year and cluster-specific insecticide resistance measurements were linked to year and cluster-specific incidence.For cross-sectional prevalence of infection data, analogous analyses were carried out using logistic regression to estimate ORs.Multiple episodes of malaria in the same child were rare; any consecutive positive test results were counted as one episode since the second positive test result could be either a false-positive result from RDTs that measure parasite protein retained from an already cleared infection or the result of a treatment failure. To test the robustness of these results against the possibility of undue influence exerted by participants who had multiple episodes of malaria, the analysis was repeated but restricted to the 550 first-time episodes that were observed in the same cohort over the same period ( i.e., excluding children from further follow-up after their first positive test result). To calculate appropriate SEs of estimated means, a robust variance estimator using the first-order Taylor-series linearization method was used to account for variation between clusters (40, 41). Poisson regression and logistic regression were performed using random effects models.To compare the differences in mean mortalities and Vgsc-1014F allele frequencies between the two intervention arms, t tests were used, while ANOVA was used to compare the differences between years. The Shapiro–Wilks test was used to assess whether mortality and allele frequency data deviated from the normal distribution.Cost Data Collection Tools and Indicators.A microcosting (ingredients approach) activities-based framework was applied to the development of cost-collection tools. Key-informant interviews and record reviews were conducted to identify all of the activities and resources needed that were expected to be utilized during the course of the trial. Care was taken to exclude activities that were specifically related to research and not necessary for the provision or performance of the intervention; these included enhanced case finding and enhanced vector surveillance beyond what was necessary for routine use of IRS or LLINs. A standardized instrument for the collection of resource quantities and prices was developed for use at the national (central), state, and locality levels. The instrument was employed by staff of the Federal Ministry of Health Integrated Vector Management Unit to collect information on resource usage at each level of the health system.Analysis of Cost Data.Resource use was quantified and valued in Sudanese pounds (SDG) in the year during which the resource use occurred. Costs were converted to US dollars using the prevailing average exchange rate for the period. All costs were valued in 2011 US dollars, after adjusting for inflation using the consumer price index for Sudan. Prices derived from the WHO-CHOICE (choosing interventions that are cost effective) database (15) were converted from international dollars using a purchasing power parity (PPP)-to-local currency ratio (1 international dollar to 1.28 SDG) for 2009.In all cases, economic costs are presented, which are also known as opportunity costs. Economic costs represent the value of a given resource in its next most appropriate use. As such, capital costs, including vehicles, buildings, LLINs, and spray equipment, were annualized and discounted using assumed lifetimes and a social discount rate of 3%.Cost Outcomes Sensitivity Analysis.Two types of outcome were measured: a process measure, numbers of persons living in clusters with vector control per year (or person-years of protection), and the effectiveness of the interventions in terms of incident cases of malaria prevented.Because most cost models and assessments are dependent on assumptions about quantities of resources used, prices of resources, and allocation of shared costs, it is necessary to conduct a sensitivity analysis to attempt to determine the robustness of the cost assessment to various assumptions made during development of the model. A one-way sensitivity analysis was conducted to determine the robustness of the cost model to various assumptions made during the assessment. Parameters, which were varied, included discount rate, prices of LLINs and insecticides used, allocation of shared costs, numbers of persons protected by the interventions, and baseline malaria incidence.Ethics.The study was approved by the Ethics Committees of the London School of Hygiene and Tropical Medicine (approval no. 5825) and Federal Ministry of Health, Sudan (approval no.116-12-09). The study was registered on ClinicalTrials.com (registration no. NCT01713517).This project was supported financially by the United Nations Environment Programme/Global Environment Facility project: Demonstration of Sustainable Alternatives to DDT and Strengthening of National Vector Control Capabilities in the Middle East and North Africa (GEF ID 2546), and by the Bill and Melinda Gates Foundation (Grant 48499.01). This research forms part of a multicountry study coordinated by the WHO Global Malaria Programme. Additional technical support was provided by the WHO Regional Office for the Eastern Mediterranean and the WHO country office in Sudan.The authors declare no conflict of interest.1World Health Organization2015World Malaria Report 2015WHOGeneva2BhattS2015The effect of malaria control on Plasmodium falciparum in Africa between 2000 and 2015Nature526207211263750083MitchellSN2012Identification and validation of a gene causing cross-resistance between insecticide classes in Anopheles gambiae from GhanaProc Natl Acad Sci USA10961476152224607954MitchellSN2014Metabolic and target-site mechanisms combine to confer strong DDT resistance in Anopheles gambiaePLoS One9e92662246757975EdiCVAKoudouBGJonesCMWeetmanDRansonH2012Multiple-insecticide resistance in Anopheles gambiae mosquitoes, Southern Côte d’IvoireEmerg Infect Dis1815081511229324786World Health Organization-GMP2012Global Plan for Insecticide Resistance Management in Malaria VectorsWHOGeneva7RansonHLissendenN2016Insecticide resistance in African Anopheles mosquitoes: A worsening situation that needs urgent action to maintain malaria controlTrends Parasitol32187196268267848KleinschmidtI2015Design of a study to determine the impact of insecticide resistance on malaria vector control: A multi-country investigationMalar J14282261946489NoorAM2012Malaria risk mapping for control in the republic of SudanAm J Trop Med Hyg87101210212303340010MalikEM2006From chloroquine to artemisinin-based combination therapy: The Sudanese experienceMalar J5651687974211PetrarcaV2000Cytogenetics of the Anopheles gambiae complex in Sudan, with special reference to An. arabiensis: Relationships with East and West African populationsMed Vet Entomol141491641087285912AbdallaH2008Insecticide susceptibility and vector status of natural populations of Anopheles arabiensis from SudanTrans R Soc Trop Med Hyg1022632711805405613HimeidanYEChenHChandreFDonnellyMJYanG2007Short report: Permethrin and DDT resistance in the malaria vector Anopheles arabiensis from eastern SudanAm J Trop Med Hyg77106610681816552314World Health Organization2012Test Procedures for Insecticide Resistance Monitoring in Malaria Vector MosquitoesWHOGeneva15World Health Organization2003Making Choices in Health: WHO Guide to Cost-Effectiveness AnalysisWHOGeneva16BradleyJ2016A cluster randomized trial comparing deltamethrin and bendiocarb as insecticides for indoor residual spraying to control malaria on Bioko Island, Equatorial GuineaMalar J153782744866717RatovonjatoJ2014Entomological and parasitological impacts of indoor residual spraying with DDT, alphacypermethrin and deltamethrin in the western foothill area of MadagascarMalar J13212442324618HamainzaB2016Incremental impact upon malaria transmission of supplementing pyrethroid-impregnated long-lasting insecticidal nets with indoor residual spraying using pyrethroids or the organophosphate, pirimiphos methylMalar J151002689301219KleinschmidtI2006Reduction in infection with Plasmodium falciparum one year after the introduction of malaria control interventions on Bioko Island, Equatorial GuineaAm J Trop Med Hyg749729781676050620KigoziR2012Indoor residual spraying of insecticide and malaria morbidity in a high transmission intensity area of UgandaPLoS One7e428572288012321MaharajRMthembuDJSharpBL2005Impact of DDT re-introduction on malaria transmission in KwaZulu-NatalS Afr Med J958718741634488522HargreavesK2000Anopheles funestus resistant to pyrethroid insecticides in South AfricaMed Vet Entomol141811891087286223MaharajR2013Epidemiology of malaria in South Africa: From control to eliminationS Afr Med J1037797832407963324KleinschmidtI2007Factors influencing the effectiveness of malaria control in Bioko Island, Equatorial GuineaAm J Trop Med Hyg76102710321755660625SharpBL2007Seven years of regional malaria control collaboration–Mozambique, South Africa, and SwazilandAm J Trop Med Hyg7642471725522726StrodeCDoneganSGarnerPEnayatiAAHemingwayJ2014The impact of pyrethroid resistance on the efficacy of insecticide-treated bed nets against African anopheline mosquitoes: Systematic review and meta-analysisPLoS Med11e10016192464279127LindbladeKA2015A cohort study of the effectiveness of insecticide-treated bed nets to prevent malaria in an area of moderate pyrethroid resistance, MalawiMalar J14312562798728WestPA2014Indoor residual spraying in combination with insecticide-treated nets compared to insecticide-treated nets alone for protection against malaria: A cluster randomised trial in TanzaniaPLoS Med11e10016302473637029BagiJ2015When a discriminating dose assay is not enough: Measuring the intensity of insecticide resistance in malaria vectorsMalar J142102598589630ClarksonCS2014Adaptive introgression between anopheles sibling species eliminates a major genomic island but not reproductive isolationNat Commun542482496364931MathiasDK2011Spatial and temporal variation in the kdr allele L1014S in Anopheles gambiae s.s. and phenotypic variability in susceptibility to insecticides in Western KenyaMalar J10102123578332NorrisLC2015Adaptive introgression in an African malaria mosquito coincident with the increased usage of insecticide-treated bed netsProc Natl Acad Sci USA1128158202556152533DonnellyMJIsaacsATWeetmanD2016Identification, validation, and application of molecular diagnostics for insecticide resistance in malaria vectorsTrends Parasitol321972062675086434HamadAA2002A marked seasonality of malaria transmission in two rural sites in eastern SudanActa Trop8371821206279535HayesRJMoultonLH2009IntroductionCluster Randomised Trials, Interdisciplinary StatisticsChapman and Hall/CRCBoca Raton, FL336SismanidisC2008Restricted randomization of ZAMSTAR: A 2 x 2 factorial cluster randomized trialClin Trials53163271869784637World Health Organization1998Test procedures for insecticide resistance monitoring in malaria vectors, bio-efficacy and persistence of insecticides on treated surfaces (WHO, Geneva), Technical Report WHO/CDS/CPC/MAL/98.1238ScottJABrogdonWGCollinsFH1993Identification of single specimens of the Anopheles gambiae complex by the polymerase chain reactionAm J Trop Med Hyg49520529821428339BassC2007Detection of knockdown resistance (kdr) mutations in Anopheles gambiae: A comparison of two new high-throughput assays with existing methodsMalar J61111769732540RaoJNScottAJ1992A simple method for the analysis of clustered binary dataBiometrics48577585163798041Stata Corporation2013Stata Survey Data Reference Manual: Release 14Stata PressCollege Station, TX', 'title': 'Impact of insecticide resistance in ', 'date': '2017-12-13'}, '21565149': {'article_id': '21565149', 'content': 'This paper examines the relationship between indoor residual spray (IRS) and malaria parasite infection in Gash Barka Zone, Eritrea, an area with near universal coverage of insecticide treated bednets (ITN) and already low malaria parasite prevalence. A community randomized control trial was conducted in 2009. Malaria parasite infection prevalence was 0.5% [95% confidence interval (CI): 0.37-0.78%], with no significant difference detected between treatment and control areas. ITN possession remains high, with over 70% of households reporting ITN ownership [95% CI: 68.4-72.9]. ITN use among individuals within ITN-owning households was just under half [46.7% (95% CI: 45.4-48.0)]. Slight differences in ITN possession and use were detected between treatment and control areas. There was no significant difference in malaria parasite infection prevalence among individuals in households with ≥1 ITN compared to those in households without ITNs, nor among individuals reporting ITN use. Among individuals in ITN-owning households, sleeping under an ITN offered no statistically significant protection from malaria parasite infection. Community participation in environmental and larval habitat management activities was low: 17.9% (95% CI: 16.0-19.7). It is likely that IRS, larval habitat management and ITN distribution alone may be insufficient to interrupt transmission without corresponding high ITN use, sustained IRS application in areas where infections are clustered, and promptly seeking laboratory diagnosis and treatment of all fevers. Eritrea is ready for elimination, irrespective of inconclusive impact evaluation results.', 'title': 'Evaluating indoor residual spray for reducing malaria infection prevalence in Eritrea: results from a community randomized control trial.', 'date': '2011-05-14'}}
| 0.666667
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Public Health, Epidemiology & Health Systems
|
82
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Is the rate of major complications higher, lower, or the same when comparing restrictive fluid therapy (RFT) to goal‐directed fluid therapy (GDFT)?
|
uncertain effect
|
very low
|
yes
|
['26471495', '22710266', '25595308', '25342408', '23132508']
| 31,829,446
| 2,019
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{'26471495': {'article_id': '26471495', 'content': 'BMC AnesthesiolBMC AnesthesiolBMC Anesthesiology1471-2253BioMed CentralLondon26471495460829213110.1186/s12871-015-0131-8Research ArticleFluid management guided by a continuous non-invasive arterial pressure device is associated with decreased postoperative morbidity after total knee and hip replacementBenesJanbenesj@fnplzen.czHaidingerovaLenkaPouskaJiriStepanikJanStenglovaAlenaZatloukalJanPradlRichardChytraIvanKasalEduardDepartment of Anesthesia and Intensive Care Medicine, Teaching Hospital and Faculty of Medicine in Plzen, Charles University Prague, alej Svobody 80, 306 40 Plzen, Czech Republic 1510201515102015201515148151220147102015© Benes et al. 2015Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.BackgroundThe use of goal directed fluid protocols in intermediate risk patients undergoing hip or knee replacement was studied in few trials using invasive monitoring. For this reason we have implemented two different fluid management protocols, both based on a novel totally non-invasive arterial pressure monitoring device and compared them to the standard (no-protocol) treatment applied before the transition in our academic institution.MethodsThree treatment groups were compared in this prospective study: the observational (CONTROL, N\u2009=\u200940) group before adoption of fluid protocols and two randomized groups after the transition to protocol fluid management with the use of the continuous non-invasive blood pressure monitoring (CNAP®) device. In the PRESSURE group (N\u2009=\u200940) standard variables were used for restrictive fluid therapy. Goal directed fluid therapy using pulse pressure variation was used in the GDFT arm (N\u2009=\u200940). The influence on the rate of postoperative complications, on the hospital length of stay and other parameters was assessed.ResultsBoth protocols were associated with decreased fluid administration and maintained hemodynamic stability. Reduced rate of postoperative infection and organ complications (22 (55 %) vs. 33 (83 %) patients; p\u2009=\u20090.016; relative risk 0.67 (0.49–0.91)) was observed in the GDFT group compared to CONTROL. Lower number of patients receiving transfusion (4 (10 %) in GDFT vs. 17 (43 %) in CONTROL; p\u2009=\u20090.005) might contribute to this observation. No significant differences were observed in other end-points.ConclusionIn our study, the use of the fluid protocol based on pulse pressure variation assessed using continuous non-invasive arterial pressure measurement seems to be associated with a reduction in postoperative complications and transfusion needs as compared to standard no-protocol treatment.Trial registrationACTRN12612001014842Electronic supplementary materialThe online version of this article (doi:10.1186/s12871-015-0131-8) contains supplementary material, which is available to authorized users.KeywordsFluid managementPerioperative careGoal directed therapyPulse pressure variationissue-copyright-statement© The Author(s) 2015BackgroundIn recent years fluid management protocols and goal-directed therapy (GDT) have gained popularity among anesthesiologists [1]. According to recent meta-analyses GDT is associated with a decreased rate of postoperative complications [2–4] and fluid optimization protocols seem to be the necessary step [5]. A rational fluid optimization protocol consisting of maintenance infusion covering basal loss and goal-directed top-ups has been proposed by other authors [6, 7]. However, according to a recently published survey among European and American anesthesiologists [8], protocols for perioperative hemodynamic care are lacking in many institutions. Another important factor stressed by this survey was the use of dynamic variations of stroke volume or its surrogates as substitutes of cardiac output monitoring. In high-risk surgical populations, the studies by Forget [9] and Lopes [10] as well as one large meta-analysis of other published trials [11] showed a positive influence of the dynamic variations-led GDT even without monitoring of cardiac output. The adoption of dynamic variations is limited in some situations [12], but can significantly simplify the delivery of fluid optimization protocols.Total hip or knee replacements are usually performed among elderly patients, but neither the chronic health state nor the procedure-associated risk usually exceed moderate risk. In one study, hemodynamic optimization using oxygen delivery targets was associated with favorable postoperative outcome [13]. However, such invasive monitoring might lead to some minor complications [14], increases the economic burden and is often deemed unnecessary. The volume clamp method for continuous non-invasive arterial pressure monitoring or similar techniques enables the delivery of a fluid therapy protocol without these disadvantages.In this trial we studied the effect of a controlled transition from non-protocolled to protocolled fluid management on the rate of postoperative complications and other relevant perioperative outcomes in patients undergoing elective total hip and knee replacement. Our hypothesis was that the fluid management protocol guided by non-invasive continuous arterial pressure and the easily obtained dynamic predictor of fluid responsiveness (respiratory variation of the pulse pressure - PPV) would help to decrease postoperative morbidity.MethodsThe study was performed at the Department of Anesthesia and Intensive Care Medicine of the Faculty of Medicine and Charles University Hospital in Plzen. The Institutional review board approved the study which was consequently registered in the primary WHO register (ACTRN12612001014842), and all patients gave and signed the informed consent. The study was performed and reported in accordance with the CONSORT statement [15] (see Additional file 1). The trial followed a two-stage “before and after” design with one control observational group and two randomized-protocol based study groups. All groups consisted of two strata (total hip replacement - 20 patients and total knee replacement – 20 patients). Basic inclusion for all study participants were: age above 18, general anesthesia, regular heart rhythm, informed consent and no need for direct and continuous blood pressure monitoring or advanced hemodynamic monitoring.First stage – observational and wash-out periodThe CONTROL group was treated according to the usual care without any fluid protocol. On the day of surgery patients were fasted and received 2\xa0ml/kg/h of crystalloid infusion from the morning until transport to the operation room. Throughout the surgery monitoring of blood pressure was performed using an automatic oscillometric non-invasive arm cuff (rate of measurement once every 5\xa0min but there were no restrictions in increasing the rate). Blood pressure fluctuations within 20 % of the baseline values were tolerated. The amounts of fluids infused were at the discretion of the treating anesthesiologist. Transfusion of red blood cells was indicated when the hemoglobin fell below 90\xa0g/l; in overall healthy patients lower thresholds (up to 70\xa0g/l) were tolerated. The blood loss was assessed by measuring the balance of closed system suction. Two independent investigators (JZ and RP) were responsible for the assessment of the CONTROL group patients. These two investigators did not participate in the following course of the study so the outcome data was concealed.After completion of the first phase a wash-out period was interposed. Within this time all study members responsible for in-study anesthesia delivery (LH, JP and JS) were trained in the use of the CNAP® monitor and the protocol (each of them had to perform at least 10 cases per protocol group).Second stage – randomized, protocol basedDuring the second stage all patients undergoing scheduled total knee or hip replacement fulfilling mentioned inclusion criteria were found eligible. Patients were equally randomized into two groups (GDFT and PRESSURE) each with 40 patients, stratified to knee and hip replacement (20 patients each). Randomization was performed by the study member responsible for the anesthesia delivery before the induction using sealed opaque envelope technique stored in non-transparent containers (one per stratum) with group allocation in a 1:1 ratio. Each envelope, holding one patient’s identification, was then returned into another non-transparent container which remained sealed till the end of the study when the concealment was broken for statistical analysis. This made all other study members as well as the surgeon and other health care staff blinded to individual patient’s allocation.Anesthesia, monitoring and protocol deliveryAll patients were fasted before the procedure, small amounts of liquids were allowed for those later on the operating schedule and for chronic medication ingestion. During fasting all patients received an infusion of Hartmann solution (2\xa0ml/kg/h) from the morning of the operative day. General anesthesia was induced using propofol (2\xa0mg/kg) and sufentanil (0.2\xa0μg/kg) and tracheal intubation was facilitated by atracurium or rocuronium (0.5\xa0mg/kg). Volatile anesthetic (sevoflurane – MAC 0.8–1.2 accounted for age) in oxygen-N2O mixture was used for anesthesia maintenance. Opioid or muscle relaxant increments were used to secure adequate analgesia and operating conditions. Under relevant circumstances a deviation in the usual induction or maintenance was tolerated at the discretion of the treating anesthesiologist or anesthesia consultant.The CNAP® device (CNSystems, Graz, Austria) was used for blood pressure monitoring in both protocol groups (GDFT and PRESSURE). The device works utilizes the principle of volume clamping described by the Czech physiologist Peňáz in 1963 and adapted later by Fortin [16]. First, a state of vascular unloading is set by inflating the cuff around the finger to reach maximal pulse oscillations (the pressure inside and outside the arterial wall is then equivalent). Next, the volume of blood compartment of the finger is measured by plethysmography and held constant with the use of fast reacting inflations/deflations of the cuff. This enables a reconstruction of the arterial pressure curve at the level of the fingers. To obtain brachial pressure, the values are calibrated at the beginning and every 15\xa0min thereafter using a standard non-invasive oscillometric measurement in the arm. The device displays blood pressure continuously, enabling the automatic calculation of the PPV (pulse pressure variation) and exports the pressure curve and values to standard monitor (Ultraview SL2700, Spacelabs Healthcare, Washington, USA). In the GDFT group all relevant data was shown to the anesthesiologist. In the PRESSURE group the screen of the CNAP® device was covered and the continuous arterial pressure curve and values (without PPV) were transferred to the bedside anesthesia monitor. The values of the PPV for the analysis were obtained off-line from stored data after the procedure by a study member (JB) blinded to patient allocation.Throughout the procedure fluid therapy was delivered according to the protocols displayed in Fig.\xa01a and b with maintenance infusion of 5\xa0ml/kg/h of crystalloids (Plasmalyte, Baxter Czech s.r.o., Praha, Czech Republic). Repeated boluses of 3\xa0ml/kg of colloids (preferentially Gelofusine 4 % or 130/0.4 HES 6 %, Volulyte; both B-Braun Melsungen, Germany) were used if indicated by usual pressure targets (PRESSURE group) or by pulse pressure variation above 13 % (GDFT group). In case of reaching the maximal dose of colloids (25\xa0ml/kg) crystalloid boluses of 3\xa0ml/kg would be used for further care. When the patient was hypotensive though reaching a “volume loaded state” (defined as PPV\u2009<\u200913 % or based on clinical assessment in the GDFT or PRESSURE groups respectively) a vasoactive rescue medication (Ephedrine 5–10\xa0mg i.v. bolus or continuous Norepinephrine) was indicated. The decision which drug to choose was on the discretion of treating anesthesiologist based on presumed duration of hypotensive period and/or underlying cause. The number of hypotensive periods requiring volume loading and/or vasoactive treatment was collected as well as total dose of vasoactive medication. The same transfusion threshold (as the CONTROL group) was used if not required otherwise due to chronic conditions of the patient.Fig. 1The protocols of fluid management in the second-stage groups (PRESSURE – panel a; GDFT – panel b). Legend: HR – hear rate; MAP – mean arterial pressure; PPV – pulse pressure variation; IPPV – Volume controlled ventilation; Vt – Tidal volume; PEEP – Positive End-Expiratory Pressure; RR – respiratory rateStudy outcomesThe number of patients with any postoperative organ or infectious complication was the primary outcome measure of the study. The list of relevant complications was based on previous GDT trials [13, 17] (Additional file 2). The treating physician was responsible for the diagnosis and treatment of all complications. Hospital length of stay and all-cause mortality were assessed as secondary outcomes. Fluid balance and lactate levels in the early (24\xa0h) postoperative period were regarded as safety measures. Besides the mentioned conditions, other potentially relevant outcomes (i.e. ICU length of stay, duration of ventilator support, number of blood products used, hemoglobin level and hemodynamic profile in the intraoperative and early postoperative period as well as vasoactive medication used) were assessed. As both the ICU and hospital lengths of stay might be influenced by many other factors not relevant to the health care conditions of the patient, a readiness for standard ward transfer and for hospital discharge were also evaluated (screening criteria are listed in the Additional file 2). Two investigators (JB, AS), blinded to study group allocation and not participating in the anesthesia care and randomization, evaluated the state of the patients during regular visits.Statistical analysisThe number of CONTROL group patients was based on previous observations in similar patient population [13]. A significant reduction of postoperative complication (odds ratio 0.38) was reported in recent meta-analysis concerning hemodynamic optimization [2]. Due to inclusion of intermediate risk patients we had expected to observe lower treatment effect. According to the rate of complications observed in the CONTROL group (33 patients (83 %)) and to treatment effect expected (conservative reduction from 83 to 50 %) a sample of 36 patients would be necessary (alpha and beta error of 0.05 and 0.2). We have decided to include 40 patients into each group in order to cover possible “drop outs” and also to facilitate the division into two strata (total hip vs. knee replacement).The analysis was performed using the SigmaStat for Windows v.3.5 (Systat Software Inc., San Jose, USA). The Kolmogorov-Smirnoff test was used for normality assessment. For inter-group comparison one-way ANOVA or Kruskall-Wallis tests were used respectively. For time-dependent variables, repeated measures ANOVA or Friedman tests were performed. Post-hoc analysis was performed with the Student-Newman-Keul’s or Dunn’s test. Categorical variables were tested using the Chi-square test. The p\u2009<\u20090.05 was taken as statistically significant.ResultsDuring the first stage (August and September 2012), 40 consecutive patients undergoing hip (20 patients) and knee (20 patients) replacements under general anesthesia were observed for peri- and postoperative outcomes (CONTROL group). All patients operated during this period were included and there were none lost to follow up. In the second stage (late November 2012 to early March 2013), a total of 97 hip or knee replacements were performed under general anesthesia and found eligible for study inclusion. Seventeen patients were excluded before randomization for various reasons (listed in Fig.\xa02), 80 patients were included and equally randomized into two groups each with two strata containing 20 patients. All patients in both stages gave informed consent and were included in the final analysis, one of them died within 30 postoperative days because of pulmonary embolization. The entire flow chart according to CONSORT statement is displayed in Fig.\xa02. No significant differences were observed between the three groups in regard to demographic parameters or chronic comorbidities (Table\xa01).Table 1Baseline and demographic characteristicsCONTROLPRESSUREGDFTP value(N\u2009=\u200940)(N\u2009=\u200940)(N\u2009=\u200940)Age (years)70 (54–84)66 (44–80)68 (33–84)0.145Sex (F/M)25/1526 / 1423/170.789Height (cm)167 (8)166 (9)169 (11)0.385Weight (kg)82 (15)82 (15)90 (16) ab0.025ASA (1/2/3)2/23/157/24/96/27/70.164Arterial hypertension30 (75 %)28 (70 %)27 (68 %)0.754Ischemic heart disease9 (23 %)7 (18 %)4 (10 %)0.320Chronic pulmonary disease6 (15 %)4 (10 %)4 (10 %)0.724Diabetes mellitus9 (23 %)6 (15 %)10 (25 %)0.519Data are presented as mean and range for age, mean (standard deviation) or number (proportion) for other parametersa - significant difference between PRESSURE vs. GDFT groupsb - significant difference between protocolled group (GDFT or PRESSURE) vs. CONTROLFig. 2The flow chart of patients through the trial. Legend: ITT – intention-to-treat analysisThe results of primary and secondary outcome data are summarized in Tables\xa02 and 3. The rate of complications among patients of the CONTROL group was higher as compared to both protocol groups. In pair-wise comparisons, only the difference between CONTROL and GDFT reached statistical significance (33 patients (83 %) vs. 22 (55 %); p\u2009=\u20090.02; relative risk 0.67 (95 % confidence interval 0.49–0.91)). The higher number of complications resulted in a trend towards the prolongation of hospital length of stay as assessed by readiness for discharge criterion.Table 2Intervention data, fluid balance and laboratory outcomeCONTROLPRESSUREGDFTP-value(N\u2009=\u200940)(N\u2009=\u200940)(N\u2009=\u200940)Length of the procedure (min)110 (100–120)105 (90–118)100 (85–113)0.06MAP before anesthesia (mmHg)119 (15)113 (17)114 (19)0.31MAP end of procedure (mmHg)118 (14)105 (12)bc103 (18)bc<0.001HR before anesthesia (beats per minute)73 (10)72 (11)68 (13)0.20HR end of procedure (beats per minute)74 (14)78 (16)c77 (14)c0.34PPV after inductionN/A7.9 (4.2) %8.9 (4.5) %0.36PPV end of procedureN/A7.2 (2.4) %8.2 (3.8) %0.15Hypotensive periods intraoperatively3 (1–5)2 (1–4)2 (0–4)0.09Ephedrin (number of interventions)2 (0–3)0 (0–1)b0 (0–1)b<0.001Ephedrin (dose - mg)10 (0–15)0 (0–10)0 (0–10)0.11Hemoglobin before anesthesia (g/l)136 (11)121 (12) ab131 (14)<0.001Hemoglobin end of procedure (g/l)117 (15)110 (13) ab118 (16)0.03Lactate end of procedure (mmol/l)N/A1.2 (0.4)1.2 (0.6)0.99Intraoperative fluid balanceBlood loss (ml)500 (300–575)500 (300–600)400 (300–600)0.77Maintenance fluids (crystalloid) (ml)1500 (1200–1500)700 (600–750)b750 (600–900)b<0.001Bolus fluids (colloid) (ml)0 (0–500)440 (100–500)b400 (0–500)b0.01Patients receiving transfusion5 (13 %)3 (8 %)1 (3 %)0.24Number of packed blood cells transfused0 (0–0)0 (0–0)0 (0–0)0.26Early postoperative fluid balance (24\xa0h)Blood loss (ml)735 (400–805)470 (390–840)500 (380–678)0.42Diuresis (ml)1300 (1025–1625)1000 (785–1378)b1075 (900–1300)b0.01Crystalloids (ml)2525 (2300–2800)2800 (2300–3150)2700 (2350–3125)0.27Colloids (ml)0 (0–0)0 (0–0)0 (0–0)0.70Patients receiving transfusion17 (43 %)11 (28 %)4 (10 %)b0.01Number of packed blood cells transfused0 (0–2)0 (0–2)0 (0–0)b0.01Hemoglobin (24\xa0h) (g/l)105 (10)102 (12) a110 (14) a0.01Lactate (24\xa0h) (mmol/l)N/A1.6 (0.8)1.7 (0.8)0.67Data are presented as mean (standard deviation), median (interquartil range) or number (proportion)PPV pulse pressure variation, HR heart rate, MAP mean arterial pressurea - significant difference between PRESSURE vs. GDFT groupsb - significant difference between protocolled group (GDFT or PRESSURE) vs. CONTROLc - significant difference against baselineTable 3Clinical outcomeCONTROLPRESSUREGDFTP-value(N\u2009=\u200940)(N\u2009=\u200940)(N\u2009=\u200940)Rate of complications (all)33 (83 %)26 (65 %)22 (55 %)a0.03Rate of complications (major)3 (8 %)6 (15 %)2 (5 %)0.27Mortality0 (0 %)1 (2.5 %)0 (0 %)0.37Hospital length of stay (days)10.5 (8–12)10 (9–12.5)10 (8.5–13.5)0.99Discharge readiness (days)9 (8–12)9 (7–12)8 (7–10)0.06ICU length of stay (days)2 (2–2)2 (2–3)2 (2–3)0.3ICU readiness (days)2 (2–2)2 (2–2)2 (2–2)0.38Number of complications (all)666135N/ANumber of complications (major)383N/ABlood transfusion (patients)30 (75 %)25 (63 %)15 (38 %)a0.001Blood transfusion (units)2 (1–4)2 (0–4)0 (0–2)N/AComplications per group (Number of patients)Cardiovascular\u2003Minor2 (5 %)4 (10 %)0 (0 %)0.12\u2003Major0 (0 %)1 (2.5 %)1 (2.5 %)0.6Respiratory\u2003Minor1 (2.5 %)1 (2.5 %)0 (0 %)0.6\u2003Major0 (0 %)1 (2.5 %)0 (0 %)0.37Infectious\u2003Minor23 (57.5 %)9 (22.5 %)a9 (22.5 %)a0.001\u2003Major2 (5 %)3 (7.5 %)2 (5 %)0.86Renal\u2003Minor5 (12.5 %)7 (17.5 %)5 (12.5 %)0.76\u2003Major0 (0 %)0 (0 %)0 (0 %)1GIT\u2003Minor20 (50 %)17 (42.5 %)11 (27.5 %)0.12\u2003Major0 (0 %)0 (0 %)0 (0 %)1Nervous\u2003Minor1 (2.5 %)3 (7.5 %)3 (7.5 %)0.55\u2003Major0 (0 %)0 (0 %)0 (0 %)1Coagulation\u2003Minor6 (15 %)7 (17.5 %)3 (7.5 %)0.39\u2003Major1 (2.5 %)2 (5 %)0 (0 %)0.36Data are presented as median (interquartil range) or number (proportion)ICU intensive care unit, GIT gastro-intestinal tracta - significant difference between protocolled group (GDFT or PRESSURE) vs. CONTROLIn both protocol groups a trend for lower number of hypotensive periods was observed intraoperatively with lower dose of rescue vasoactive therapy. No significant differences were found between PPV values of both protocol groups (PRESSURE and GDFT). Pulse pressure variation was low in both groups in the beginning as well as at the end of the procedure. The overall fluid status (amount of fluids administered, blood loss etc.) was comparable in both protocol groups. Contrarily, the CONTROL patients received significantly higher amounts of fluid compared to both groups managed with protocol. A drop in hemoglobin level was observed among all patients, but was more pronounced in the CONTROL group patients (Fig.\xa03). A higher proportion of CONTROL patients needed transfusion during early as well as late postoperative periods. Serum lactate levels were assessed only in the prospective groups’ patients and showed no significant differences between PRESSURE and GDFT.Fig. 3Haemoglobin levels in perioperative period. Legend: # - significant difference PRESSURE vs. GDFT groups; $ - significant difference PRESSURE vs. CONTROL groups; * - significant difference GDFT vs. CONTROL groups (all ANOVA with Student-Neuman-Keul’s post hoc analysis); the drop against baseline measurement was significant in all groups and time-pointsDiscussionIn our study, the adoption of a fluid administration protocol guided by pulse pressure variation assessed by continuous non-invasive arterial pressure monitoring seems to be associated with lower rate of postoperative complications compared to standard no-protocol care. Reduced amounts of infused fluids with maintained hemodynamic stability, lower dose of rescue vasoactive medication and lower rate of transfusion requirements were observed among patients of the GDFT group compared to CONTROL patients.Fluid administration based on protocols with use of goal-directed hemodynamic optimization seems to be associated with improved postoperative outcomes in high risk surgical patients [3]. However, among intermediate risk patients, (for instance total hip or knee replacement) the evidence has been scarce and liberal strategies without proper monitoring are often accepted. Holte et al. [18] observed lower incidence in postoperative vomiting among patients managed with the liberal as opposed to the restrictive approach. The authors of this study hypothesized that preoperative fasting might influence this outcome and that a liberal regimen helps to cover the preoperative hypovolemia. According to values of PPV observed after induction, our patients were not hypovolemic before the procedure. In such cases a liberal approach might drive them into hypervolemia and resulting hemodilution. Red blood cell transfusions can exhibit immunosuppressive effect [19] and lead to increased incidence of infectious complications. In our study the protocol approach to fluid administration itself (PRESSURE group) was associated with a trend towards better clinical outcomes and lower transfusion needs. But it seems that only a complex protocol (restrictive maintenance with fluid responsiveness assessment- GDFT group) can adapt for the variable blood loss and individual needs. This is supported by our results or by the study by Cecconi [13]. In that trial, goal-directed fluid management was further combined with dopexamine infusion in order to reach a predefined goal of oxygen delivery. Lower incidence of cardiac and minor organ complications was observed, resembling our data. However, the use of inotropic support might be questioned in patients without significant cardiac morbidity and the use of arterial catheters is also not standard for these procedures.The outcomes of the GDFT group patients show that fluid optimization itself might be sufficient in this intermediate risk population. Recent meta-analysis demonstrated that dynamic predictors of fluid responsiveness are useful as goals of perioperative GDT [11]. Using them is much easier than complex cardiac output monitoring and oxygen delivery calculation. In addition, the number of limitations in intermediate risk groups seems to be much lower than reported by Maguire [12]: atrial fibrillation was present only in 3 (3 %) out of 97 eligible patients and no other limitations for the use of PPV were observed among our patients. The ventilation strategy (tidal volume of 8\xa0ml/kg and positive end expiratory pressure of 0.6 kPa) is in line with recent recommendations for intraoperative protective ventilation [20], but still enabling the use of dynamic variations. An important aspect of our trial is that the protocol was based on measurements obtained totally non-invasively.Our study is the first one using the novel non-invasive continuous pressure device based on volume-clamped method for goal-directed treatment. Both the reliability and limits of the measurement should be recognized, even though the device is marketed worldwide and approved by most certification authorities. As for now three large scale [21–23] and multiple smaller studies demonstrated the validity of the pressure values obtained by the CNAP® monitor, showing acceptable agreement with direct arterial pressure monitoring. Some inaccuracies seem to exist in cases of profound pressure fluctuations (i.e. deep hypotension following anesthesia induction etc.). The trending ability remained unaffected by these inaccuracies [24, 25]. In addition, as pointed out by Hahn [22], the device uses the oscillometric cuff as a reference, making it equivalent to contemporary practice in the studied population. It was demonstrated by our group [26] as well as by others [27, 28] that the use of continuous non-invasive pressure monitoring devices enables faster recognition of blood pressure drops and helps to maintain the hemodynamic stability during surgery. The reliability of the PPV values obtained by the CNAP® monitor was tested recently by two studies and was found to be comparable to its invasively assessing counterparts [29, 30]. Given these positive factors, the CNAP® device is already widely and routinely used in many clinical institutions; therefore our study could serve as a proof of concept for this praxis.The design of our study poses an important selection and assessment bias and hence limits the generalizability of our results. Firstly, the use of a two-stage (“before and after”) design does not allow us to compare the CONTROL group and protocol groups in parallel. However, our aim was to quantify the effect of change in approach during the unique moment of transition between no-protocol and protocol-led care. In order to avoid selection bias, all patients undergoing the procedure within the defined stages were found eligible. In the first stage there were no dropouts and only a limited number of patients was excluded during the second stage. Secondly, our study was not set to evaluate between the groups of phase two so we can derive only indirect conclusions in regard of superiority of the goal-directed fluid optimization over the restrictive regimen. This observed difference resulted mainly from the lower incidence of minor infectious complications (mostly urinary tract and surgical site infections). Besides blood and fluids management this might also be confounded by a slightly uneven distribution of comorbidities. Even though not statistically significant, patients in the GDFT group tended to be healthier. This could influence both the transfusion trigger and also the risk for complications as well as help reach the predefined readiness for discharge criteria earlier.Beside these specific limitations, our trial suffers from flaws inherent to single centre studies with “keen investigators” and a low number of patients. This might be especially true for intermediate risk patients with a low number of complications. For this reason our conclusions should be regarded as a hypothesis generating at best. A much larger study would be necessary to prove this concept. However, it seems that the use of the continuous non-invasive arterial pressure device might offer a safe alternative for monitoring and enable better adoption of fluid protocols.ConclusionsIn conclusion, in our study the transition from standard no-protocol treatment to the fluid management protocol based on pulse pressure variation assessed by continuous non-invasive arterial pressure measurement seems to be associated with reduction of postoperative infections, of organ complications, and of transfusion needs.Additional filesAdditional file 1:The CONSORT Check list. (DOC 217\xa0kb)Additional file 2:List of predefined morbidity criteria for ICU and hospital discharge and list of complications. (DOCX 15\xa0kb)AbbreviationsASAAmerican Society of Anesthesiology physical statusCNAPContinuous Non-invasive Arterial Pressure (name of the device)CONTROLName of the prospective observational groupGDFTName of the randomized group with fluid management based on pulse pressure variationGDTGoal-directed therapyGITGastro-intestinal tractHRHeart rateICUIntensive Care UnitMACMinimal alveolar concentrationMAPMean arterial pressurePPVPulse pressure variationPONVPostoperative nausea and vomitingPRESSUREName of the randomized group based on standard fluid managementWHOWorld Health OrganizationCompeting interestsJB is an advisory board member for Edwards Lifesciences Inc., all other co-authors declare to have no competing interests.Authors’ contributionsJB: Designed the study, performed the data analysis and wrote the manuscript. LH, JP and JS: Performed the patients’ recruitment, randomization and anaesthesia care, revised the manuscript. AS: Was responsible for the postoperative clinical assessment and revised the manuscript. JZ and RP: Performed the clinical assessment of the observational group and helped to write the manuscript. ICh and EK: Helped to design the study, participated on data analysis and writing the manuscript. All authors approved the final form of the text.AcknowledgementThe study was supported by the Charles University Research Fund (project number P36), the open access fee was granted by the CNSystems Graz, Austria.The CNAP® Monitor and Task Force® Monitor software were supplied by CNSystems, Graz, Austria.There were no additional payments depending on the results of the study.References1.SrinivasaSKahokehrASoopMTaylorMHillAGGoal-directed fluid therapy- a survey of anaesthetists in the UK, USA, Australia and New ZealandBMC Anesthesiol201313510.1186/1471-2253-13-5234330642.HamiltonMACecconiMRhodesAA systematic review and meta-analysis on the Use of preemptive hemodynamic intervention to improve postoperative outcomes in moderate and high-risk surgical patientsAnesth Analg20111126139240210.1213/ANE.0b013e3181eeaae5209664363.CorcoranTRhodesJEJClarkeSMylesPSHoKMPerioperative fluid management strategies in major surgery: a stratified meta-analysisAnesth Analg201211436405110.1213/ANE.0b013e318240d6eb222532744.GrocottMPWDushianthanAHamiltonMAMythenMGHarrisonDRowanKPerioperative increase in global blood flow to explicit defined goals and outcomes after surgery: a cochrane systematic reviewBr J Anaesth201311145354810.1093/bja/aet155236614035.CecconiMBennettDShould we use early less invasive hemodynamic monitoring in unstable ICU patients?Crit Care201115417310.1186/cc10287218886816.Bundgaard-NielsenMSecherNHKehletH‘Liberal’ vs. ‘restrictive’ perioperative fluid therapy--a critical assessment of the evidenceActa Anaesthesiol Scand20095378435110.1111/j.1399-6576.2009.02029.x195197237.GlassfordNJMylesPBellomoRThe Australian approach to peri-operative fluid balanceCurr Opin Anaesthesiol20122511021010.1097/ACO.0b013e32834decd7221131858.CannessonMPestelGRicksCHoeftAPerelAHemodynamic monitoring and management in patients undergoing high risk surgery: a survey among North American and European anesthesiologistsCrit Care2011154R19710.1186/cc10364218433539.ForgetPLoisFde KockMGoal-directed fluid management based on the pulse oximeter-derived pleth variability index reduces lactate levels and improves fluid managementAnesth Analg2010111491042070578510.LopesMROliveiraMAPereiraVLemosIAulerJMichardFGoal-directed fluid management based on pulse pressure variation monitoring during high-risk surgery: a pilot randomized controlled trialCrit Care2007115R10010.1186/cc61171782256511.BenesJGiglioMBrienzaNMichardFThe effects of goal-directed fluid therapy based on dynamic parameters on post-surgical outcome: a meta-analysis of randomized controlled trialsCrit Care201418558410.1186/s13054-014-0584-z2534890012.MaguireSRinehartJVakhariaSCannessonMTechnical communication: respiratory variation in pulse pressure and plethysmographic waveforms: intraoperative applicability in a North American academic centerAnesth Analg2011112194610.1213/ANE.0b013e318200366b2097824613.CecconiMFasanoNLangianoNDivellaMCostaMRhodesAGoal directed haemodynamic therapy during elective total hip arthroplasty under regional anaesthesiaCrit Care2011153R13210.1186/cc102462162413814.ScheerBPerelAPfeifferUJClinical review: complications and risk factors of peripheral arterial catheters used for haemodynamic monitoring in anaesthesia and intensive care medicineCrit Care20026319920410.1186/cc14891213317815.SchulzKFAltmanDGMoherDCONSORT GroupCONSORT 2010 statement: updated guidelines for reporting parallel group randomised trialsBMJ2010340c33210.1136/bmj.c3322033250916.FortinJMarteWGrüllenbergerRHackerAHabenbacherWHellerAContinuous non-invasive blood pressure monitoring using concentrically interlocking control loopsComput Biol Med20063699415710.1016/j.compbiomed.2005.04.0031648356217.BenesJChytraIAltmannPHluchyMKasalESvitakRIntraoperative fluid optimization using stroke volume variation in high risk surgical patients: results of prospective randomized studyCrit Care2010143R11810.1186/cc90702055358618.HolteKKristensenBBValentinerLFossNBHustedHKehletHLiberal versus restrictive fluid management in knee arthroplasty: a randomized, double-blind studyAnesth Analg200710524657410.1213/01.ane.0000263268.08222.191764650719.VamvakasECWhite-blood-cell-containing allogeneic blood transfusion and postoperative infection or mortality: an updated meta-analysisVox Sang20079232243210.1111/j.1423-0410.2006.00889.x1734887120.FutierEConstantinJMPaugam-BurtzCPascalJEurinMNeuschwanderAA trial of intraoperative low-tidal-volume ventilation in abdominal surgeryN Engl J Med201336954283710.1056/NEJMoa13010822390248221.BiaisMVidilLRoulletSMassonFQuinartARevelPContinuous non-invasive arterial pressure measurement: evaluation of CNAP device during vascular surgeryAnn Fr Anesth Reanim2010297–8530510.1016/j.annfar.2010.05.0022054240522.HahnRRinöslHNeunerMKettnerSCClinical validation of a continuous non-invasive haemodynamic monitor (CNAP 500) during general anaesthesiaBr J Anaesth20121084581510.1093/bja/aer4992230724223.JeleazcovCKrajinovicLMünsterTBirkholzTFriedRSchüttlerJPrecision and accuracy of a new device (CNAPTM) for continuous non-invasive arterial pressure monitoring: assessment during general anaesthesiaBr J Anaesth201010532647210.1093/bja/aeq1432062787824.IliesCBauerMBergPRosenbergJHedderichJBeinBInvestigation of the agreement of a continuous non-invasive arterial pressure device in comparison with invasive radial artery measurementBr J Anaesth201210822021010.1093/bja/aer3942217135825.GayatEMongardonNTuilOSievertKChazotTLiuNCNAP(®) does not reliably detect minimal or maximal arterial blood pressures during induction of anaesthesia and tracheal intubationActa Anaesthesiol Scand20135744687310.1111/aas.120282318602226.Benes J, Simanova A, Tovarnicka T, Sevcikova S, Kletecka J, Zatloukal J, et al. Continuous non-invasive monitoring improves blood pressure stability in upright position: randomized controlled trial. J Clin Monit Comput. 2014.27.ChenGChungEMengLAlexanderBVuTRinehartJImpact of non invasive and beat-to-beat arterial pressure monitoring on intraoperative hemodynamic managementJ Clin Monit Comput20122621334010.1007/s10877-012-9344-22238292028.IliesCKiskaltHSiedenhansDMeybohmPSteinfathMBeinBDetection of hypotension during Caesarean section with continuous non-invasive arterial pressure device or intermittent oscillometric arterial pressure measurementBr J Anaesth20121093413910.1093/bja/aes2242279827329.BiaisMSteckenLOttolenghiLRoulletSQuinartAMassonFThe ability of pulse pressure variations obtained with CNAP™ device to predict fluid responsiveness in the operating roomAnesth Analg2011113352382164260630.MonnetXDresMFerréALe TeuffGJozwiakMBleibtreuAPrediction of fluid responsiveness by a continuous non-invasive assessment of arterial pressure in critically ill patients: comparison with four other dynamic indicesBr J Anaesth20121093330810.1093/bja/aes18222735299', 'title': 'Fluid management guided by a continuous non-invasive arterial pressure device is associated with decreased postoperative morbidity after total knee and hip replacement.', 'date': '2015-10-17'}, '22710266': {'article_id': '22710266', 'content': 'We aimed to investigate whether fluid therapy with a goal of near-maximal stroke volume (SV) guided by oesophageal Doppler (ED) monitoring result in a better outcome than that with a goal of maintaining bodyweight (BW) and zero fluid balance in patients undergoing colorectal surgery.\nIn a double-blinded clinical multicentre trial, 150 patients undergoing elective colorectal surgery were randomized to receive fluid therapy after either the goal of near-maximal SV guided by ED (Doppler, D group) or the goal of zero balance and normal BW (Zero balance, Z group). Stratification for laparoscopic and open surgery was performed. The postoperative fluid therapy was similar in the two groups. The primary endpoint was postoperative complications defined and divided into subgroups by protocol. Analysis was performed by intention-to-treat. The follow-up was 30 days. The trial had 85% power to show a difference between the groups.\nThe number of patients undergoing laparoscopic or open surgery and the patient characteristics were similar between the groups. No significant differences between the groups were found for overall, major, minor, cardiopulmonary, or tissue-healing complications (P-values: 0.79; 0.62; 0.97; 0.48; and 0.48, respectively). One patient died in each group. No significant difference was found for the length of hospital stay [median (range) Z: 5.00 (1-61) vs D: 5.00 (2-41); P=0.206].\nGoal-directed fluid therapy to near-maximal SV guided by ED adds no extra value to the fluid therapy using zero balance and normal BW in patients undergoing elective colorectal surgery.', 'title': 'Which goal for fluid therapy during colorectal surgery is followed by the best outcome: near-maximal stroke volume or zero fluid balance?', 'date': '2012-06-20'}, '25595308': {'article_id': '25595308', 'content': 'The use of adequate fluid therapy during cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) remains controversial. The aim of the study was to assess whether the use of fluid therapy protocol combined with goal-directed therapy (GDT) is associated with a significant change in morbidity, length of hospital stay, and mortality compared to standard fluid therapy. Patients American Society of Anesthesiologists (ASA) II-III undergoing CRS and HIPEC were randomized into two groups. The GDT group (N\u2009=\u200938) received fluid therapy according to a protocol guided by monitored hemodynamic parameters. The control group (N\u2009=\u200942) received standard fluid therapy. We evaluated incidence of major complications, total length of hospital stay, total amount of fluids administered, and mortality rate. The incidence of major abdominal complications was 10.5% in GDT group and 38.1% in the control group (P\u2009=\u20090.005). The median duration of hospitalization was 19 days in GDT group and 29 days in the control group (P\u2009<\u20090.0001). The mortality rate was zero in GDT group vs. 9.5% in the control group (P\u2009=\u20090.12). GDT group received a significantly (P\u2009<\u20090.0001) lower amount of fluid (5812\u2009±\u20091244 ml) than the control group (8269\u2009±\u20091452 ml), with a significantly (P\u2009<\u20090.0001) lower volume of crystalloids (3884\u2009±\u20091003 vs. 68,528\u2009±\u20091413 ml). In CRS and HIPEC, the use of a GDT improves outcome in terms of incidence of major abdominal and systemic postoperative complications and length of hospital stay, compared to standard fluid therapy protocol.', 'title': 'A randomized trial of goal directed vs. standard fluid therapy in cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.', 'date': '2015-01-18'}, '25342408': {'article_id': '25342408', 'content': 'There is continued controversy regarding the benefits of goal-directed fluid therapy, with earlier studies showing marked improvement in morbidity and length-of-stay that have not been replicated more recently. The aim of this study was to compare patient outcomes in elective colorectal surgery patients having goal-directed versus restrictive fluid therapy. Inclusion criteria included suitability for an Enhanced Recovery After Surgery care pathway and patients with an American Society of Anesthesiologists Physical Status score of 1 to 3. Patients were intraoperatively randomised to either restrictive or Doppler-guided goal-directed fluid therapy. The primary outcome was length-of-stay; secondary outcomes included complication rate, change in haemodynamic variables and fluid volumes. Compared to restrictive therapy, goal-directed therapy resulted in a greater volume of intraoperative fluid, 2115 (interquartile range 1350 to 2560) ml versus 1500 (1200 to 2000) ml, P=0.008, and was associated with an increase in Doppler-derived stroke volume index from beginning to end of surgery, 43.7 (16.3) to 54.2 (21.1) ml/m(2), P <0.001, in the latter group. Length-of-stay was similar, 6.5 (5 to 9) versus 6 (4 to 9) days, P=0.421. The number of patients with any complication (minor or major) was similar; 0% (30) versus 52% (26), P=0.42, or major complications, 1 (2%) versus 4 (8%), P=0.36, respectively. The increased perioperative fluid volumes and increased stroke volumes at the end of surgery in patients receiving goal-directed therapy did not translate to a significant difference in length-of-stay and we did not observe a difference in the number of patients experiencing minor or major complications.', 'title': 'A randomised controlled trial of fluid restriction compared to oesophageal Doppler-guided goal-directed fluid therapy in elective major colorectal surgery within an Enhanced Recovery After Surgery program.', 'date': '2014-10-25'}, '23132508': {'article_id': '23132508', 'content': "Goal-directed fluid therapy (GDFT) has been compared with liberal fluid administration in non-optimized perioperative settings. It is not known whether GDFT is of value within an enhanced recovery protocol incorporating fluid restriction. This study evaluated GDFT under these circumstances in patients undergoing elective colectomy.\nPatients undergoing elective laparoscopic or open colectomy within an established enhanced recovery protocol (including fluid restriction) were randomized to GDFT or no GDFT. Bowel preparation was permitted for left colonic operations at the surgeon's discretion. Exclusion criteria included rectal tumours and stoma formation. The primary outcome was a patient-reported surgical recovery score (SRS). Secondary endpoints included clinical outcomes and physiological measures of recovery.\nEighty-five patients were randomized, and there were 37 patients in each group for analysis. Nine patients in the GDFT and four in the fluid restriction group received oral bowel preparation for either anterior resection (12) or subtotal colectomy (1). Patients in the GDFT group received more colloid during surgery (mean 591 versus 297 ml; P = 0·012) and had superior cardiac indices (mean corrected flow time 374 versus 355 ms; P = 0·018). However, no differences were observed between the GDFT and fluid restriction groups with regard to surgical recovery (mean SRS after 7 days 47 versus 46 respectively; P = 0·853), other secondary outcomes (mean aldosterone/renin ratio 9 versus 8; P = 0·898), total postoperative fluid (median 3750 versus 2400 ml; P = 0·604), length of hospital stay (median 6 versus 5 days; P = 0·570) or number of patients with complications (26 versus 27; P = 1·000).\nGDFT did not provide clinical benefit in patients undergoing elective colectomy within a protocol incorporating fluid restriction.\nNCT00911391 (http://www.clinicaltrials.gov).", 'title': 'Randomized clinical trial of goal-directed fluid therapy within an enhanced recovery protocol for elective colectomy.', 'date': '2012-11-08'}}
| 0
|
Surgery
|
83
|
Is the length of hospital stay higher, lower, or the same when comparing restrictive fluid therapy (RFT) to goal‐directed fluid therapy (GDFT)?
|
no difference
|
very low
|
yes
|
['23070341', '26471495', '22710266', '25342408', '23132508']
| 31,829,446
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{'23070341': {'article_id': '23070341', 'content': "Clinics (Sao Paulo)Clinics (Sao Paulo)Clinics1807-59321980-5322Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo23070341346001710.6061/clinics/2012(10)06cln_67p1149Clinical ScienceIntraoperative fluid management in open gastrointestinal surgery: goal-directed versus restrictiveZhangJunQiaoHuiHeZhiyongWangYunCheXuehuaLiangWeiminFudan University, Department of Anesthesiology, Huashan Hospital, Shanghai, China. Zhang J conceived the study, participated in the study design and coordination, and wrote the manuscript. Qiao H conducted the study and performed the statistical analysis. He Z conducted the study and performed the data collection. Wang Y helped to draft the manuscript. Che X participated in the coordination of the study. Liang W helped to revise the study protocol.E-mail: snapzhang@yahoo.com.cn Tel.: 86-21-528876931020126710114911557320127320122852012Copyright © 2012 Hospital das Clínicas da FMUSP2012This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.OBJECTIVE:The optimal strategy for fluid management during gastrointestinal surgery remains unclear. Minimizing the variation in arterial pulse pressure, which is induced by mechanical ventilation, is a potential strategy to improve postoperative outcomes. We tested this hypothesis in a prospective, randomized study with lactated Ringer's solution and 6% hydroxyethyl starch solution.METHOD:A total of 60 patients who were undergoing gastrointestinal surgery were randomized into a restrictive lactated Ringer's group (n\u200a=\u200a20), a goal-directed lactated Ringer's group (n\u200a=\u200a20) and a goal-directed hydroxyethyl starch group (n\u200a=\u200a20). The goal-directed fluid treatment was guided by pulse pressure variation, which was recorded during surgery using a simple manual method with a Datex Ohmeda S/5 Monitor and minimized to 11% or less by volume loading with either lactated Ringer's solution or 6% hydroxyethyl starch solution (130/0.4). The postoperative flatus time, the length of hospital stay and the incidence of complications were recorded as endpoints.RESULTS:The goal-directed lactated Ringer's group received the greatest amount of total operative fluid compared with the two other groups. The flatus time and the length of hospital stay in the goal-directed hydroxyethyl starch group were shorter than those in the goal-directed lactated Ringer's group and the restrictive lactated Ringer's group. No significant differences were found in the postoperative complications among the three groups.CONCLUSION:Monitoring and minimizing pulse pressure variation by 6% hydroxyethyl starch solution (130/0.4) loading during gastrointestinal surgery improves postoperative outcomes and decreases the discharge time of patients who are graded American Society of Anesthesiologists physical status I/II.Pulse Pressure VariationGoal-Directed Fluid TherapyRestrictive Fluid TherapyGastrointestinal SurgeryINTRODUCTIONFluid therapy is a routine practice during surgery; however, the type, amount and timing of fluids administered to patients who undergo major abdominal surgery are under debate among anesthesiologists. The perioperative fluid balance has been highlighted as a major contributory factor in postoperative morbidity and mortality. Fluid therapy strategies have been developed and implemented in clinical practice over several decades. The data suggest that aggressive or “liberal” intraoperative fluid resuscitation is harmful during open abdominal operations, whereas a restrictive fluid protocol has better outcomes, including fewer postoperative complications and a shorter discharge time (1)-(3). However, a restrictive fluid regimen has several limitations (4). Overly restricted or inadequate fluid administration may lead to insufficient intravascular volume, tissue hypoperfusion, cellular oxygenation impairment and potential organ dysfunction (5), which will increase the complication rate, hospital stay and mortality.Recently, goal-directed fluid therapy has been the focus of several studies on fluid therapy strategies. These studies demonstrated a reduction in the postoperative complication rate and the length of hospital stay with a goal-directed strategy compared with a conventional strategy (6). However, few studies have examined the comparative outcome performances of restrictive and goal-directed fluid therapy in major intra-abdominal surgery; therefore, we conducted a prospective, randomized, controlled study to compare the length of postoperative hospital stay and the recovery of bowel function in patients who were undergoing gastrointestinal surgery with either an intraoperative restrictive or pulse pressure variation [PPV]-directed fluid therapy protocol.MATERIALS AND METHODSSubjectsAfter receiving approval from the institutional review board of Huashan hospital and obtaining written informed consent from the study participants, 60 patients who were undergoing elective gastrointestinal surgeries with an anticipated blood loss of less than 500 ml were included in the study. The inclusion criteria were patients with gastric or colonic cancer who were 18-64 years of age. Patients with a body mass index (BMI)>30, significant arrhythmias, cardiopulmonary dysfunction, extensive peripheral arterial occlusive disease, significant renal or liver diseases, pregnancy or lactation and coagulopathy were excluded.Anesthesia and monitoringThe surgery was preceded by an 8-hour fasting period. Upon the arrival of the patients in the operating room, the left side of the cubital vein was catheterized in all of the patients. In addition to routing monitoring, including noninvasive arterial blood pressure, electrocardiography and pulse oximetry, invasive hemodynamic monitoring (Datex Ohmeda S/5, Helsinki, Finland) was initiated in all of the patients under local anesthesia. An A-line was established via a 20-G catheter that was inserted in the radial artery for invasive arterial pressure measurement. A double-lumen central venous catheter (CV-17702, Arrow International, Inc., Reading, PA) was inserted in the right internal jugular vein to monitor the central venous pressure (CVP). All of the monitoring transducers were positioned and zeroed at the midaxillary level. The data registration was excluded when a fast flush test indicated an unacceptable pressure recording. The heart rate, the mean arterial pressure (MAP) and the CVP were continuously monitored during the operation.The induction of anesthesia was conducted with intravenous (IV) midazolam (0.04 mg/kg), propofol (1.5-2 mg/kg) and fentanyl (3 µg/kg). Succinylcholine (2 mg/kg) IV was used to facilitate tracheal intubation. A volume-controlled mode with zero end-expiratory pressure was used to ventilate the lungs in all of the patients (Drager Julian, Philips Healthcare, Tilburg, The Netherlands). The tidal volume was maintained at 8-10 ml/kg, and the respiratory rate was maintained at 10 beats/minute to maintain the end-tidal carbon dioxide partial pressure at 35-40 mmHg. The ventilator settings were unchanged during the study. Patients whose peak airway pressures exceeded 40 mmHg were excluded from the study. Anesthesia was maintained with a 2.5-3% concentration of sevoflurane in O2, and fentanyl and vecuronium were administered intermittently for intraoperative analgesia and muscle relaxation. Immediately after induction, all of the patients received 2.0 g of cefazolin intravenously as an antibiotic prophylaxis. The body temperature was maintained over 36°C with a fluid warmer throughout surgery. All of the surgeries in this study were performed by the same surgical team.Pulse pressure variation measurementThe PPV was measured using the simple tools in the Datex Ohmeda S/5 Monitor as previously described (7,8). The PPV (%) was calculated using the following formula:$${\\rm PPV }\\left( \\% \\right)\\equals {\\rm 2}00 \\times \\left( {{\\rm PP}_{{\\rm max}} \\minus {\\rm PP}_{{\\rm min}} } \\right)/\\left( {{\\rm PP}_{{\\rm max}} \\plus {\\rm PP}_{{\\rm min}} } \\right)$$where PPmax and PPmin are the maximal and minimal pulse pressure values, respectively, within one respiratory cycle. The PPV (%) was calculated in triplicate over three consecutive respiratory cycles. The mean value of the three determinations was used for the analysis. As a reference for fluid administration in the goal-directed therapy groups, the PPV values were measured every 15 minutes during the operation.Grouping and fluid therapy protocolBaseline measurements were instituted after induction and hemodynamic stabilization. Next, the patients were randomly assigned to one of three groups according to the intraoperative fluid protocol using a random number generator in sealed envelopes.The restrictive Ringer's lactate (R-RL) group (n\u200a=\u200a20) received a fixed infusion of 4 ml/kg per hour of lactated Ringer's solution exclusively throughout the operation. The PPV was not measured in the R-RL group. If the urine output was continuously <0.5 ml/kg/h over two hours or the CVP was less than 4 mmHg, 250-ml boluses of lactated Ringer's solution were administered until these targets were restored.The goal-directed Ringer's lactate (GD-RL) group (n\u200a=\u200a20) received a fixed infusion of 4 ml/kg per hour of lactated Ringer's solution throughout the operation. In addition, this group received 250 ml of lactated Ringer's solution as a bolus in 15 minutes if the PPV was >11%.The goal-directed colloid (GD-C) group (n\u200a=\u200a20) received a fixed infusion of 4 ml/kg per hour of lactated Ringer's solution throughout the operation. In addition, this group received 250 ml of 6% hydroxyethyl starch (HES, 130/0.4) as a bolus in 15 minutes if the PPV was >11%.Intraoperative 4 ml/kg/h lactated Ringer's solution was infused continuously at a constant rate via an infusion pump (TOP-3300®, TOP Corporation, Japan). The mean arterial pressure was maintained within ±20% of the baseline value during the operation. Blood loss was replaced with HES at a 1:1 ratio, and the blood transfusion was started when clinically indicated and supported by laboratory evidence of a hematocrit less than 28%.Postoperative managementAnesthesia was discontinued when the operation was completed. A total of 80 mg of parecoxib and 5 mg of morphine was injected intravenously for analgesia 30 minutes before the end of the surgery. Patients were extubated in the operating room when they fulfilled the standard clinical criteria (adequate protective reflexes, adequate oxygenation, and stable hemodynamics). Once the patients were sent to the ward, follow-up was conducted by an independent researcher (Zhiyong He) who was unaware of the randomization of the patient until the patient was discharged from the hospital. The same surgical team was in charge of the postoperative care of the patients, including fluid infusion (a baseline crystalloid infusion of 1.5-2 ml/kg/h to maintain normovolemia with 2.0 grams of cefazolin daily for three days) and postoperative analgesia (a daily intravenous infusion of 100 mg of flurbiprofen axetil for three days following surgery and an intramuscular injection of 10 mg of morphine as a rescue analgesic). To treat postoperative nausea and vomiting, 10 mg of metoclopramide was administered intravenously. The discharge criteria adopted the standard protocol that was predefined by the Department of General Surgery at our hospital.The endpoints of the studyIn this study, the primary endpoint was the postoperative length of hospital stay, and the secondary endpoints were the time to bowel flatus and postoperative complications. Additionally, the preoperative and postoperative biochemical and hemodynamic variables; the type and volume of the intraoperative fluid infusions; the estimation of blood loss; the urine output; and the medications were recorded.Statistical analysisTo calculate the sample size, we used the retrospective data that were available for the same surgical population at our hospital. A one-day reduction in the postoperative length of hospital stay was considered to be clinically relevant, which required approximately 20 patients with a type I error of 0.05 and a power of at least 90%.The patient characteristics and the perioperative data were analyzed using a one-way analysis of variance (ANOVA), and the differences between the individual treatment groups were determined using the Student–Newman–Keuls test. The differences between the treatment groups according to the incidence of adverse events were determined using the two-tailed Fisher's exact test. The statistical analysis was performed using the SPSS 15.0 statistical software (SPSS, Inc., Chicago, IL). The statistical significance was accepted at p<0.05.RESULTSA total of 60 patients with gastrointestinal cancer who were undergoing laparotomy were enrolled. No patients were excluded or dropped out of the study. There were no significant differences between the groups regarding the demographic characteristics and preoperative diseases (Table 1).The perioperative data are shown in Table 2. No differences were observed between the types of surgery, operation duration, intraoperative blood loss, and analgesic consumption (fentanyl). However, the urine output in the GD-RL group (485.0±93.3 ml) was greater than that in the other two groups (GD-C: 295.0±48.4 ml, p<0.001; R-RL: 277.5±63.8 ml, p<0.001). The patients in the GD-C group required less vasopressors (phenylephrine or ephedrine) than the patients in the GD-RL group (p\u200a=\u200a0.001) or the R-RL group (p<0.001). The amount of the intraoperative fluid infusion in the GD-RL group (2109.50±474.25 ml) was significantly higher than those in the other groups (GD-C: 1742.50±333.01 ml, p\u200a=\u200a0.007; R-RL: 1260.00±269.44 ml, p<0.001) (Figure 1). Specifically, the GD-RL group (1853.0±381.3 ml) received more crystalloid solution than the GD-C group (877.5±130.0 ml, p<0.001) or the R-RL group (1012.5±238.4 ml, p<0.001), whereas the GD-C group (865.0±297.4 ml) received more colloid solution than the GD-RL group (256.5±139.9 ml, p<0.001) and the R-RL group (252.5±44.4 ml, p<0.001) (Figure 1). No patient required a blood transfusion according to the hematocrit measurements during the operation.The baseline hematocrit, biochemical parameters (albumin and creatine levels) and hemodynamic variables (CVP and PPV) were comparable among the three groups (Table 2). Significant differences were found between the hematocrit, albumin and PPV values at the end of surgery and the baseline values in the GD-RL and GD-C groups (Table 2).The postoperative analgesic consumption, fluid administration and complications were similar among the three groups (p>0.05, Table 3. No anastomotic leaks or intra-abdominal bleeding occurred, and all of the patients survived during the study period. The time to first passage of flatus was 86.2±7.2 h in the GD-C group versus 92.1±9.7 h (p\u200a=\u200a0.03) in the R-RL group and 95.4±9.1 h (p<0.001) in the GD-RL group (Figure 2). The length of postoperative hospital stay was 9.1±1.4 days in the GD-C group versus 10.9±1.2 days (p<0.001) in the R-RL group and 11.9±1.2 days (p<0.001) in the GD-RL group (Figure 3).DISCUSSIONPerioperative fluid replacement is a challenging issue in surgical care, especially in a procedure-specific model. Recently, goal-directed fluid therapy has been introduced into clinical practice as part of perioperative management. To our knowledge, this study is the first to directly compare the effects of an intraoperative restrictive protocol with a PPV-directed protocol on the outcomes of patients undergoing gastrointestinal surgery. Our results suggest that PPV-directed therapy with HES solution results in a shorter postoperative hospital stay and faster bowel function recovery than an infusion with either restricted or PPV-directed lactated Ringer's solution. However, the incidence of postoperative complications was similar among the patients who were treated with the three fluid strategies.The accuracy and early recognition of the intravascular volume status is essential to prevent both hypoperfusion due to volume depletion and fluid overload due to an unnecessary infusion. Therefore, appropriate hemodynamic monitoring is necessary for intraoperative fluid management. A simple, affordable and reliable method to achieve this goal would be appropriate for routine intraoperative application. PPV measurement with a multiparameter monitor that is commonly used in clinical practice has been described and successfully used for intraoperative fluid therapy (9,10). This type of PPV monitoring is not associated with additional costs or complications other than arterial catheterization. PPV monitoring has been recommended to guide volume expansion in surgical patients. Lopes et al. demonstrated that intraoperative PPV-guided fluid therapy during high-risk surgery improved postoperative outcomes and decreased the length of hospital stay (11). Our previous studies demonstrated that the PPV, which was derived from the Datex method, was comparable with the stroke volume variation (SVV) using the FloTracTM/VigileoTM system (7) and better than the CVP measurement (8) for intravascular volume assessment. Therefore, we used PVV\u200a=\u200a11%, which was obtained from our previous study (7), as the threshold of hypovolemia to target volume optimization in this study.Many studies have investigated the effects of the amount of intraoperative fluid administration on perioperative outcomes. A meta-analysis demonstrated that a restrictive intraoperative (3,12,13) and postoperative (14) fluid protocol in major abdominal surgery reduces the incidence of perioperative complications, such as cardiopulmonary events and disturbances in bowel motility; improves wound and anastomotic healing; and reduces the length of the hospital stay. In addition, several studies examined the effects of intraoperative fluid therapy that is guided by various hemodynamic targets, such as conventional hemodynamic parameter-guided and functional hemodynamic parameter-directed fluid therapy, on perioperative outcomes. Studies demonstrated that patient outcomes improved after functional hemodynamic parameter (PPV or SVV)-directed fluid therapy in major surgery (15)-(18). Therefore, two optimal intraoperative strategies have been proposed: restrictive and goal-directed fluid therapy. However, patients who are treated using a goal-directed protocol receive greater amounts of fluid than patients who are treated with a restrictive protocol. Several studies have questioned the positive effects of goal-directed fluid therapy. Senagore et al. (19) revealed that esophageal Doppler monitoring-guided fluid administration in laparoscopic colectomy predisposed patients to a longer hospital stay and significantly increased complications. Lahner et al. (20) demonstrated that SVV may not be a reliable predictor of fluid responsiveness in the setting of major abdominal surgery. PPV is considered to be more reliable than SVV and can be used to recognize volume contraction earlier than other indicators (21,22); however, amplified PPV does not represent the hypovolemic status, such as anesthesia or inflammation-induced vasodilation (10). Therefore, restrictive fluid infusion with vasopressor administration during abdominal surgery has been advocated to prevent fluid retention after the anesthetic effects have subsided. However, recent randomized trials did not confirm the potential benefits of fluid restriction on recovery after elective surgery (3,13). Intraoperative fluid restriction was associated with frequent episodes of intraoperative hypovolemia (23), which is a major determinant of postoperative organ dysfunction (11) and an independent predictor of postoperative complications, such as an anastomotic leak and postoperative sepsis (5). Whether goal-directed therapy is superior to a restrictive fluid strategy in major abdominal surgery remains uncertain. Therefore, we designed a prospective, randomized study to compare the effects of restrictive and goal-directed fluid therapy on perioperative outcomes in patients who were undergoing open gastrointestinal surgery. The goal-directed therapy group was further divided into two subgroups, a GD-RL group and a GD-C group, to compare the role of fluid type in intraoperative fluid therapy. In this study, a total fluid volume of 1742 ml in the GD-C group was sufficient for organ perfusion in open abdominal surgery over a 3-hour period; however, a greater volume (2109 ml in the GD-RL group) or reduced volume (1260 ml in the R-RL group) was less effective.Another factor that may influence the outcomes of patients who undergo major abdominal surgery is the type of fluid. In normovolemic healthy volunteers, the blood volume expansion was significantly greater after an infusion of 1 L of colloids (6% HES 130/0.4) than after an infusion of 1 L of crystalloids (saline) over one hour (24). Only 16% of the HES solution and more than 68% of the saline solution escaped into the extravascular fluid compartment after one hour. In the setting of moderate hypovolemia, an infusion of colloids increases blood volume and cardiac output more effectively than the same volume of crystalloids, even when the crystalloid infusion is rapidly administered (over 5-7 min) (25). Therefore, the patients in the GD-C group required less vasoactivators to achieve hemodynamic stability than the patients in the GD-RL and R-RL groups. A greater volume (≈1000 ml) of lactated Ringer's solution was infused into the GD-RL group to achieve PPV≤11% than that (≈600 ml) of the HES solution in the GD-C group. However, in contrast to the crystalloid-to-colloid volume ratio of 4:1 or more, our results (RL: HES\u200a=\u200a1.67) are consistent with those of a recent study on goal-directed resuscitation, in which lower ratios that ranged from 1-1.6 were observed (26). Crystalloids enter the extravascular space more rapidly and in greater quantities than colloid; therefore, third-space fluid accumulation and altered capillary permeability may occur (23). Large amounts of intravenous crystalloid solutions can lead to an interstitial volume load, the development of interstitial edema and the impairment of the diffusion of O2 in gut tissues (27), which may prolong the period of ileus and increase postoperative complications and thus undermine the healing process (12). The large amounts of crystalloids that were administered in the GD-RL group may have offset the beneficial effects of the goal-directed therapy during the surgery. Subsequently, the elimination of flatus and the postoperative discharge times were delayed in the goal-directed crystalloid therapy group compared with the restrictive regimen group (23).Two studies have compared the outcomes between intraoperative restrictive and goal-directed fluid management strategies in animal experiments. Kimberger et al. (28) demonstrated that goal-directed therapy with colloids significantly increased perianastomotic tissue oxygen tension compared with goal-directed crystalloid therapy and restrictive crystalloid therapy after 4 hours of treatment in a pig model of colon anastomosis surgery. In contrast to the mucosal tissue, the microcirculatory blood flow in the perianastomotic muscularis tissue was significantly higher in the GD-C group compared with the GD-RL group. Another study with the same fluid protocol found that the hemodynamic parameters were significantly better in the GD-C and GD-RL groups than in the R-RL group (29). The microcirculatory flow and tissue oxygen tension in the intestinal mucosa increased in the GD-C group but remained unchanged or decreased in the GD-RL and R-RL groups. These results suggest that goal-directed therapy with colloids during gastrointestinal surgery can lead to more stable intraoperative hemodynamics, faster bowel function recovery and a shorter postoperative discharge time compared with the goal-directed therapy with crystalloids in this study. However, several authors have questioned the beneficial role of goal-directed fluid therapy and indicated that the better outcomes in the goal-directed groups can be solely attributed to the larger amounts of colloids that are used in these groups compared with the control groups (30). Studies have demonstrated that the beneficial local tissue effects are likely due to the anti-inflammatory and antioxidant properties of colloids (HES 130/0.4), which augment the healing of anastomosis (31)-(34). A restrictive colloid group was not included in our fluid protocols; therefore, we cannot completely rule out the possibility that additional colloids may have contributed to our findings. However, in another experimental study with a small bowel anastomosis rat model, Marjanovic et al. (35) demonstrated that the animals that were treated with an intraoperative crystalloid volume overcharge with a fixed high flow rate exhibited worse anastomotic bursting pressure and poor histological results (submucosal edema) compared with the colloid overload group and the crystalloid or colloid volume restriction group that had a fixed low flow rate. However, the colloid restriction group had only comparable, but not better, results than the colloid overload and crystalloid restriction groups.There are several limitations to this study. The first limitation is that an accelerated surgical recovery program was not adopted. The morphine administration for postoperative rescue analgesia may have affected the results because this treatment can delay bowel function recovery and cause PONV. Moreover, nasogastric tubes are routinely applied during gastrointestinal surgery at our hospital. However, the three groups in our series were similar with respect to the surgeons (the same surgical team), clinical characteristics and postoperative quality of care (conventional but standardized). Second, we did not establish a restrictive colloid group; therefore, the improvement in the outcomes could be due to the fluid type rather than the fluid therapy strategy. However, colloid replacement alone is not recommended in the textbooks and guidelines on intravenous fluid therapy in surgical patients. Finally, we did not evaluate the 30-day mortality; however, there were no deaths during the hospital stay of each patient. Additionally, this study did not have the power to detect significant differences in the cardiorespiratory outcomes because of the small number of patients. Therefore, the clinical benefits of the intraoperative goal-directed colloid strategy require further assessment.In summary, the PPV, which can be obtained using a simple and inexpensive method, could be helpful in the implementation of intraoperative goal-directed therapy. Our data demonstrate that intraoperative treatment with PPV-directed 6% HES (130/0.4) leads to more stable hemodynamics, faster bowel function recovery and a shorter postoperative hospital stay than treatment with restrictive or PPV-directed lactated Ringer's solution, which suggests that intraoperative goal-directed therapy with colloids may be beneficial in ASA I/II patients during major gastrointestinal surgery. In addition, our results support the use of intraoperative fluid therapy with the accurate targeting of colloid fluid boluses, which prevents excessive crystalloid administration, even in goal-directed therapy. Relatively healthy and young adult patients participated in this study; however, the effects of fluid therapy strategies on the outcomes in elderly patients with comorbidities (ASA III-IV) who undergo major abdominal surgery remain unclear. 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an in vitro studyIntensive Care Med199420(1)3741751300332\nHofbauerRMoserDHornykewyczSFrassMKapiotisSHydroxyethyl starch reduces the chemotaxis of white cells through endothelial cell monolayersTransfusion199939(3)289941020459233\nHoffmannJNVollmarBLaschkeMWInthornDSchildbergFWMengerMDHydroxyethyl starch (130 kD), but not crystalloid volume support, improves microcirculation during normotensive endotoxemiaAnesthesiology200297(2)460701215193834\nWangPGongGLiYLiJHydroxyethyl starch 130/0.4 augments healing of colonic anastomosis in a rat model of peritonitisAm J Surg2010199(2)23291989717135\nMarjanovicGVillainCTimmeSzur HausenAHoeppnerJMakowiecFColloid vs. crystalloid infusions in gastrointestinal surgery and their different impact on the healing of intestinal anastomosesInt J Colorectal Dis201025(4)491819943164Figure 1Intraoperative fluid infusion volume.Figure 2Time to first passage of flatus.Figure 3Postoperative days of hospital stay.Table 1Patient demographic data and clinical characteristics.GD-RL(n\u200a=\u200a20)GD-C(n\u200a=\u200a20)R-RL(n\u200a=\u200a20)Age (yrs)56.7±6.952.8±11.853.3±13.0Sex (M/F)14/614/614/6Height (cm)167.1±6.6167.3±9.4165.0±8.0Weight (kg)60.1±10.762.9±7.462.3±9.6ASA class (I/II)11/910/1011/9Comorbidity\xa0\xa0\xa0\xa0Diabetes3 (15%)2 (10%)3 (15%)\xa0\xa0\xa0\xa0Hypertension5 (25%)4 (25%)3 (15%)\xa0\xa0\xa0\xa0CAD2 (10%)1 (5%)1 (5%)\xa0\xa0\xa0\xa0COPD4 (20%)5 (20%)3 (15%)\xa0\xa0\xa0\xa0Asthma1 (5%)0 (0)0 (0)ASA: American Society of Anesthesiologists; CAD: coronary artery disease; COPD: chronic obstructive pulmonary disease.The data are presented as the means±SD or the number (%).Notes: All of the patients with comorbidities had been optimized before anesthesia and surgery.Table 2Perioperative data.GD-RLGD-CR-RLType of surgeryGastrectomy151213Colectomy587Duration of surgery (min)190.3±40.2183.0±13.8182.5±18.0Blood loss (ml)256.5±139.9265.0±46.2252.5±44.4Urine output (ml)485.0±93.3†295.0±48.4277.5±63.8MedicationsPhenylephrine (µg)120 (120-160)80 (40-80) †190 (180-200)\xa0\xa0\xa0\xa0Ephedrine (mg)12.5 (10-18.75)5 (0-5) †15 (15-20)\xa0\xa0\xa0\xa0Fentanyl (µg)625.0±67.9655.0±48.4660.0±80.5PPV value (%)\xa0\xa0\xa0\xa0Baseline13.6±2.413.7±2.1–\xa0\xa0\xa0\xa0End of surgery7.1±1.2*)7.0±1.0*)–CVP value (mmHg)\xa0\xa0\xa0\xa0Baseline6.2±1.16.3±1.26.2±1.0\xa0\xa0\xa0\xa0End of surgery8.7±0.98.6±1.07.8±1.5Albumin (g/l)\xa0\xa0\xa0\xa0Preoperative39.5±2.540.0±2.840.1±3.5\xa0\xa0\xa0\xa0First postoperative day33.5±2.1*)34.1±2.0*)38.7±2.9†Creatine (µmol/l)\xa0\xa0\xa0\xa0Preoperative71.1±8.066.8±10.468.9±10.6\xa0\xa0\xa0\xa0First postoperative day66.7±8.161.4±8.963.1±10.2Hematocrit (%)\xa0\xa0\xa0\xa0Preoperative41.9±3.043.3±3.842.5±2.8\xa0\xa0\xa0\xa0First postoperative day35.9±2.0*)38.8±2.3*)41.3±2.6†HES: 6% hydroxyethyl starch (130/0.4); CVP: central venous pressure.The data are presented as the means±SD or the medians (25-75 interquartile range).*, p<0.05, compared with the preoperative data; †, p<0.05, compared with the GD-RL group and the GD-C group.Table 3Postoperative data (n\u200a=\u200a20).GD-RLGD-CR-RLMorphine consumption (mg)61.7±28.452.5±30.259.0±32.0Fluid infusion volume per day (ml)2342.5±242.42442.5±164.12412.5±217.6ComplicationsPostoperative vomiting534Arrhythmia*100Pulmonary infection100Bowel obstruction001SSI110Total complications845SSI: surgical site infection; Arrhythmia*: paroxysmal ventricular premature.The data are presented as the means±SD or the number.", 'title': 'Intraoperative fluid management in open gastrointestinal surgery: goal-directed versus restrictive.', 'date': '2012-10-17'}, '26471495': {'article_id': '26471495', 'content': 'BMC AnesthesiolBMC AnesthesiolBMC Anesthesiology1471-2253BioMed CentralLondon26471495460829213110.1186/s12871-015-0131-8Research ArticleFluid management guided by a continuous non-invasive arterial pressure device is associated with decreased postoperative morbidity after total knee and hip replacementBenesJanbenesj@fnplzen.czHaidingerovaLenkaPouskaJiriStepanikJanStenglovaAlenaZatloukalJanPradlRichardChytraIvanKasalEduardDepartment of Anesthesia and Intensive Care Medicine, Teaching Hospital and Faculty of Medicine in Plzen, Charles University Prague, alej Svobody 80, 306 40 Plzen, Czech Republic 1510201515102015201515148151220147102015© Benes et al. 2015Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.BackgroundThe use of goal directed fluid protocols in intermediate risk patients undergoing hip or knee replacement was studied in few trials using invasive monitoring. For this reason we have implemented two different fluid management protocols, both based on a novel totally non-invasive arterial pressure monitoring device and compared them to the standard (no-protocol) treatment applied before the transition in our academic institution.MethodsThree treatment groups were compared in this prospective study: the observational (CONTROL, N\u2009=\u200940) group before adoption of fluid protocols and two randomized groups after the transition to protocol fluid management with the use of the continuous non-invasive blood pressure monitoring (CNAP®) device. In the PRESSURE group (N\u2009=\u200940) standard variables were used for restrictive fluid therapy. Goal directed fluid therapy using pulse pressure variation was used in the GDFT arm (N\u2009=\u200940). The influence on the rate of postoperative complications, on the hospital length of stay and other parameters was assessed.ResultsBoth protocols were associated with decreased fluid administration and maintained hemodynamic stability. Reduced rate of postoperative infection and organ complications (22 (55 %) vs. 33 (83 %) patients; p\u2009=\u20090.016; relative risk 0.67 (0.49–0.91)) was observed in the GDFT group compared to CONTROL. Lower number of patients receiving transfusion (4 (10 %) in GDFT vs. 17 (43 %) in CONTROL; p\u2009=\u20090.005) might contribute to this observation. No significant differences were observed in other end-points.ConclusionIn our study, the use of the fluid protocol based on pulse pressure variation assessed using continuous non-invasive arterial pressure measurement seems to be associated with a reduction in postoperative complications and transfusion needs as compared to standard no-protocol treatment.Trial registrationACTRN12612001014842Electronic supplementary materialThe online version of this article (doi:10.1186/s12871-015-0131-8) contains supplementary material, which is available to authorized users.KeywordsFluid managementPerioperative careGoal directed therapyPulse pressure variationissue-copyright-statement© The Author(s) 2015BackgroundIn recent years fluid management protocols and goal-directed therapy (GDT) have gained popularity among anesthesiologists [1]. According to recent meta-analyses GDT is associated with a decreased rate of postoperative complications [2–4] and fluid optimization protocols seem to be the necessary step [5]. A rational fluid optimization protocol consisting of maintenance infusion covering basal loss and goal-directed top-ups has been proposed by other authors [6, 7]. However, according to a recently published survey among European and American anesthesiologists [8], protocols for perioperative hemodynamic care are lacking in many institutions. Another important factor stressed by this survey was the use of dynamic variations of stroke volume or its surrogates as substitutes of cardiac output monitoring. In high-risk surgical populations, the studies by Forget [9] and Lopes [10] as well as one large meta-analysis of other published trials [11] showed a positive influence of the dynamic variations-led GDT even without monitoring of cardiac output. The adoption of dynamic variations is limited in some situations [12], but can significantly simplify the delivery of fluid optimization protocols.Total hip or knee replacements are usually performed among elderly patients, but neither the chronic health state nor the procedure-associated risk usually exceed moderate risk. In one study, hemodynamic optimization using oxygen delivery targets was associated with favorable postoperative outcome [13]. However, such invasive monitoring might lead to some minor complications [14], increases the economic burden and is often deemed unnecessary. The volume clamp method for continuous non-invasive arterial pressure monitoring or similar techniques enables the delivery of a fluid therapy protocol without these disadvantages.In this trial we studied the effect of a controlled transition from non-protocolled to protocolled fluid management on the rate of postoperative complications and other relevant perioperative outcomes in patients undergoing elective total hip and knee replacement. Our hypothesis was that the fluid management protocol guided by non-invasive continuous arterial pressure and the easily obtained dynamic predictor of fluid responsiveness (respiratory variation of the pulse pressure - PPV) would help to decrease postoperative morbidity.MethodsThe study was performed at the Department of Anesthesia and Intensive Care Medicine of the Faculty of Medicine and Charles University Hospital in Plzen. The Institutional review board approved the study which was consequently registered in the primary WHO register (ACTRN12612001014842), and all patients gave and signed the informed consent. The study was performed and reported in accordance with the CONSORT statement [15] (see Additional file 1). The trial followed a two-stage “before and after” design with one control observational group and two randomized-protocol based study groups. All groups consisted of two strata (total hip replacement - 20 patients and total knee replacement – 20 patients). Basic inclusion for all study participants were: age above 18, general anesthesia, regular heart rhythm, informed consent and no need for direct and continuous blood pressure monitoring or advanced hemodynamic monitoring.First stage – observational and wash-out periodThe CONTROL group was treated according to the usual care without any fluid protocol. On the day of surgery patients were fasted and received 2\xa0ml/kg/h of crystalloid infusion from the morning until transport to the operation room. Throughout the surgery monitoring of blood pressure was performed using an automatic oscillometric non-invasive arm cuff (rate of measurement once every 5\xa0min but there were no restrictions in increasing the rate). Blood pressure fluctuations within 20 % of the baseline values were tolerated. The amounts of fluids infused were at the discretion of the treating anesthesiologist. Transfusion of red blood cells was indicated when the hemoglobin fell below 90\xa0g/l; in overall healthy patients lower thresholds (up to 70\xa0g/l) were tolerated. The blood loss was assessed by measuring the balance of closed system suction. Two independent investigators (JZ and RP) were responsible for the assessment of the CONTROL group patients. These two investigators did not participate in the following course of the study so the outcome data was concealed.After completion of the first phase a wash-out period was interposed. Within this time all study members responsible for in-study anesthesia delivery (LH, JP and JS) were trained in the use of the CNAP® monitor and the protocol (each of them had to perform at least 10 cases per protocol group).Second stage – randomized, protocol basedDuring the second stage all patients undergoing scheduled total knee or hip replacement fulfilling mentioned inclusion criteria were found eligible. Patients were equally randomized into two groups (GDFT and PRESSURE) each with 40 patients, stratified to knee and hip replacement (20 patients each). Randomization was performed by the study member responsible for the anesthesia delivery before the induction using sealed opaque envelope technique stored in non-transparent containers (one per stratum) with group allocation in a 1:1 ratio. Each envelope, holding one patient’s identification, was then returned into another non-transparent container which remained sealed till the end of the study when the concealment was broken for statistical analysis. This made all other study members as well as the surgeon and other health care staff blinded to individual patient’s allocation.Anesthesia, monitoring and protocol deliveryAll patients were fasted before the procedure, small amounts of liquids were allowed for those later on the operating schedule and for chronic medication ingestion. During fasting all patients received an infusion of Hartmann solution (2\xa0ml/kg/h) from the morning of the operative day. General anesthesia was induced using propofol (2\xa0mg/kg) and sufentanil (0.2\xa0μg/kg) and tracheal intubation was facilitated by atracurium or rocuronium (0.5\xa0mg/kg). Volatile anesthetic (sevoflurane – MAC 0.8–1.2 accounted for age) in oxygen-N2O mixture was used for anesthesia maintenance. Opioid or muscle relaxant increments were used to secure adequate analgesia and operating conditions. Under relevant circumstances a deviation in the usual induction or maintenance was tolerated at the discretion of the treating anesthesiologist or anesthesia consultant.The CNAP® device (CNSystems, Graz, Austria) was used for blood pressure monitoring in both protocol groups (GDFT and PRESSURE). The device works utilizes the principle of volume clamping described by the Czech physiologist Peňáz in 1963 and adapted later by Fortin [16]. First, a state of vascular unloading is set by inflating the cuff around the finger to reach maximal pulse oscillations (the pressure inside and outside the arterial wall is then equivalent). Next, the volume of blood compartment of the finger is measured by plethysmography and held constant with the use of fast reacting inflations/deflations of the cuff. This enables a reconstruction of the arterial pressure curve at the level of the fingers. To obtain brachial pressure, the values are calibrated at the beginning and every 15\xa0min thereafter using a standard non-invasive oscillometric measurement in the arm. The device displays blood pressure continuously, enabling the automatic calculation of the PPV (pulse pressure variation) and exports the pressure curve and values to standard monitor (Ultraview SL2700, Spacelabs Healthcare, Washington, USA). In the GDFT group all relevant data was shown to the anesthesiologist. In the PRESSURE group the screen of the CNAP® device was covered and the continuous arterial pressure curve and values (without PPV) were transferred to the bedside anesthesia monitor. The values of the PPV for the analysis were obtained off-line from stored data after the procedure by a study member (JB) blinded to patient allocation.Throughout the procedure fluid therapy was delivered according to the protocols displayed in Fig.\xa01a and b with maintenance infusion of 5\xa0ml/kg/h of crystalloids (Plasmalyte, Baxter Czech s.r.o., Praha, Czech Republic). Repeated boluses of 3\xa0ml/kg of colloids (preferentially Gelofusine 4 % or 130/0.4 HES 6 %, Volulyte; both B-Braun Melsungen, Germany) were used if indicated by usual pressure targets (PRESSURE group) or by pulse pressure variation above 13 % (GDFT group). In case of reaching the maximal dose of colloids (25\xa0ml/kg) crystalloid boluses of 3\xa0ml/kg would be used for further care. When the patient was hypotensive though reaching a “volume loaded state” (defined as PPV\u2009<\u200913 % or based on clinical assessment in the GDFT or PRESSURE groups respectively) a vasoactive rescue medication (Ephedrine 5–10\xa0mg i.v. bolus or continuous Norepinephrine) was indicated. The decision which drug to choose was on the discretion of treating anesthesiologist based on presumed duration of hypotensive period and/or underlying cause. The number of hypotensive periods requiring volume loading and/or vasoactive treatment was collected as well as total dose of vasoactive medication. The same transfusion threshold (as the CONTROL group) was used if not required otherwise due to chronic conditions of the patient.Fig. 1The protocols of fluid management in the second-stage groups (PRESSURE – panel a; GDFT – panel b). Legend: HR – hear rate; MAP – mean arterial pressure; PPV – pulse pressure variation; IPPV – Volume controlled ventilation; Vt – Tidal volume; PEEP – Positive End-Expiratory Pressure; RR – respiratory rateStudy outcomesThe number of patients with any postoperative organ or infectious complication was the primary outcome measure of the study. The list of relevant complications was based on previous GDT trials [13, 17] (Additional file 2). The treating physician was responsible for the diagnosis and treatment of all complications. Hospital length of stay and all-cause mortality were assessed as secondary outcomes. Fluid balance and lactate levels in the early (24\xa0h) postoperative period were regarded as safety measures. Besides the mentioned conditions, other potentially relevant outcomes (i.e. ICU length of stay, duration of ventilator support, number of blood products used, hemoglobin level and hemodynamic profile in the intraoperative and early postoperative period as well as vasoactive medication used) were assessed. As both the ICU and hospital lengths of stay might be influenced by many other factors not relevant to the health care conditions of the patient, a readiness for standard ward transfer and for hospital discharge were also evaluated (screening criteria are listed in the Additional file 2). Two investigators (JB, AS), blinded to study group allocation and not participating in the anesthesia care and randomization, evaluated the state of the patients during regular visits.Statistical analysisThe number of CONTROL group patients was based on previous observations in similar patient population [13]. A significant reduction of postoperative complication (odds ratio 0.38) was reported in recent meta-analysis concerning hemodynamic optimization [2]. Due to inclusion of intermediate risk patients we had expected to observe lower treatment effect. According to the rate of complications observed in the CONTROL group (33 patients (83 %)) and to treatment effect expected (conservative reduction from 83 to 50 %) a sample of 36 patients would be necessary (alpha and beta error of 0.05 and 0.2). We have decided to include 40 patients into each group in order to cover possible “drop outs” and also to facilitate the division into two strata (total hip vs. knee replacement).The analysis was performed using the SigmaStat for Windows v.3.5 (Systat Software Inc., San Jose, USA). The Kolmogorov-Smirnoff test was used for normality assessment. For inter-group comparison one-way ANOVA or Kruskall-Wallis tests were used respectively. For time-dependent variables, repeated measures ANOVA or Friedman tests were performed. Post-hoc analysis was performed with the Student-Newman-Keul’s or Dunn’s test. Categorical variables were tested using the Chi-square test. The p\u2009<\u20090.05 was taken as statistically significant.ResultsDuring the first stage (August and September 2012), 40 consecutive patients undergoing hip (20 patients) and knee (20 patients) replacements under general anesthesia were observed for peri- and postoperative outcomes (CONTROL group). All patients operated during this period were included and there were none lost to follow up. In the second stage (late November 2012 to early March 2013), a total of 97 hip or knee replacements were performed under general anesthesia and found eligible for study inclusion. Seventeen patients were excluded before randomization for various reasons (listed in Fig.\xa02), 80 patients were included and equally randomized into two groups each with two strata containing 20 patients. All patients in both stages gave informed consent and were included in the final analysis, one of them died within 30 postoperative days because of pulmonary embolization. The entire flow chart according to CONSORT statement is displayed in Fig.\xa02. No significant differences were observed between the three groups in regard to demographic parameters or chronic comorbidities (Table\xa01).Table 1Baseline and demographic characteristicsCONTROLPRESSUREGDFTP value(N\u2009=\u200940)(N\u2009=\u200940)(N\u2009=\u200940)Age (years)70 (54–84)66 (44–80)68 (33–84)0.145Sex (F/M)25/1526 / 1423/170.789Height (cm)167 (8)166 (9)169 (11)0.385Weight (kg)82 (15)82 (15)90 (16) ab0.025ASA (1/2/3)2/23/157/24/96/27/70.164Arterial hypertension30 (75 %)28 (70 %)27 (68 %)0.754Ischemic heart disease9 (23 %)7 (18 %)4 (10 %)0.320Chronic pulmonary disease6 (15 %)4 (10 %)4 (10 %)0.724Diabetes mellitus9 (23 %)6 (15 %)10 (25 %)0.519Data are presented as mean and range for age, mean (standard deviation) or number (proportion) for other parametersa - significant difference between PRESSURE vs. GDFT groupsb - significant difference between protocolled group (GDFT or PRESSURE) vs. CONTROLFig. 2The flow chart of patients through the trial. Legend: ITT – intention-to-treat analysisThe results of primary and secondary outcome data are summarized in Tables\xa02 and 3. The rate of complications among patients of the CONTROL group was higher as compared to both protocol groups. In pair-wise comparisons, only the difference between CONTROL and GDFT reached statistical significance (33 patients (83 %) vs. 22 (55 %); p\u2009=\u20090.02; relative risk 0.67 (95 % confidence interval 0.49–0.91)). The higher number of complications resulted in a trend towards the prolongation of hospital length of stay as assessed by readiness for discharge criterion.Table 2Intervention data, fluid balance and laboratory outcomeCONTROLPRESSUREGDFTP-value(N\u2009=\u200940)(N\u2009=\u200940)(N\u2009=\u200940)Length of the procedure (min)110 (100–120)105 (90–118)100 (85–113)0.06MAP before anesthesia (mmHg)119 (15)113 (17)114 (19)0.31MAP end of procedure (mmHg)118 (14)105 (12)bc103 (18)bc<0.001HR before anesthesia (beats per minute)73 (10)72 (11)68 (13)0.20HR end of procedure (beats per minute)74 (14)78 (16)c77 (14)c0.34PPV after inductionN/A7.9 (4.2) %8.9 (4.5) %0.36PPV end of procedureN/A7.2 (2.4) %8.2 (3.8) %0.15Hypotensive periods intraoperatively3 (1–5)2 (1–4)2 (0–4)0.09Ephedrin (number of interventions)2 (0–3)0 (0–1)b0 (0–1)b<0.001Ephedrin (dose - mg)10 (0–15)0 (0–10)0 (0–10)0.11Hemoglobin before anesthesia (g/l)136 (11)121 (12) ab131 (14)<0.001Hemoglobin end of procedure (g/l)117 (15)110 (13) ab118 (16)0.03Lactate end of procedure (mmol/l)N/A1.2 (0.4)1.2 (0.6)0.99Intraoperative fluid balanceBlood loss (ml)500 (300–575)500 (300–600)400 (300–600)0.77Maintenance fluids (crystalloid) (ml)1500 (1200–1500)700 (600–750)b750 (600–900)b<0.001Bolus fluids (colloid) (ml)0 (0–500)440 (100–500)b400 (0–500)b0.01Patients receiving transfusion5 (13 %)3 (8 %)1 (3 %)0.24Number of packed blood cells transfused0 (0–0)0 (0–0)0 (0–0)0.26Early postoperative fluid balance (24\xa0h)Blood loss (ml)735 (400–805)470 (390–840)500 (380–678)0.42Diuresis (ml)1300 (1025–1625)1000 (785–1378)b1075 (900–1300)b0.01Crystalloids (ml)2525 (2300–2800)2800 (2300–3150)2700 (2350–3125)0.27Colloids (ml)0 (0–0)0 (0–0)0 (0–0)0.70Patients receiving transfusion17 (43 %)11 (28 %)4 (10 %)b0.01Number of packed blood cells transfused0 (0–2)0 (0–2)0 (0–0)b0.01Hemoglobin (24\xa0h) (g/l)105 (10)102 (12) a110 (14) a0.01Lactate (24\xa0h) (mmol/l)N/A1.6 (0.8)1.7 (0.8)0.67Data are presented as mean (standard deviation), median (interquartil range) or number (proportion)PPV pulse pressure variation, HR heart rate, MAP mean arterial pressurea - significant difference between PRESSURE vs. GDFT groupsb - significant difference between protocolled group (GDFT or PRESSURE) vs. CONTROLc - significant difference against baselineTable 3Clinical outcomeCONTROLPRESSUREGDFTP-value(N\u2009=\u200940)(N\u2009=\u200940)(N\u2009=\u200940)Rate of complications (all)33 (83 %)26 (65 %)22 (55 %)a0.03Rate of complications (major)3 (8 %)6 (15 %)2 (5 %)0.27Mortality0 (0 %)1 (2.5 %)0 (0 %)0.37Hospital length of stay (days)10.5 (8–12)10 (9–12.5)10 (8.5–13.5)0.99Discharge readiness (days)9 (8–12)9 (7–12)8 (7–10)0.06ICU length of stay (days)2 (2–2)2 (2–3)2 (2–3)0.3ICU readiness (days)2 (2–2)2 (2–2)2 (2–2)0.38Number of complications (all)666135N/ANumber of complications (major)383N/ABlood transfusion (patients)30 (75 %)25 (63 %)15 (38 %)a0.001Blood transfusion (units)2 (1–4)2 (0–4)0 (0–2)N/AComplications per group (Number of patients)Cardiovascular\u2003Minor2 (5 %)4 (10 %)0 (0 %)0.12\u2003Major0 (0 %)1 (2.5 %)1 (2.5 %)0.6Respiratory\u2003Minor1 (2.5 %)1 (2.5 %)0 (0 %)0.6\u2003Major0 (0 %)1 (2.5 %)0 (0 %)0.37Infectious\u2003Minor23 (57.5 %)9 (22.5 %)a9 (22.5 %)a0.001\u2003Major2 (5 %)3 (7.5 %)2 (5 %)0.86Renal\u2003Minor5 (12.5 %)7 (17.5 %)5 (12.5 %)0.76\u2003Major0 (0 %)0 (0 %)0 (0 %)1GIT\u2003Minor20 (50 %)17 (42.5 %)11 (27.5 %)0.12\u2003Major0 (0 %)0 (0 %)0 (0 %)1Nervous\u2003Minor1 (2.5 %)3 (7.5 %)3 (7.5 %)0.55\u2003Major0 (0 %)0 (0 %)0 (0 %)1Coagulation\u2003Minor6 (15 %)7 (17.5 %)3 (7.5 %)0.39\u2003Major1 (2.5 %)2 (5 %)0 (0 %)0.36Data are presented as median (interquartil range) or number (proportion)ICU intensive care unit, GIT gastro-intestinal tracta - significant difference between protocolled group (GDFT or PRESSURE) vs. CONTROLIn both protocol groups a trend for lower number of hypotensive periods was observed intraoperatively with lower dose of rescue vasoactive therapy. No significant differences were found between PPV values of both protocol groups (PRESSURE and GDFT). Pulse pressure variation was low in both groups in the beginning as well as at the end of the procedure. The overall fluid status (amount of fluids administered, blood loss etc.) was comparable in both protocol groups. Contrarily, the CONTROL patients received significantly higher amounts of fluid compared to both groups managed with protocol. A drop in hemoglobin level was observed among all patients, but was more pronounced in the CONTROL group patients (Fig.\xa03). A higher proportion of CONTROL patients needed transfusion during early as well as late postoperative periods. Serum lactate levels were assessed only in the prospective groups’ patients and showed no significant differences between PRESSURE and GDFT.Fig. 3Haemoglobin levels in perioperative period. Legend: # - significant difference PRESSURE vs. GDFT groups; $ - significant difference PRESSURE vs. CONTROL groups; * - significant difference GDFT vs. CONTROL groups (all ANOVA with Student-Neuman-Keul’s post hoc analysis); the drop against baseline measurement was significant in all groups and time-pointsDiscussionIn our study, the adoption of a fluid administration protocol guided by pulse pressure variation assessed by continuous non-invasive arterial pressure monitoring seems to be associated with lower rate of postoperative complications compared to standard no-protocol care. Reduced amounts of infused fluids with maintained hemodynamic stability, lower dose of rescue vasoactive medication and lower rate of transfusion requirements were observed among patients of the GDFT group compared to CONTROL patients.Fluid administration based on protocols with use of goal-directed hemodynamic optimization seems to be associated with improved postoperative outcomes in high risk surgical patients [3]. However, among intermediate risk patients, (for instance total hip or knee replacement) the evidence has been scarce and liberal strategies without proper monitoring are often accepted. Holte et al. [18] observed lower incidence in postoperative vomiting among patients managed with the liberal as opposed to the restrictive approach. The authors of this study hypothesized that preoperative fasting might influence this outcome and that a liberal regimen helps to cover the preoperative hypovolemia. According to values of PPV observed after induction, our patients were not hypovolemic before the procedure. In such cases a liberal approach might drive them into hypervolemia and resulting hemodilution. Red blood cell transfusions can exhibit immunosuppressive effect [19] and lead to increased incidence of infectious complications. In our study the protocol approach to fluid administration itself (PRESSURE group) was associated with a trend towards better clinical outcomes and lower transfusion needs. But it seems that only a complex protocol (restrictive maintenance with fluid responsiveness assessment- GDFT group) can adapt for the variable blood loss and individual needs. This is supported by our results or by the study by Cecconi [13]. In that trial, goal-directed fluid management was further combined with dopexamine infusion in order to reach a predefined goal of oxygen delivery. Lower incidence of cardiac and minor organ complications was observed, resembling our data. However, the use of inotropic support might be questioned in patients without significant cardiac morbidity and the use of arterial catheters is also not standard for these procedures.The outcomes of the GDFT group patients show that fluid optimization itself might be sufficient in this intermediate risk population. Recent meta-analysis demonstrated that dynamic predictors of fluid responsiveness are useful as goals of perioperative GDT [11]. Using them is much easier than complex cardiac output monitoring and oxygen delivery calculation. In addition, the number of limitations in intermediate risk groups seems to be much lower than reported by Maguire [12]: atrial fibrillation was present only in 3 (3 %) out of 97 eligible patients and no other limitations for the use of PPV were observed among our patients. The ventilation strategy (tidal volume of 8\xa0ml/kg and positive end expiratory pressure of 0.6 kPa) is in line with recent recommendations for intraoperative protective ventilation [20], but still enabling the use of dynamic variations. An important aspect of our trial is that the protocol was based on measurements obtained totally non-invasively.Our study is the first one using the novel non-invasive continuous pressure device based on volume-clamped method for goal-directed treatment. Both the reliability and limits of the measurement should be recognized, even though the device is marketed worldwide and approved by most certification authorities. As for now three large scale [21–23] and multiple smaller studies demonstrated the validity of the pressure values obtained by the CNAP® monitor, showing acceptable agreement with direct arterial pressure monitoring. Some inaccuracies seem to exist in cases of profound pressure fluctuations (i.e. deep hypotension following anesthesia induction etc.). The trending ability remained unaffected by these inaccuracies [24, 25]. In addition, as pointed out by Hahn [22], the device uses the oscillometric cuff as a reference, making it equivalent to contemporary practice in the studied population. It was demonstrated by our group [26] as well as by others [27, 28] that the use of continuous non-invasive pressure monitoring devices enables faster recognition of blood pressure drops and helps to maintain the hemodynamic stability during surgery. The reliability of the PPV values obtained by the CNAP® monitor was tested recently by two studies and was found to be comparable to its invasively assessing counterparts [29, 30]. Given these positive factors, the CNAP® device is already widely and routinely used in many clinical institutions; therefore our study could serve as a proof of concept for this praxis.The design of our study poses an important selection and assessment bias and hence limits the generalizability of our results. Firstly, the use of a two-stage (“before and after”) design does not allow us to compare the CONTROL group and protocol groups in parallel. However, our aim was to quantify the effect of change in approach during the unique moment of transition between no-protocol and protocol-led care. In order to avoid selection bias, all patients undergoing the procedure within the defined stages were found eligible. In the first stage there were no dropouts and only a limited number of patients was excluded during the second stage. Secondly, our study was not set to evaluate between the groups of phase two so we can derive only indirect conclusions in regard of superiority of the goal-directed fluid optimization over the restrictive regimen. This observed difference resulted mainly from the lower incidence of minor infectious complications (mostly urinary tract and surgical site infections). Besides blood and fluids management this might also be confounded by a slightly uneven distribution of comorbidities. Even though not statistically significant, patients in the GDFT group tended to be healthier. This could influence both the transfusion trigger and also the risk for complications as well as help reach the predefined readiness for discharge criteria earlier.Beside these specific limitations, our trial suffers from flaws inherent to single centre studies with “keen investigators” and a low number of patients. This might be especially true for intermediate risk patients with a low number of complications. For this reason our conclusions should be regarded as a hypothesis generating at best. A much larger study would be necessary to prove this concept. However, it seems that the use of the continuous non-invasive arterial pressure device might offer a safe alternative for monitoring and enable better adoption of fluid protocols.ConclusionsIn conclusion, in our study the transition from standard no-protocol treatment to the fluid management protocol based on pulse pressure variation assessed by continuous non-invasive arterial pressure measurement seems to be associated with reduction of postoperative infections, of organ complications, and of transfusion needs.Additional filesAdditional file 1:The CONSORT Check list. (DOC 217\xa0kb)Additional file 2:List of predefined morbidity criteria for ICU and hospital discharge and list of complications. (DOCX 15\xa0kb)AbbreviationsASAAmerican Society of Anesthesiology physical statusCNAPContinuous Non-invasive Arterial Pressure (name of the device)CONTROLName of the prospective observational groupGDFTName of the randomized group with fluid management based on pulse pressure variationGDTGoal-directed therapyGITGastro-intestinal tractHRHeart rateICUIntensive Care UnitMACMinimal alveolar concentrationMAPMean arterial pressurePPVPulse pressure variationPONVPostoperative nausea and vomitingPRESSUREName of the randomized group based on standard fluid managementWHOWorld Health OrganizationCompeting interestsJB is an advisory board member for Edwards Lifesciences Inc., all other co-authors declare to have no competing interests.Authors’ contributionsJB: Designed the study, performed the data analysis and wrote the manuscript. LH, JP and JS: Performed the patients’ recruitment, randomization and anaesthesia care, revised the manuscript. AS: Was responsible for the postoperative clinical assessment and revised the manuscript. JZ and RP: Performed the clinical assessment of the observational group and helped to write the manuscript. ICh and EK: Helped to design the study, participated on data analysis and writing the manuscript. All authors approved the final form of the text.AcknowledgementThe study was supported by the Charles University Research Fund (project number P36), the open access fee was granted by the CNSystems Graz, Austria.The CNAP® Monitor and Task Force® Monitor software were supplied by CNSystems, Graz, Austria.There were no additional payments depending on the results of the study.References1.SrinivasaSKahokehrASoopMTaylorMHillAGGoal-directed fluid therapy- a survey of anaesthetists in the UK, USA, Australia and New ZealandBMC Anesthesiol201313510.1186/1471-2253-13-5234330642.HamiltonMACecconiMRhodesAA systematic review and meta-analysis on the Use of preemptive hemodynamic intervention to improve postoperative outcomes in moderate and high-risk surgical patientsAnesth Analg20111126139240210.1213/ANE.0b013e3181eeaae5209664363.CorcoranTRhodesJEJClarkeSMylesPSHoKMPerioperative fluid management strategies in major surgery: a stratified meta-analysisAnesth Analg201211436405110.1213/ANE.0b013e318240d6eb222532744.GrocottMPWDushianthanAHamiltonMAMythenMGHarrisonDRowanKPerioperative increase in global blood flow to explicit defined goals and outcomes after surgery: a cochrane systematic reviewBr J Anaesth201311145354810.1093/bja/aet155236614035.CecconiMBennettDShould we use early less invasive hemodynamic monitoring in unstable ICU patients?Crit Care201115417310.1186/cc10287218886816.Bundgaard-NielsenMSecherNHKehletH‘Liberal’ vs. ‘restrictive’ perioperative fluid therapy--a critical assessment of the evidenceActa Anaesthesiol Scand20095378435110.1111/j.1399-6576.2009.02029.x195197237.GlassfordNJMylesPBellomoRThe Australian approach to peri-operative fluid balanceCurr Opin Anaesthesiol20122511021010.1097/ACO.0b013e32834decd7221131858.CannessonMPestelGRicksCHoeftAPerelAHemodynamic monitoring and management in patients undergoing high risk surgery: a survey among North American and European anesthesiologistsCrit Care2011154R19710.1186/cc10364218433539.ForgetPLoisFde KockMGoal-directed fluid management based on the pulse oximeter-derived pleth variability index reduces lactate levels and improves fluid managementAnesth Analg2010111491042070578510.LopesMROliveiraMAPereiraVLemosIAulerJMichardFGoal-directed fluid management based on pulse pressure variation monitoring during high-risk surgery: a pilot randomized controlled trialCrit Care2007115R10010.1186/cc61171782256511.BenesJGiglioMBrienzaNMichardFThe effects of goal-directed fluid therapy based on dynamic parameters on post-surgical outcome: a meta-analysis of randomized controlled trialsCrit Care201418558410.1186/s13054-014-0584-z2534890012.MaguireSRinehartJVakhariaSCannessonMTechnical communication: respiratory variation in pulse pressure and plethysmographic waveforms: intraoperative applicability in a North American academic centerAnesth Analg2011112194610.1213/ANE.0b013e318200366b2097824613.CecconiMFasanoNLangianoNDivellaMCostaMRhodesAGoal directed haemodynamic therapy during elective total hip arthroplasty under regional anaesthesiaCrit Care2011153R13210.1186/cc102462162413814.ScheerBPerelAPfeifferUJClinical review: complications and risk factors of peripheral arterial catheters used for haemodynamic monitoring in anaesthesia and intensive care medicineCrit Care20026319920410.1186/cc14891213317815.SchulzKFAltmanDGMoherDCONSORT GroupCONSORT 2010 statement: updated guidelines for reporting parallel group randomised trialsBMJ2010340c33210.1136/bmj.c3322033250916.FortinJMarteWGrüllenbergerRHackerAHabenbacherWHellerAContinuous non-invasive blood pressure monitoring using concentrically interlocking control loopsComput Biol Med20063699415710.1016/j.compbiomed.2005.04.0031648356217.BenesJChytraIAltmannPHluchyMKasalESvitakRIntraoperative fluid optimization using stroke volume variation in high risk surgical patients: results of prospective randomized studyCrit Care2010143R11810.1186/cc90702055358618.HolteKKristensenBBValentinerLFossNBHustedHKehletHLiberal versus restrictive fluid management in knee arthroplasty: a randomized, double-blind studyAnesth Analg200710524657410.1213/01.ane.0000263268.08222.191764650719.VamvakasECWhite-blood-cell-containing allogeneic blood transfusion and postoperative infection or mortality: an updated meta-analysisVox Sang20079232243210.1111/j.1423-0410.2006.00889.x1734887120.FutierEConstantinJMPaugam-BurtzCPascalJEurinMNeuschwanderAA trial of intraoperative low-tidal-volume ventilation in abdominal surgeryN Engl J Med201336954283710.1056/NEJMoa13010822390248221.BiaisMVidilLRoulletSMassonFQuinartARevelPContinuous non-invasive arterial pressure measurement: evaluation of CNAP device during vascular surgeryAnn Fr Anesth Reanim2010297–8530510.1016/j.annfar.2010.05.0022054240522.HahnRRinöslHNeunerMKettnerSCClinical validation of a continuous non-invasive haemodynamic monitor (CNAP 500) during general anaesthesiaBr J Anaesth20121084581510.1093/bja/aer4992230724223.JeleazcovCKrajinovicLMünsterTBirkholzTFriedRSchüttlerJPrecision and accuracy of a new device (CNAPTM) for continuous non-invasive arterial pressure monitoring: assessment during general anaesthesiaBr J Anaesth201010532647210.1093/bja/aeq1432062787824.IliesCBauerMBergPRosenbergJHedderichJBeinBInvestigation of the agreement of a continuous non-invasive arterial pressure device in comparison with invasive radial artery measurementBr J Anaesth201210822021010.1093/bja/aer3942217135825.GayatEMongardonNTuilOSievertKChazotTLiuNCNAP(®) does not reliably detect minimal or maximal arterial blood pressures during induction of anaesthesia and tracheal intubationActa Anaesthesiol Scand20135744687310.1111/aas.120282318602226.Benes J, Simanova A, Tovarnicka T, Sevcikova S, Kletecka J, Zatloukal J, et al. Continuous non-invasive monitoring improves blood pressure stability in upright position: randomized controlled trial. J Clin Monit Comput. 2014.27.ChenGChungEMengLAlexanderBVuTRinehartJImpact of non invasive and beat-to-beat arterial pressure monitoring on intraoperative hemodynamic managementJ Clin Monit Comput20122621334010.1007/s10877-012-9344-22238292028.IliesCKiskaltHSiedenhansDMeybohmPSteinfathMBeinBDetection of hypotension during Caesarean section with continuous non-invasive arterial pressure device or intermittent oscillometric arterial pressure measurementBr J Anaesth20121093413910.1093/bja/aes2242279827329.BiaisMSteckenLOttolenghiLRoulletSQuinartAMassonFThe ability of pulse pressure variations obtained with CNAP™ device to predict fluid responsiveness in the operating roomAnesth Analg2011113352382164260630.MonnetXDresMFerréALe TeuffGJozwiakMBleibtreuAPrediction of fluid responsiveness by a continuous non-invasive assessment of arterial pressure in critically ill patients: comparison with four other dynamic indicesBr J Anaesth20121093330810.1093/bja/aes18222735299', 'title': 'Fluid management guided by a continuous non-invasive arterial pressure device is associated with decreased postoperative morbidity after total knee and hip replacement.', 'date': '2015-10-17'}, '22710266': {'article_id': '22710266', 'content': 'We aimed to investigate whether fluid therapy with a goal of near-maximal stroke volume (SV) guided by oesophageal Doppler (ED) monitoring result in a better outcome than that with a goal of maintaining bodyweight (BW) and zero fluid balance in patients undergoing colorectal surgery.\nIn a double-blinded clinical multicentre trial, 150 patients undergoing elective colorectal surgery were randomized to receive fluid therapy after either the goal of near-maximal SV guided by ED (Doppler, D group) or the goal of zero balance and normal BW (Zero balance, Z group). Stratification for laparoscopic and open surgery was performed. The postoperative fluid therapy was similar in the two groups. The primary endpoint was postoperative complications defined and divided into subgroups by protocol. Analysis was performed by intention-to-treat. The follow-up was 30 days. The trial had 85% power to show a difference between the groups.\nThe number of patients undergoing laparoscopic or open surgery and the patient characteristics were similar between the groups. No significant differences between the groups were found for overall, major, minor, cardiopulmonary, or tissue-healing complications (P-values: 0.79; 0.62; 0.97; 0.48; and 0.48, respectively). One patient died in each group. No significant difference was found for the length of hospital stay [median (range) Z: 5.00 (1-61) vs D: 5.00 (2-41); P=0.206].\nGoal-directed fluid therapy to near-maximal SV guided by ED adds no extra value to the fluid therapy using zero balance and normal BW in patients undergoing elective colorectal surgery.', 'title': 'Which goal for fluid therapy during colorectal surgery is followed by the best outcome: near-maximal stroke volume or zero fluid balance?', 'date': '2012-06-20'}, '25342408': {'article_id': '25342408', 'content': 'There is continued controversy regarding the benefits of goal-directed fluid therapy, with earlier studies showing marked improvement in morbidity and length-of-stay that have not been replicated more recently. The aim of this study was to compare patient outcomes in elective colorectal surgery patients having goal-directed versus restrictive fluid therapy. Inclusion criteria included suitability for an Enhanced Recovery After Surgery care pathway and patients with an American Society of Anesthesiologists Physical Status score of 1 to 3. Patients were intraoperatively randomised to either restrictive or Doppler-guided goal-directed fluid therapy. The primary outcome was length-of-stay; secondary outcomes included complication rate, change in haemodynamic variables and fluid volumes. Compared to restrictive therapy, goal-directed therapy resulted in a greater volume of intraoperative fluid, 2115 (interquartile range 1350 to 2560) ml versus 1500 (1200 to 2000) ml, P=0.008, and was associated with an increase in Doppler-derived stroke volume index from beginning to end of surgery, 43.7 (16.3) to 54.2 (21.1) ml/m(2), P <0.001, in the latter group. Length-of-stay was similar, 6.5 (5 to 9) versus 6 (4 to 9) days, P=0.421. The number of patients with any complication (minor or major) was similar; 0% (30) versus 52% (26), P=0.42, or major complications, 1 (2%) versus 4 (8%), P=0.36, respectively. The increased perioperative fluid volumes and increased stroke volumes at the end of surgery in patients receiving goal-directed therapy did not translate to a significant difference in length-of-stay and we did not observe a difference in the number of patients experiencing minor or major complications.', 'title': 'A randomised controlled trial of fluid restriction compared to oesophageal Doppler-guided goal-directed fluid therapy in elective major colorectal surgery within an Enhanced Recovery After Surgery program.', 'date': '2014-10-25'}, '23132508': {'article_id': '23132508', 'content': "Goal-directed fluid therapy (GDFT) has been compared with liberal fluid administration in non-optimized perioperative settings. It is not known whether GDFT is of value within an enhanced recovery protocol incorporating fluid restriction. This study evaluated GDFT under these circumstances in patients undergoing elective colectomy.\nPatients undergoing elective laparoscopic or open colectomy within an established enhanced recovery protocol (including fluid restriction) were randomized to GDFT or no GDFT. Bowel preparation was permitted for left colonic operations at the surgeon's discretion. Exclusion criteria included rectal tumours and stoma formation. The primary outcome was a patient-reported surgical recovery score (SRS). Secondary endpoints included clinical outcomes and physiological measures of recovery.\nEighty-five patients were randomized, and there were 37 patients in each group for analysis. Nine patients in the GDFT and four in the fluid restriction group received oral bowel preparation for either anterior resection (12) or subtotal colectomy (1). Patients in the GDFT group received more colloid during surgery (mean 591 versus 297 ml; P = 0·012) and had superior cardiac indices (mean corrected flow time 374 versus 355 ms; P = 0·018). However, no differences were observed between the GDFT and fluid restriction groups with regard to surgical recovery (mean SRS after 7 days 47 versus 46 respectively; P = 0·853), other secondary outcomes (mean aldosterone/renin ratio 9 versus 8; P = 0·898), total postoperative fluid (median 3750 versus 2400 ml; P = 0·604), length of hospital stay (median 6 versus 5 days; P = 0·570) or number of patients with complications (26 versus 27; P = 1·000).\nGDFT did not provide clinical benefit in patients undergoing elective colectomy within a protocol incorporating fluid restriction.\nNCT00911391 (http://www.clinicaltrials.gov).", 'title': 'Randomized clinical trial of goal-directed fluid therapy within an enhanced recovery protocol for elective colectomy.', 'date': '2012-11-08'}}
| 0.8
|
Surgery
|
84
|
Is survival to hospital discharge higher, lower, or the same when comparing biphasic waveform defibrillation to monophasic waveform defibrillation?
|
no difference
| null |
no
|
['11719116', '17060379', '12867305', '15992986']
| 26,904,970
| 2,016
|
{'11719116': {'article_id': '11719116', 'content': 'Advances in early defibrillation access, key to the "Chain of Survival", will depend on innovations in defibrillation waveforms, because of their impact on device size and weight. This study compared standard monophasic waveform automatic external defibrillators (AEDs) to an innovative biphasic waveform AED.\nImpedance-compensated biphasic truncated exponential (ICBTE) and either monophasic truncated exponential (MTE) or monophasic damped sine (MDS) AEDs were prospectively, randomly assigned by date in four emergency medical services. The study design compared ICBTE with MTE and MDS combined. This subset analysis distinguishes between the two classes of monophasic waveform, MTE and MDS, and compares their performance to each other and to the biphasic waveform, contingent on significant overall effects (ICBTE vs. MTE vs. MDS). Primary endpoint: Defibrillation efficacy with < or =3 shocks. Secondary endpoints: shock efficacy with < or =1 shock, < or =2 shocks, and survival to hospital admission and discharge. Observations included return of spontaneous circulation (ROSC), refibrillation, and time to first shock and to first successful shock.\nOf 338 out-of-hospital cardiac arrests, 115 had a cardiac aetiology, presented with ventricular fibrillation, and were shocked by an AED. Defibrillation efficacy for the first "stack" of up to 3 shocks, for up to 2 shocks and for the first shock alone was superior for the ICBTE waveform than for either the MTE or the MDS waveform, while there was no difference between the efficacy of MTE and MDS. Time from the beginning of analysis by the AED to the first shock and to the first successful shock was also superior for the ICBTE devices compared to either the MTE or the MDS devices, while again there was no difference between the MTE and MDS devices. More ICBTE patients achieved ROSC pre-hospital than did MTE patients. While the rates of ROSC were identical for MTE and MDS patients, the difference between ICBTE and MDS was not significant. Rates of refibrillation and survival to hospital admission and discharge did not differ among the three populations.\nICBTE was superior to MTE and MDS in defibrillation efficacy and speed and to MTE in ROSC. MTE and MDS did not differ in efficacy. There were no differences among the waveforms in refibrillation or survival.', 'title': 'Optimal Response to Cardiac Arrest study: defibrillation waveform effects.', 'date': '2001-11-24'}, '17060379': {'article_id': '17060379', 'content': 'Although biphasic, as compared with monophasic, waveform defibrillation for cardiac arrest is increasing in use and popularity, whether it is truly a more lifesaving waveform is unproven.\nConsecutive adults with nontraumatic out-of-hospital ventricular fibrillation cardiac arrest were randomly allocated to defibrillation according to the waveform from automated external defibrillators administered by prehospital medical providers. The primary event of interest was admission alive to the hospital. Secondary events included return of rhythm and circulation, survival, and neurological outcome. Providers were blinded to automated defibrillator waveform. Of 168 randomized patients, 80 (48%) and 68 (40%) consistently received only monophasic or biphasic waveform shocks, respectively, throughout resuscitation. The prevalence of ventricular fibrillation, asystole, or organized rhythms at 5, 10, or 20 seconds after each shock did not differ significantly between treatment groups. The proportion of patients admitted alive to the hospital was relatively high: 73% in monophasic and 76% in biphasic treatment groups (P=0.58). Several favorable trends were consistently associated with receipt of biphasic waveform shock, none of which reached statistical significance. Notably, 27 of 80 monophasic shock recipients (34%), compared with 28 of 68 biphasic shock recipients (41%), survived (P=0.35). Neurological outcome was similar in both treatment groups (P=0.4). Earlier administration of shock did not significantly alter the performance of one waveform relative to the other, nor did shock waveform predict any clinical outcome after multivariate adjustment.\nNo statistically significant differences in outcome could be ascribed to use of one waveform over another when out-of-hospital ventricular fibrillation was treated.', 'title': 'Transthoracic incremental monophasic versus biphasic defibrillation by emergency responders (TIMBER): a randomized comparison of monophasic with biphasic waveform ascending energy defibrillation for the resuscitation of out-of-hospital cardiac arrest due to ventricular fibrillation.', 'date': '2006-10-25'}, '12867305': {'article_id': '12867305', 'content': 'Evidence suggests that biphasic waveforms are more effective than monophasic waveforms for defibrillation in out-of-hospital cardiac arrest (OHCA), yet their performance has only been compared in un-blinded studies.\nWe compared the success of biphasic truncated exponential (BTE) and monophasic damped sine (MDS) shocks for defibrillation in OHCA in a prospective, randomised, double blind clinical trial. First responders were equipped with MDS and BTE automated external defibrillators (AEDs) in a random fashion. Patients in ventricular fibrillation (VF) received BTE or MDS first shocks of 200 J. The ECG was recorded for subsequent analysis continuously. The success of the first shock as a primary endpoint was removal of VF and required a return of an organized rhythm for at least two QRS complexes, with an interval of <5 s, within 1 min after the first shock. The secondary endpoint was termination of VF at 5 s. VF was the initial recorded rhythm in 120 patients in OHCA, 51 patients received BTE and 69 received MDS shocks. The success rate of 200 J first shocks was significantly higher for BTE than for MDS shocks, 35/51 (69%) and 31/69 (45%), P=0.01. In a logistic regression model the odds ratio of success for a BTE shock was 4.01 (95% CI 1.01-10.0), adjusted for baseline cardiopulmonary resuscitation, VF-amplitude and time between collapse and first shock. No difference was found with respect to the secondary endpoint, termination of VF at 5 s (RR 1.07 95% CI: 0.99-1.11) and with respect to survival to hospital discharge (RR 0.73 95% CI: 0.31-1.70).\nBTE-waveform AEDs provide significantly higher rates of successful defibrillation with return of an organized rhythm in OHCA than MDS waveform AEDs.', 'title': 'A prospective, randomised and blinded comparison of first shock success of monophasic and biphasic waveforms in out-of-hospital cardiac arrest.', 'date': '2003-07-18'}, '15992986': {'article_id': '15992986', 'content': 'Although biphasic defibrillation waveforms appear to be superior to monophasic waveforms in terminating VF, their relative benefits in out-of-hospital resuscitation are incompletely understood. Prior comparisons of defibrillation waveform efficacy in out-of-hospital cardiac arrest (OHCA) are confined to patients presenting in a shockable rhythm and resuscitated by first responder (basic life support). This effectiveness study compared monophasic and biphasic defibrillation waveform for conversion of ventricular arrhythmias in all OHCA treated with advance life support (ALS).\nThis prospective randomized controlled trial compared the rectilinear biphasic (RLB) waveform with the monophasic damped sine (MDS) waveform, using step-up energy levels. The study enrolled OHCA patients requiring at least one shock delivered by ALS providers, regardless of initial presenting rhythm. Shock success was defined as conversion at 5s to organized rhythm after one to three escalating shocks. We report efficacy results for the cohort of patients treated by ALS paramedics who presented with an initially shockable rhythm who had not received a shock from a first responder (MDS: n=83; RLB: n=86). Shock success within the first three ascending energy shocks for RLB (120, 150, 200J) was superior to MDS (200, 300, 360J) for patients initially presenting in a shockable rhythm (52% versus 34%, p=0.01). First shock conversion was 23% and12%, for RLB and MDS, respectively (p=0.07). There were no significant differences in return of spontaneous circulation (47% versus 47%), survival to 24h (31% versus 27%), and survival to discharge (9% versus 7%). Mean 24h survival rates of bystander witnessed events showed differences between waveforms in the early circulatory phase at 4-10 min post event (mean (S.D.) RLB 0.45 (0.07) versus MDS 0.31 (0.06), p=0.0002) and demonstrated decline as time to first shock increased to 20 min.\nShock success to an organized rhythm comparing step-up protocol for energy settings demonstrated the RLB waveform was superior to MDS in ALS treatment of OHCA. Survival rates for both waveforms are consistent with current theories on the circulatory and metabolic phases of out-of-hospital cardiac arrest.', 'title': 'Out-of-hospital cardiac arrest rectilinear biphasic to monophasic damped sine defibrillation waveforms with advanced life support intervention trial (ORBIT).', 'date': '2005-07-05'}}
| 1
|
Emergency Medicine & Critical Care
|
85
|
Is survival to hospital admission higher, lower, or the same when comparing biphasic waveform defibrillation to monophasic waveform defibrillation?
|
no difference
| null |
no
|
['11719116', '17060379']
| 26,904,970
| 2,016
|
{'11719116': {'article_id': '11719116', 'content': 'Advances in early defibrillation access, key to the "Chain of Survival", will depend on innovations in defibrillation waveforms, because of their impact on device size and weight. This study compared standard monophasic waveform automatic external defibrillators (AEDs) to an innovative biphasic waveform AED.\nImpedance-compensated biphasic truncated exponential (ICBTE) and either monophasic truncated exponential (MTE) or monophasic damped sine (MDS) AEDs were prospectively, randomly assigned by date in four emergency medical services. The study design compared ICBTE with MTE and MDS combined. This subset analysis distinguishes between the two classes of monophasic waveform, MTE and MDS, and compares their performance to each other and to the biphasic waveform, contingent on significant overall effects (ICBTE vs. MTE vs. MDS). Primary endpoint: Defibrillation efficacy with < or =3 shocks. Secondary endpoints: shock efficacy with < or =1 shock, < or =2 shocks, and survival to hospital admission and discharge. Observations included return of spontaneous circulation (ROSC), refibrillation, and time to first shock and to first successful shock.\nOf 338 out-of-hospital cardiac arrests, 115 had a cardiac aetiology, presented with ventricular fibrillation, and were shocked by an AED. Defibrillation efficacy for the first "stack" of up to 3 shocks, for up to 2 shocks and for the first shock alone was superior for the ICBTE waveform than for either the MTE or the MDS waveform, while there was no difference between the efficacy of MTE and MDS. Time from the beginning of analysis by the AED to the first shock and to the first successful shock was also superior for the ICBTE devices compared to either the MTE or the MDS devices, while again there was no difference between the MTE and MDS devices. More ICBTE patients achieved ROSC pre-hospital than did MTE patients. While the rates of ROSC were identical for MTE and MDS patients, the difference between ICBTE and MDS was not significant. Rates of refibrillation and survival to hospital admission and discharge did not differ among the three populations.\nICBTE was superior to MTE and MDS in defibrillation efficacy and speed and to MTE in ROSC. MTE and MDS did not differ in efficacy. There were no differences among the waveforms in refibrillation or survival.', 'title': 'Optimal Response to Cardiac Arrest study: defibrillation waveform effects.', 'date': '2001-11-24'}, '17060379': {'article_id': '17060379', 'content': 'Although biphasic, as compared with monophasic, waveform defibrillation for cardiac arrest is increasing in use and popularity, whether it is truly a more lifesaving waveform is unproven.\nConsecutive adults with nontraumatic out-of-hospital ventricular fibrillation cardiac arrest were randomly allocated to defibrillation according to the waveform from automated external defibrillators administered by prehospital medical providers. The primary event of interest was admission alive to the hospital. Secondary events included return of rhythm and circulation, survival, and neurological outcome. Providers were blinded to automated defibrillator waveform. Of 168 randomized patients, 80 (48%) and 68 (40%) consistently received only monophasic or biphasic waveform shocks, respectively, throughout resuscitation. The prevalence of ventricular fibrillation, asystole, or organized rhythms at 5, 10, or 20 seconds after each shock did not differ significantly between treatment groups. The proportion of patients admitted alive to the hospital was relatively high: 73% in monophasic and 76% in biphasic treatment groups (P=0.58). Several favorable trends were consistently associated with receipt of biphasic waveform shock, none of which reached statistical significance. Notably, 27 of 80 monophasic shock recipients (34%), compared with 28 of 68 biphasic shock recipients (41%), survived (P=0.35). Neurological outcome was similar in both treatment groups (P=0.4). Earlier administration of shock did not significantly alter the performance of one waveform relative to the other, nor did shock waveform predict any clinical outcome after multivariate adjustment.\nNo statistically significant differences in outcome could be ascribed to use of one waveform over another when out-of-hospital ventricular fibrillation was treated.', 'title': 'Transthoracic incremental monophasic versus biphasic defibrillation by emergency responders (TIMBER): a randomized comparison of monophasic with biphasic waveform ascending energy defibrillation for the resuscitation of out-of-hospital cardiac arrest due to ventricular fibrillation.', 'date': '2006-10-25'}}
| 1
|
Emergency Medicine & Critical Care
|
86
|
Is the incidence of surgical site infection (SSI) for patients undergoing breast cancer surgery without reconstruction higher, lower, or the same when comparing prophylactic antibiotics administered preoperatively to no antibiotic or placebo?
|
lower
|
moderate
|
no
|
['11063500', '23001082', '16989011', '7480237', '9776150', '23052809', '10873356', '19673597', '2403655', '2403697']
| 31,557,310
| 2,019
|
{'11063500': {'article_id': '11063500', 'content': 'Based on the observation that administration of clarithromycin led to an attenuation of the inflammatory response induced by surgical trauma in a guinea pig model, we investigated the potential beneficial effects of clarithromycin on the local and systemic inflammatory response in patients undergoing mastectomy in an open-label prospective study. During a 16-month period, 54 patients who underwent mastectomy were randomly divided into two groups. In one group, the patients received oral clarithromycin at a dose of 500 mg twice a day, from the day before to 3 days after mastectomy. There was no significant difference in the incidence of antibiotic prophylaxis-related toxicities or postoperative infections between the patients who received clarithromycin and those who did not. Clarithromycin treatment was significantly associated with an attenuation of febrile response, tachycardia, tachypnea, and an increase in monocyte counts (P, <0.0001, <0.01, <0.05, and <0.01, respectively). Clarithromycin also reduced the intensity and duration of postoperative pain (P, <0.05 and <0.005, respectively) and increased the range of motion of the involved shoulder (P < 0.05 for abduction and flexion). We conclude that clarithromycin effectively modulates the acute inflammatory response associated with mastectomy and produces a better clinical outcome.', 'title': 'Clarithromycin attenuates mastectomy-induced acute inflammatory response.', 'date': '2000-11-04'}, '23001082': {'article_id': '23001082', 'content': 'To assess the impact of prophylactic antibiotics on the prevention of surgical site infection (SSI) and the cost-effectiveness of this prophylaxis for breast cancer surgery in overweight or obese women.\nSSI is higher than expected after breast surgery. Obesity was found to be one of the risk factors.\nThe trial was designed as a phase IV randomized, controlled, parallel-group efficacy trial. It was conducted at a tertiary university hospital. Overweight or obese women with clinically early-stage breast cancer who had been assigned to undergo surgery were eligible. Patients were randomly allocated to either a prophylaxis or a control group by using a computer-generated list. The prophylaxis group received 1 g ampicillin-sulbactam intravenously at anesthesia. The control group received no intervention. Patients and observers were blinded to the assignments. The primary outcome was the comparison of SSI incidences of the 2 groups. Patients were monitored for 30 days.\nA total of 369 patients were included in final analysis, out of which 187 were allocated for prophylaxis and 182 were randomly assigned to the control group. Analysis was done according to the intention-to-treat principle. Prophylaxis significantly reduced the SSI rate (4.8%) in the prophylaxis group when compared with that in the control group [13.7%; relative risk (RR) 0.35; 95% CI: 0.17-0.73]. No adverse reaction was observed. The mean SSI-related cost (20.26 USD) was found to be significantly higher in the control group when compared with that (8.48 USD) in the prophylaxis group.\nAntibiotic prophylaxis significantly decreased SSI incidence after elective surgery and was shown to be cost-effective in obese breast cancer patients. ClinicalTrials.gov Identifier: NCT00356148.', 'title': 'Efficacy of prophylactic antibiotic administration for breast cancer surgery in overweight or obese patients: a randomized controlled trial.', 'date': '2012-09-25'}, '16989011': {'article_id': '16989011', 'content': 'The aim of this randomized clinical trial was to determine whether a single intravenous dose of 2 g flucloxacillin could prevent wound infection after primary non-reconstructive breast surgery.\nThe study included 618 patients undergoing local excision (n = 490), mastectomy (n = 107) or microdochectomy (n = 21). Patients were randomized to receive either a single dose of flucloxacillin immediately after the induction of anaesthesia or no intervention. Wound morbidity was monitored by an independent research nurse for 42 days after surgery.\nThe incidence of wound infection was similar in the two groups: 10 of 311 (3.2 percent) in the flucloxacillin group and 14 of 307 (4.6 percent) in the control group (chi(2) = 0.75, P = 0.387; relative risk 0.71, 95 percent confidence interval 0.32 to 1.53). The groups also had similar wound scores and rates of moderate or severe cellulitis. Wound infection presented a median of 16 days after surgery.\nThe administration of a single dose of flucloxacillin failed to reduce the rate of wound infection after non-reconstructive breast surgery.', 'title': 'Randomized clinical trial of single-dose antibiotic prophylaxis for non-reconstructive breast surgery.', 'date': '2006-09-22'}, '7480237': {'article_id': '7480237', 'content': 'Over a 9-month period from September of 1991 to May of 1992, 339 patients were included in a randomized, double-blind, placebo-controlled study using azithromycin as the prophylactic agent to determine whether it effects a clinically meaningful reduction in postoperative surgical infections in plastic surgery. Azithromycin was given as prophylaxis in 171 patients and placebo in 168 patients. The study medication was a single oral dose taken at 8 P.M. the day before surgery. The patients were followed up for a minimum of 4 weeks after surgery. The patients who received wound infection prophylaxis had 5.1 percent infections compared with 20.5 percent in the placebo group (p = 0.00009). Eighty percent of all wound infections were first seen after discharge, explaining why plastic surgeons might overlook their infectious complications. There was a significant reduction in postoperative complications (p = 0.04) and in the additional use of antibiotics postoperatively (p = 0.007) in the prophylaxis group. Subgroup analysis showed a significant reduction in surgical infections in breast surgery (p < 0.05) and reconstructive surgery with flaps (p < 0.05). No effect of the prophylactic regime was demonstrated in patients undergoing secondary surgery for cleft lip and palate disease.', 'title': 'A prospective, double-blind, placebo-controlled trial of a single dose of azithromycin on postoperative wound infections in plastic surgery.', 'date': '1995-11-01'}, '9776150': {'article_id': '9776150', 'content': 'Antibiotic prophylaxis is controversial in patients undergoing axillary lymph node dissection (ALND). We determined whether preoperative antibiotics decreased incidence or treatment cost of infectious complications following ALND.\nTwo hundred patients entered this prospective, randomized, double-blind trial. Patients received either placebo or cefonicid preoperatively. Loco-regional signs of infection were monitored for 4 weeks postoperatively.\nThere was a trend toward fewer infections in the prophylactic group (placebo 13% versus cefonicid 6%; P = 0.080). Cefonicid significantly decreased severe infections requiring hospitalization (placebo 8% versus cefonicid 1%; P = 0.033). Cefonicid also decreased the treatment cost of infection per patient ($49.80 versus $364.87).\nWe demonstrated a trend toward fewer overall infections and significantly fewer severe infections in patients given prophylactic antibiotics, which translated into a decrease in the cost of treatment for infectious complications. These findings support antibiotic prophylaxis for patients undergoing ALND.', 'title': 'Prospective, randomized, double-blind study of prophylactic antibiotics in axillary lymph node dissection.', 'date': '1998-10-17'}, '23052809': {'article_id': '23052809', 'content': 'The effectiveness of antibiotic prophylaxis for prevention of surgical site infection (SSI) following specific types of breast cancer surgery remains uncertain. This study assessed the effectiveness of prophylaxis in modified radical mastectomy (MRM).\nWomen undergoing MRM for breast cancer were recruited. Women were excluded who had diabetes mellitus, severe malnutrition or known allergy to cephalosporins; were receiving corticosteroid therapy or were treated with antibiotics within one week prior to surgery; were scheduled for simultaneous breast reconstruction or bilateral oophorectomy; had existing local infection. Participants were randomized to receive either intravenous cefazolin 1 g or placebo within 30 min prior to skin incision. Standard skin preparation and operative technique for MRM were carried out. Wounds were assessed for SSI and other complications weekly for 30 days.\nA total of 254 women were recruited. Age, clinical stage, prior chemotherapy, and operative time were similar for antibiotic and placebo groups. The overall incidence of SSI was 14.2 %. There were no significant differences in the infection rate over the 30-day follow-up period between the placebo and antibiotic groups (15 % vs 13.4 %; p = 0.719) or at each week. The majority of SSI were either cellulitis or superficial infection for both groups. There were no significant differences between groups in treatments required for SSI, incidence of hematoma or seroma.\nThe findings of this study, alone and when meta-analyzed with data from studies in similar surgical populations, do not support the use of antibiotic prophylaxis in MRM.', 'title': 'A randomized, double-blinded placebo-controlled clinical trial of the routine use of preoperative antibiotic prophylaxis in modified radical mastectomy.', 'date': '2012-10-12'}, '10873356': {'article_id': '10873356', 'content': 'Antibiotic prophylaxis has been used to good effect in the prevention of post-operative wound infections in patients undergoing gastrointestinal operations. We have assessed the use of a single dose of intravenous antibiotic (Augmentin 1.2 g), given with induction of anaesthesia as prophylaxis, against post-operative wound infection in women undergoing clean, elective breast surgery. Three hundred and thirty-four patients were recruited. Of the 164 receiving antibiotic prophylaxis 29 (17.7%) had wound infections compared with 32 (18.8%) in the placebo group (P=0.79). There were no significant differences in any other post-operative infective complications. Antibiotic prophylaxis is probably not required in clean, elective breast surgery.', 'title': 'Antibiotic prophylaxis for post-operative wound infection in clean elective breast surgery.', 'date': '2000-06-30'}, '19673597': {'article_id': '19673597', 'content': 'Preoperative core needle biopsies may increase the risk of surgical site infection (SSI) in breast cancer surgery. The purpose of this randomized trial was to determine whether a prophylactic antibiotic would prevent SSI under these conditions.\nImaging-guided multiple core needle biopsies were performed one to two weeks prior to surgery to obtain confirmation of the presence of breast cancer. Then the patients were randomized to receive either a single intravenous dose of 1.0 g of dicloxacillin (n = 144) or placebo infusion of saline (n = 148) 30 min prior to operation. After breast surgery, incisional morbidity was monitored for 30 days. The number of SSIs was compared with that in 672 patients treated before the implementation of core needle biopsies.\nThe patient characteristics and risk factors for SSI were similar in the antibiotic prophylaxis and placebo groups. The incidence of SSI was 7.2% (21/292) in the prospective trial compared with 6.8% (46/672) in the retrospective cohort (p = 0.890). The incidence of postoperative SSIs was 5.6% (8/144) in the dicloxacillin group and 8.8% (13/148) in the placebo group (p = 0.371). For the first two weeks, there was a non-significant trend to fewer SSIs in the antibiotic group (n = 1) than the placebo group (n = 4). Body mass index, smoking, or previous illness did not affect the likelihood of SSI.\nCore needle biopsy did not increase the incidence of SSI. Antibiotic prophylaxis did not prevent SSI, probably because so few infections occurred.', 'title': 'Does preoperative core needle biopsy increase surgical site infections in breast cancer surgery? Randomized study of antibiotic prophylaxis.', 'date': '2009-08-14'}, '2403655': {'article_id': '2403655', 'content': 'We assessed the efficacy of perioperative antibiotic prophylaxis for surgery in a randomized, double-blind trial of 1218 patients undergoing herniorrhaphy or surgery involving the breast, including excision of a breast mass, mastectomy, reduction mammoplasty, and axillary-node dissection. The prophylactic regimen was a single dose of cefonicid (1 g intravenously) administered approximately half an hour before surgery. The patients were followed up for four to six weeks after surgery. Blinding was maintained until the last patient completed the follow-up and all diagnoses of infection had been made. The patients who received prophylaxis had 48 percent fewer probable or definite infections than those who did not (Mantel-Haenszel risk ratio, 0.52; 95 percent confidence interval, 0.32 to 0.84; P = 0.01). For patients undergoing a procedure involving the breast, infection occurred in 6.6 percent of the cefonicid recipients (20 of 303) and 12.2 percent of the placebo recipients (37 of 303); for those undergoing herniorrhaphy, infection occurred in 2.3 percent of the cefonicid recipients (7 of 301) and 4.2 percent of the placebo recipients (13 of 311). There were comparable reductions in the numbers of definite wound infections (Mantel-Haenszel risk ratio, 0.49), wounds that drained pus (risk ratio, 0.43), Staphylococcus aureus wound isolates (risk ratio, 0.49), and urinary tract infections (risk ratio, 0.40). There were also comparable reductions in the need for postoperative antibiotic therapy, non-routine visits to a physician for problems involving wound healing, incision and drainage procedures, and readmission because of problems with wound healing. We conclude that perioperative antibiotic prophylaxis with cefonicid is useful for herniorrhaphy and certain types of breast surgery.', 'title': 'Perioperative antibiotic prophylaxis for herniorrhaphy and breast surgery.', 'date': '1990-01-18'}, '2403697': {'article_id': '2403697', 'content': 'The ability of perioperative cefazolin to reduce the incidence of postoperative wound infection in patients undergoing ablative surgical treatment for carcinoma of the breast was tested in this prospective, randomized, double-blinded study. From May 1983 until December 1985, 118 women were divided into two groups at random. Group 1 consisted of 59 patients and received cefazolin and group 2 was made up of 59 patients who received a placebo. The groups were similar with respect to age, operative procedure, operative time and time to discharge after operation. Three infections occurred among those in group 1 and five among those in group 2 (p = 0.72). The time to onset of infection was delayed in the patients in group 1 versus those in group 2 (17.7 days versus 9.6 days, p = 0.04). Six of eight infections occurred in patients in whom an interval between biopsy and definitive surgical treatment was present. Prophylactic antibiotics in mammary operations did not reduce postoperative wound infections in this study.', 'title': 'A prospective, randomized double-blind study of the use of antibiotics at the time of mastectomy.', 'date': '1990-01-01'}}
| 0.1
|
Surgery
|
87
|
Is the rate of hospital readmission higher, lower, or the same when comparing prophylactic antibiotics administered preoperatively to placebo?
|
uncertain effect
|
low
|
no
|
['9776150', '2403655']
| 31,557,310
| 2,019
|
{'9776150': {'article_id': '9776150', 'content': 'Antibiotic prophylaxis is controversial in patients undergoing axillary lymph node dissection (ALND). We determined whether preoperative antibiotics decreased incidence or treatment cost of infectious complications following ALND.\nTwo hundred patients entered this prospective, randomized, double-blind trial. Patients received either placebo or cefonicid preoperatively. Loco-regional signs of infection were monitored for 4 weeks postoperatively.\nThere was a trend toward fewer infections in the prophylactic group (placebo 13% versus cefonicid 6%; P = 0.080). Cefonicid significantly decreased severe infections requiring hospitalization (placebo 8% versus cefonicid 1%; P = 0.033). Cefonicid also decreased the treatment cost of infection per patient ($49.80 versus $364.87).\nWe demonstrated a trend toward fewer overall infections and significantly fewer severe infections in patients given prophylactic antibiotics, which translated into a decrease in the cost of treatment for infectious complications. These findings support antibiotic prophylaxis for patients undergoing ALND.', 'title': 'Prospective, randomized, double-blind study of prophylactic antibiotics in axillary lymph node dissection.', 'date': '1998-10-17'}, '2403655': {'article_id': '2403655', 'content': 'We assessed the efficacy of perioperative antibiotic prophylaxis for surgery in a randomized, double-blind trial of 1218 patients undergoing herniorrhaphy or surgery involving the breast, including excision of a breast mass, mastectomy, reduction mammoplasty, and axillary-node dissection. The prophylactic regimen was a single dose of cefonicid (1 g intravenously) administered approximately half an hour before surgery. The patients were followed up for four to six weeks after surgery. Blinding was maintained until the last patient completed the follow-up and all diagnoses of infection had been made. The patients who received prophylaxis had 48 percent fewer probable or definite infections than those who did not (Mantel-Haenszel risk ratio, 0.52; 95 percent confidence interval, 0.32 to 0.84; P = 0.01). For patients undergoing a procedure involving the breast, infection occurred in 6.6 percent of the cefonicid recipients (20 of 303) and 12.2 percent of the placebo recipients (37 of 303); for those undergoing herniorrhaphy, infection occurred in 2.3 percent of the cefonicid recipients (7 of 301) and 4.2 percent of the placebo recipients (13 of 311). There were comparable reductions in the numbers of definite wound infections (Mantel-Haenszel risk ratio, 0.49), wounds that drained pus (risk ratio, 0.43), Staphylococcus aureus wound isolates (risk ratio, 0.49), and urinary tract infections (risk ratio, 0.40). There were also comparable reductions in the need for postoperative antibiotic therapy, non-routine visits to a physician for problems involving wound healing, incision and drainage procedures, and readmission because of problems with wound healing. We conclude that perioperative antibiotic prophylaxis with cefonicid is useful for herniorrhaphy and certain types of breast surgery.', 'title': 'Perioperative antibiotic prophylaxis for herniorrhaphy and breast surgery.', 'date': '1990-01-18'}}
| 0
|
Surgery
|
88
|
Is the incidence of surgical site infection (SSI) for patients undergoing breast cancer surgery without reconstruction higher, lower, or the same when comparing prophylactic antibiotics administered preoperatively to no antibiotic?
|
lower
|
moderate
|
no
|
['11063500', '23001082', '16989011']
| 31,557,310
| 2,019
|
{'11063500': {'article_id': '11063500', 'content': 'Based on the observation that administration of clarithromycin led to an attenuation of the inflammatory response induced by surgical trauma in a guinea pig model, we investigated the potential beneficial effects of clarithromycin on the local and systemic inflammatory response in patients undergoing mastectomy in an open-label prospective study. During a 16-month period, 54 patients who underwent mastectomy were randomly divided into two groups. In one group, the patients received oral clarithromycin at a dose of 500 mg twice a day, from the day before to 3 days after mastectomy. There was no significant difference in the incidence of antibiotic prophylaxis-related toxicities or postoperative infections between the patients who received clarithromycin and those who did not. Clarithromycin treatment was significantly associated with an attenuation of febrile response, tachycardia, tachypnea, and an increase in monocyte counts (P, <0.0001, <0.01, <0.05, and <0.01, respectively). Clarithromycin also reduced the intensity and duration of postoperative pain (P, <0.05 and <0.005, respectively) and increased the range of motion of the involved shoulder (P < 0.05 for abduction and flexion). We conclude that clarithromycin effectively modulates the acute inflammatory response associated with mastectomy and produces a better clinical outcome.', 'title': 'Clarithromycin attenuates mastectomy-induced acute inflammatory response.', 'date': '2000-11-04'}, '23001082': {'article_id': '23001082', 'content': 'To assess the impact of prophylactic antibiotics on the prevention of surgical site infection (SSI) and the cost-effectiveness of this prophylaxis for breast cancer surgery in overweight or obese women.\nSSI is higher than expected after breast surgery. Obesity was found to be one of the risk factors.\nThe trial was designed as a phase IV randomized, controlled, parallel-group efficacy trial. It was conducted at a tertiary university hospital. Overweight or obese women with clinically early-stage breast cancer who had been assigned to undergo surgery were eligible. Patients were randomly allocated to either a prophylaxis or a control group by using a computer-generated list. The prophylaxis group received 1 g ampicillin-sulbactam intravenously at anesthesia. The control group received no intervention. Patients and observers were blinded to the assignments. The primary outcome was the comparison of SSI incidences of the 2 groups. Patients were monitored for 30 days.\nA total of 369 patients were included in final analysis, out of which 187 were allocated for prophylaxis and 182 were randomly assigned to the control group. Analysis was done according to the intention-to-treat principle. Prophylaxis significantly reduced the SSI rate (4.8%) in the prophylaxis group when compared with that in the control group [13.7%; relative risk (RR) 0.35; 95% CI: 0.17-0.73]. No adverse reaction was observed. The mean SSI-related cost (20.26 USD) was found to be significantly higher in the control group when compared with that (8.48 USD) in the prophylaxis group.\nAntibiotic prophylaxis significantly decreased SSI incidence after elective surgery and was shown to be cost-effective in obese breast cancer patients. ClinicalTrials.gov Identifier: NCT00356148.', 'title': 'Efficacy of prophylactic antibiotic administration for breast cancer surgery in overweight or obese patients: a randomized controlled trial.', 'date': '2012-09-25'}, '16989011': {'article_id': '16989011', 'content': 'The aim of this randomized clinical trial was to determine whether a single intravenous dose of 2 g flucloxacillin could prevent wound infection after primary non-reconstructive breast surgery.\nThe study included 618 patients undergoing local excision (n = 490), mastectomy (n = 107) or microdochectomy (n = 21). Patients were randomized to receive either a single dose of flucloxacillin immediately after the induction of anaesthesia or no intervention. Wound morbidity was monitored by an independent research nurse for 42 days after surgery.\nThe incidence of wound infection was similar in the two groups: 10 of 311 (3.2 percent) in the flucloxacillin group and 14 of 307 (4.6 percent) in the control group (chi(2) = 0.75, P = 0.387; relative risk 0.71, 95 percent confidence interval 0.32 to 1.53). The groups also had similar wound scores and rates of moderate or severe cellulitis. Wound infection presented a median of 16 days after surgery.\nThe administration of a single dose of flucloxacillin failed to reduce the rate of wound infection after non-reconstructive breast surgery.', 'title': 'Randomized clinical trial of single-dose antibiotic prophylaxis for non-reconstructive breast surgery.', 'date': '2006-09-22'}}
| 0
|
Surgery
|
89
|
Is the incidence of surgical site infection (SSI) for patients undergoing breast cancer surgery without reconstruction higher, lower, or the same when comparing prophylactic antibiotics administered preoperatively to placebo?
|
lower
|
moderate
|
no
|
['7480237', '9776150', '23052809', '10873356', '19673597', '2403655', '2403697']
| 31,557,310
| 2,019
|
{'7480237': {'article_id': '7480237', 'content': 'Over a 9-month period from September of 1991 to May of 1992, 339 patients were included in a randomized, double-blind, placebo-controlled study using azithromycin as the prophylactic agent to determine whether it effects a clinically meaningful reduction in postoperative surgical infections in plastic surgery. Azithromycin was given as prophylaxis in 171 patients and placebo in 168 patients. The study medication was a single oral dose taken at 8 P.M. the day before surgery. The patients were followed up for a minimum of 4 weeks after surgery. The patients who received wound infection prophylaxis had 5.1 percent infections compared with 20.5 percent in the placebo group (p = 0.00009). Eighty percent of all wound infections were first seen after discharge, explaining why plastic surgeons might overlook their infectious complications. There was a significant reduction in postoperative complications (p = 0.04) and in the additional use of antibiotics postoperatively (p = 0.007) in the prophylaxis group. Subgroup analysis showed a significant reduction in surgical infections in breast surgery (p < 0.05) and reconstructive surgery with flaps (p < 0.05). No effect of the prophylactic regime was demonstrated in patients undergoing secondary surgery for cleft lip and palate disease.', 'title': 'A prospective, double-blind, placebo-controlled trial of a single dose of azithromycin on postoperative wound infections in plastic surgery.', 'date': '1995-11-01'}, '9776150': {'article_id': '9776150', 'content': 'Antibiotic prophylaxis is controversial in patients undergoing axillary lymph node dissection (ALND). We determined whether preoperative antibiotics decreased incidence or treatment cost of infectious complications following ALND.\nTwo hundred patients entered this prospective, randomized, double-blind trial. Patients received either placebo or cefonicid preoperatively. Loco-regional signs of infection were monitored for 4 weeks postoperatively.\nThere was a trend toward fewer infections in the prophylactic group (placebo 13% versus cefonicid 6%; P = 0.080). Cefonicid significantly decreased severe infections requiring hospitalization (placebo 8% versus cefonicid 1%; P = 0.033). Cefonicid also decreased the treatment cost of infection per patient ($49.80 versus $364.87).\nWe demonstrated a trend toward fewer overall infections and significantly fewer severe infections in patients given prophylactic antibiotics, which translated into a decrease in the cost of treatment for infectious complications. These findings support antibiotic prophylaxis for patients undergoing ALND.', 'title': 'Prospective, randomized, double-blind study of prophylactic antibiotics in axillary lymph node dissection.', 'date': '1998-10-17'}, '23052809': {'article_id': '23052809', 'content': 'The effectiveness of antibiotic prophylaxis for prevention of surgical site infection (SSI) following specific types of breast cancer surgery remains uncertain. This study assessed the effectiveness of prophylaxis in modified radical mastectomy (MRM).\nWomen undergoing MRM for breast cancer were recruited. Women were excluded who had diabetes mellitus, severe malnutrition or known allergy to cephalosporins; were receiving corticosteroid therapy or were treated with antibiotics within one week prior to surgery; were scheduled for simultaneous breast reconstruction or bilateral oophorectomy; had existing local infection. Participants were randomized to receive either intravenous cefazolin 1 g or placebo within 30 min prior to skin incision. Standard skin preparation and operative technique for MRM were carried out. Wounds were assessed for SSI and other complications weekly for 30 days.\nA total of 254 women were recruited. Age, clinical stage, prior chemotherapy, and operative time were similar for antibiotic and placebo groups. The overall incidence of SSI was 14.2 %. There were no significant differences in the infection rate over the 30-day follow-up period between the placebo and antibiotic groups (15 % vs 13.4 %; p = 0.719) or at each week. The majority of SSI were either cellulitis or superficial infection for both groups. There were no significant differences between groups in treatments required for SSI, incidence of hematoma or seroma.\nThe findings of this study, alone and when meta-analyzed with data from studies in similar surgical populations, do not support the use of antibiotic prophylaxis in MRM.', 'title': 'A randomized, double-blinded placebo-controlled clinical trial of the routine use of preoperative antibiotic prophylaxis in modified radical mastectomy.', 'date': '2012-10-12'}, '10873356': {'article_id': '10873356', 'content': 'Antibiotic prophylaxis has been used to good effect in the prevention of post-operative wound infections in patients undergoing gastrointestinal operations. We have assessed the use of a single dose of intravenous antibiotic (Augmentin 1.2 g), given with induction of anaesthesia as prophylaxis, against post-operative wound infection in women undergoing clean, elective breast surgery. Three hundred and thirty-four patients were recruited. Of the 164 receiving antibiotic prophylaxis 29 (17.7%) had wound infections compared with 32 (18.8%) in the placebo group (P=0.79). There were no significant differences in any other post-operative infective complications. Antibiotic prophylaxis is probably not required in clean, elective breast surgery.', 'title': 'Antibiotic prophylaxis for post-operative wound infection in clean elective breast surgery.', 'date': '2000-06-30'}, '19673597': {'article_id': '19673597', 'content': 'Preoperative core needle biopsies may increase the risk of surgical site infection (SSI) in breast cancer surgery. The purpose of this randomized trial was to determine whether a prophylactic antibiotic would prevent SSI under these conditions.\nImaging-guided multiple core needle biopsies were performed one to two weeks prior to surgery to obtain confirmation of the presence of breast cancer. Then the patients were randomized to receive either a single intravenous dose of 1.0 g of dicloxacillin (n = 144) or placebo infusion of saline (n = 148) 30 min prior to operation. After breast surgery, incisional morbidity was monitored for 30 days. The number of SSIs was compared with that in 672 patients treated before the implementation of core needle biopsies.\nThe patient characteristics and risk factors for SSI were similar in the antibiotic prophylaxis and placebo groups. The incidence of SSI was 7.2% (21/292) in the prospective trial compared with 6.8% (46/672) in the retrospective cohort (p = 0.890). The incidence of postoperative SSIs was 5.6% (8/144) in the dicloxacillin group and 8.8% (13/148) in the placebo group (p = 0.371). For the first two weeks, there was a non-significant trend to fewer SSIs in the antibiotic group (n = 1) than the placebo group (n = 4). Body mass index, smoking, or previous illness did not affect the likelihood of SSI.\nCore needle biopsy did not increase the incidence of SSI. Antibiotic prophylaxis did not prevent SSI, probably because so few infections occurred.', 'title': 'Does preoperative core needle biopsy increase surgical site infections in breast cancer surgery? Randomized study of antibiotic prophylaxis.', 'date': '2009-08-14'}, '2403655': {'article_id': '2403655', 'content': 'We assessed the efficacy of perioperative antibiotic prophylaxis for surgery in a randomized, double-blind trial of 1218 patients undergoing herniorrhaphy or surgery involving the breast, including excision of a breast mass, mastectomy, reduction mammoplasty, and axillary-node dissection. The prophylactic regimen was a single dose of cefonicid (1 g intravenously) administered approximately half an hour before surgery. The patients were followed up for four to six weeks after surgery. Blinding was maintained until the last patient completed the follow-up and all diagnoses of infection had been made. The patients who received prophylaxis had 48 percent fewer probable or definite infections than those who did not (Mantel-Haenszel risk ratio, 0.52; 95 percent confidence interval, 0.32 to 0.84; P = 0.01). For patients undergoing a procedure involving the breast, infection occurred in 6.6 percent of the cefonicid recipients (20 of 303) and 12.2 percent of the placebo recipients (37 of 303); for those undergoing herniorrhaphy, infection occurred in 2.3 percent of the cefonicid recipients (7 of 301) and 4.2 percent of the placebo recipients (13 of 311). There were comparable reductions in the numbers of definite wound infections (Mantel-Haenszel risk ratio, 0.49), wounds that drained pus (risk ratio, 0.43), Staphylococcus aureus wound isolates (risk ratio, 0.49), and urinary tract infections (risk ratio, 0.40). There were also comparable reductions in the need for postoperative antibiotic therapy, non-routine visits to a physician for problems involving wound healing, incision and drainage procedures, and readmission because of problems with wound healing. We conclude that perioperative antibiotic prophylaxis with cefonicid is useful for herniorrhaphy and certain types of breast surgery.', 'title': 'Perioperative antibiotic prophylaxis for herniorrhaphy and breast surgery.', 'date': '1990-01-18'}, '2403697': {'article_id': '2403697', 'content': 'The ability of perioperative cefazolin to reduce the incidence of postoperative wound infection in patients undergoing ablative surgical treatment for carcinoma of the breast was tested in this prospective, randomized, double-blinded study. From May 1983 until December 1985, 118 women were divided into two groups at random. Group 1 consisted of 59 patients and received cefazolin and group 2 was made up of 59 patients who received a placebo. The groups were similar with respect to age, operative procedure, operative time and time to discharge after operation. Three infections occurred among those in group 1 and five among those in group 2 (p = 0.72). The time to onset of infection was delayed in the patients in group 1 versus those in group 2 (17.7 days versus 9.6 days, p = 0.04). Six of eight infections occurred in patients in whom an interval between biopsy and definitive surgical treatment was present. Prophylactic antibiotics in mammary operations did not reduce postoperative wound infections in this study.', 'title': 'A prospective, randomized double-blind study of the use of antibiotics at the time of mastectomy.', 'date': '1990-01-01'}}
| 0.142857
|
Surgery
|
90
|
Is the cost of care higher, lower, or the same when comparing prophylactic antibiotics administered preoperatively to no antibiotic or placebo?
|
uncertain effect
|
low
|
no
|
['23001082', '9776150']
| 31,557,310
| 2,019
|
{'23001082': {'article_id': '23001082', 'content': 'To assess the impact of prophylactic antibiotics on the prevention of surgical site infection (SSI) and the cost-effectiveness of this prophylaxis for breast cancer surgery in overweight or obese women.\nSSI is higher than expected after breast surgery. Obesity was found to be one of the risk factors.\nThe trial was designed as a phase IV randomized, controlled, parallel-group efficacy trial. It was conducted at a tertiary university hospital. Overweight or obese women with clinically early-stage breast cancer who had been assigned to undergo surgery were eligible. Patients were randomly allocated to either a prophylaxis or a control group by using a computer-generated list. The prophylaxis group received 1 g ampicillin-sulbactam intravenously at anesthesia. The control group received no intervention. Patients and observers were blinded to the assignments. The primary outcome was the comparison of SSI incidences of the 2 groups. Patients were monitored for 30 days.\nA total of 369 patients were included in final analysis, out of which 187 were allocated for prophylaxis and 182 were randomly assigned to the control group. Analysis was done according to the intention-to-treat principle. Prophylaxis significantly reduced the SSI rate (4.8%) in the prophylaxis group when compared with that in the control group [13.7%; relative risk (RR) 0.35; 95% CI: 0.17-0.73]. No adverse reaction was observed. The mean SSI-related cost (20.26 USD) was found to be significantly higher in the control group when compared with that (8.48 USD) in the prophylaxis group.\nAntibiotic prophylaxis significantly decreased SSI incidence after elective surgery and was shown to be cost-effective in obese breast cancer patients. ClinicalTrials.gov Identifier: NCT00356148.', 'title': 'Efficacy of prophylactic antibiotic administration for breast cancer surgery in overweight or obese patients: a randomized controlled trial.', 'date': '2012-09-25'}, '9776150': {'article_id': '9776150', 'content': 'Antibiotic prophylaxis is controversial in patients undergoing axillary lymph node dissection (ALND). We determined whether preoperative antibiotics decreased incidence or treatment cost of infectious complications following ALND.\nTwo hundred patients entered this prospective, randomized, double-blind trial. Patients received either placebo or cefonicid preoperatively. Loco-regional signs of infection were monitored for 4 weeks postoperatively.\nThere was a trend toward fewer infections in the prophylactic group (placebo 13% versus cefonicid 6%; P = 0.080). Cefonicid significantly decreased severe infections requiring hospitalization (placebo 8% versus cefonicid 1%; P = 0.033). Cefonicid also decreased the treatment cost of infection per patient ($49.80 versus $364.87).\nWe demonstrated a trend toward fewer overall infections and significantly fewer severe infections in patients given prophylactic antibiotics, which translated into a decrease in the cost of treatment for infectious complications. These findings support antibiotic prophylaxis for patients undergoing ALND.', 'title': 'Prospective, randomized, double-blind study of prophylactic antibiotics in axillary lymph node dissection.', 'date': '1998-10-17'}}
| 0
|
Surgery
|
91
|
Is the likelihood of detoxification at six‐month follow‐up higher, lower, or the same when comparing dihydrocodeine (DHC) to buprenorphine?
|
no difference
|
low
|
no
|
['19196468', '17210079']
| 32,068,247
| 2,020
|
{'19196468': {'article_id': '19196468', 'content': 'Subst Abuse Treat Prev PolicySubstance Abuse Treatment, Prevention, and Policy1747-597XBioMed Central1919646826490651747-597X-4-110.1186/1747-597X-4-1ResearchThe Leeds Evaluation of Efficacy of Detoxification Study (LEEDS) prisons project: a randomised controlled trial comparing dihydrocodeine and buprenorphine for opiate detoxificationSheardLaura1l.sheard@leeds.ac.ukWrightNat MJ2n.wright@leeds.ac.ukEl-SayehHany G3hany.el-sayeh@nyypct.nhs.ukAdamsClive E4clive.adams@nottingham.ac.ukLiRyan5ryan.li@ucl.ac.ukTompkinsCharlotte NE1c.tompkins@leeds.ac.uk1Leeds Institute of Health Sciences, Charles Thackrah Building, 101 Clarendon Road, Leeds, LS2 9LJ, UK2HMP Leeds and Leeds PCT based at Leeds Institute of Health Sciences, Charles Thackrah Building, 101 Clarendon Road, Leeds, LS2 9LJ, UK3North Yorkshire and York Primary Care Trust, The Briary Wing, Harrogate District Hospital, Lancaster Park Road, Harrogate HG2 7SX, UK4Mental Health Services Research, Division of Psychiatry, University of Nottingham Duncan MacMillan House, Portchester Road, Nottingham, NG3 6AA, UK5Department of Mental Health Sciences, University College London Holborn Union Building, Highgate Hill, London, N19 5LW, England, UK20095220094111792008522009Copyright © 2009 Sheard et al; licensee BioMed Central Ltd.2009Sheard et al; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.BackgroundMany opiate users entering British prisons require prescribed medication to help them achieve abstinence. This commonly takes the form of a detoxification regime. Previously, a range of detoxification agents have been prescribed without a clear evidence base to recommend a drug of choice. There are few trials and very few in the prison setting. This study compares dihydrocodeine with buprenorphine.MethodsOpen label, pragmatic, randomised controlled trial in a large remand prison in the North of England. Ninety adult male prisoners requesting an opiate detoxification were randomised to receive either daily sublingual buprenorphine or daily oral dihydrocodeine, given in the context of routine care. All participants gave written, informed consent. Reducing regimens were within a standard regimen of not more than 20 days and were at the discretion of the prescribing doctor. Primary outcome was abstinence from illicit opiates as indicated by a urine test at five days post detoxification. Secondary outcomes were collected during the detoxification period and then at one, three and six months post detoxification. Analysis was undertaken using relative risk tests for categorical data and unpaired t-tests for continuous data.Results64% of those approached took part in the study. 63 men (70%) gave a urine sample at five days post detoxification. At the completion of detoxification, by intention to treat analysis, a higher proportion of people allocated to buprenorphine provided a urine sample negative for opiates (abstinent) compared with those who received dihydrocodeine (57% vs 35%, RR 1.61 CI 1.02–2.56). At the 1, 3 and 6 month follow-up points, there were no significant differences for urine samples negative for opiates between the two groups. Follow up rates were low for those participants who had subsequently been released into the community.ConclusionThese findings would suggest that dihydrocodeine should not be routinely used for detoxification from opiates in the prison setting. The high relapse rate amongst those achieving abstinence would suggest the need for an increased emphasis upon opiate maintenance programmes in the prison setting.Trial registrationCurrent Controlled Trials ISRCTN07752728BackgroundPrison populations include a high proportion of people who use illicit substances and are dependent upon illicit opiates [1]. Levels of drug use among prisoners tend to be much higher than in the general population [2]. In the United Kingdom (UK) almost two thirds of injecting drug users have spent some time in prison [3] and repeat drug-related offending and re-incarceration is common [3]. Illicit opiate users who enter the prison estate in the UK are typically offered pharmacological interventions of opiate maintenance treatment, or an opiate detoxification regime complimented by psychosocial support according to individual health need [4].Historically, healthcare provision for injecting drug users in prisons in England and Wales has not been equivalent to that offered in community settings. There has recently been a phased re-organisation in prison healthcare with responsibility in England and Wales being transferred from the Home Office to individual National Health Service (NHS) Primary Care Trusts (PCT) [5]. Alongside this, current developments in drug policy have been designed to facilitate a change in prison based clinical practice to enable it to become equivalent to that offered in the community [6-9]. In support of this policy directive, financial resource is being provided to prisons to supply an integrated system for drug maintenance or detoxification treatment within nationally agreed clinical guidelines [4]. Consequently, all prisoners whose urine tests are positive for illicit opiates should be offered an opiate detoxification of equivalent standard to that in the community.As many drug users reduce or cease illicit drug use whilst in prison, providing treatment for opiate detoxification is a core function of prison healthcare provision [4]. However, during the period when the current research was conducted (2004/2005) the evidence base and the national guidelines on the clinical management of drug misuse [10] did not stipulate a \'drug of choice\' for opiate detoxification. In the absence of this evidence base, a wide variety of agents for opiate detoxification have previously been prescribed at the discretion of prison clinicians. Such medications include methadone, dihydrocodeine, buprenorphine, lofexidine and clonidine. Historically within UK prisons, the most commonly used drug for opiate detoxification has been dihydrocodeine. Anecdotally this was partly due to a reluctance to prescribe methadone following a small number of methadone related deaths in the prison setting. Dihydrocodeine has been attractive to clinicians as it has a shorter half-life than methadone, and seems equally acceptable to users. Robertson et al (2006) found that there was no significant difference in retention in treatment between dihydrocodeine and methadone for maintenance treatment in the community [11]. Towards the end of the study period (late 2005), there was a national move away from prescribing dihydrocodeine in the British prison setting due to its potential for diversion by prisoners into the shadow economy.Buprenorphine, in the form of sub-lingual tablets, has the potential advantage of having a good safety profile, better retention in treatment and lower withdrawal severity when compared to methadone, lofexidine or clonidine [12-16]. Comparatively, it has been increasingly prescribed in the community for the purpose of opiate detoxification [17]. The latest Department of Health guidelines recommend either buprenorphine or methadone as first line agents for prisoners requesting an opiate detoxification, subject to clinician discretion [4].Recently, the results of the Leeds Evaluation of Efficacy of Detoxification Study (LEEDS) were published [18]. The study was a randomised controlled trial (RCT) comparing buprenorphine and dihydrocodeine for opiate detoxification in the community drug treatment setting and showed that participants were more likely to achieve abstinence from illicit opiates at completion of detoxification with buprenorphine. However there are potentially differences in the demographics, drug histories and structuring of drug treatment in the community compared to the prison which limits the external validity of these findings in the prison treatment setting. Consequently, the research team considered it imperative that the same detoxification agents were compared within the prison estate. Additionally, there appears to be a paucity of clinical trials conducted worldwide in the prison setting which have evaluated medication for opiate detoxification. Whilst one British study evaluated the withdrawal severity of methadone versus lofexidine, the rates of completion were not sufficient to detect a statistically significant difference between the medications [19]. Given the dearth of randomised controlled trials for opiate detoxification in this environment, we felt it appropriate to introduce this methodology to answer an important research question which could inform clinical policy, decision making and prison policy directives [20]. This paper reports the findings of a trial comparing dihydrocodeine and buprenorphine for opiate detoxification in the UK prison setting.MethodsSettingHer Majesty\'s Prison Leeds. This is a large category B local remand prison1 in the North of England, with over 1200 bed spaces. It accepts over 6000 adult male prisoners per year, primarily from the West Yorkshire area.DesignPragmatic open label randomised controlled trial comparing two detoxification interventions – oral dihydrocodeine and sublingual buprenorphine. Randomisation sequence, with random block size, was generated using Microsoft Excel RAND function, by CEA in the Department of Psychiatry at the University of Leeds. CEA prepared sealed opaque consecutively numbered envelopes concealing the name of the allocated intervention. CEA had no contact with eligible participants.The Multi Centre Research Ethics Committee for Wales (MREC Wales) approved the study in May 2004, and the Research Governance Organisation (Bradford South and West PCT) in April 2004.EligibilityInclusion criteria1. Male (since research only took place in the male estate, thereby implicitly excluding women)2. 18 – 65 years3. Using illicit opiates as confirmed by a urine test taken at first assessment4. Expressing a wish to detoxify through the standard monitored process and remain abstinent from opiates5. Willing to give informed consent after receiving the participant information sheet6. Remaining in custody in HMP Leeds for longer than 28 daysExclusion criteria1. Contraindications to dihydrocodeine or buprenorphine2. Co-existing acute medical conditions requiring emergency admission for hospital care so precluding detoxification in the prison setting3. Currently undergoing detoxification from other illicit drugs whereby concurrent detoxification from opiates would not be clinically indicated4. Previous randomisation into the trialRecruitmentParticipants were recruited from the medical reception area on arrival into HMP Leeds. On their first night in HMP Leeds, those with a current history of illicit opiate use (as confirmed by a Sure Screen multi panel drugs test) are routinely offered a detoxification regime. When prisoners who fulfilled the inclusion criteria approached the prison doctor, the purpose and rationale of the trial was explained to them. If they provided informed consent, the prison doctor (NW or HE) randomised them by opening the next pre-prepared opaque envelope and prescribing the intervention named within. Up to the point of opening the envelope both prisoner and doctor were blind to the intervention; once the envelope was open both prisoner and doctor knew the allocated intervention. On the opening of the envelope, the prison nursing staff and the prison pharmacist were informed of the allocated intervention for each participant. Standard clinical care continued from this point onwards.Randomisation took place between July 2004 and July 2005. Some prisoners may have chosen to enter the trial as during this period, the standard detoxification choices offered to prisoners were dihydrocodeine and buprenorphine. This was regardless of whether they entered the trial or not, so it was only strong patient preference which predominantly meant people declined to take part. Recruitment was disappointing during the first five months of the trial (See Table 1 for breakdown of the actual rates of recruitment per month and also anticipated recruitment). So, in September 2004 (following MREC approval) the research team decided to provide an incentive of £5 which was credited to the prisoners\' phone accounts (operated by a PIN number). The incentive was credited upon entry to the trial and prisoners were aware that they could withdraw at any time, yet keep the accredited incentive. We felt this incentive was an appropriate gratitude for prisoners to provide the voluntary urine samples and information that were required as part of taking part in the study. After introduction of the incentive, recruitment rates remained static but then increased in December and fluctuated somewhat. Ideally, it would have been beneficial to be able to provide incentives for urine samples at the secondary outcome points in order to increase the follow up rates.Table 1Rates of recruitment per month versus anticipated recruitmentActual recruitmentAnticipated recruitmentJul 2004110Aug 2004210Sep 2004210Oct 2004210Nov 2004010Dec 2004710Jan 20051910Feb 20051710Mar 20051310Apr 2005410May 20051210Jun 2005310Jul 2005810InterventionsDihydrocodeine was given openly in the context of the standard prison doctor and drugs worker support. It was prescribed as a 30 mg oral tablet preparation "in-possession" medication. The medication was administered once a day to the participant who held the supply of medication to take in four daily divided doses.Buprenorphine was given openly, in the context of the standard prison doctor and drugs worker support. It was dispensed either as 8 mg, 2 mg or 0.4 mg sublingual tablet preparation under daily supervised consumption.The reducing regimen of both medications was at the discretion of the prescribing doctor. However, in practice, the detoxification regimes were subject to a protocol so as to fit into the high volume, busy nature of the prison regime. The dose prescribed did not exceed the standard regimes (Table 2). Therefore, the total dose administered was 96 mg of buprenorphine over 20 days and 6660 mg of dihydrocodeine over 20 days.Table 2Detoxification regimensBuprenorphineDihydrocodeineDayDose (mg)morningevening162 × 1202 × 120282 × 1202 × 120382 × 1202 × 120482 × 1202 × 120582 × 1202 × 120682 × 1202 × 120782 × 1202 × 120881 × 120, 1 × 901 × 120, 1 × 90961 × 120, 1 × 901 × 120, 1 × 901062 × 902 × 901142 × 902 × 90123.61 × 90, 1 × 601 × 90, 1 × 60133.21 × 90, 1 × 601 × 90, 1 × 60142.82 × 602 × 60152.42 × 602 × 60162.01 × 602 × 60171.61 × 602 × 60181.21 × 601 × 60190.81 × 601 × 60200.4XXXX1 × 60Sample sizeAs no randomised controlled trials relevant to these comparisons have been previously undertaken in the prison setting, there was no comparable study on which to base the sample size calculation. The only other controlled trial comparing agents for detoxification (methadone and lofexidine) in a UK prison randomised 74 prisoners [19]. However, the project team completed a detoxification trial in the homeless community comparing dihydrocodeine with buprenorphine [20]. From this, we estimated that with a sample size of 60 we would have a finding of clinical and statistical significance for differences in the primary outcome. Due to loss of follow-up we determined a sample size of 120 would have sufficient power (i.e 80%) to determine a difference in the secondary outcomes between the two arms of 70% versus 45% [OR 1.56; α = 0.05 (two-sided)]. The power calculation was undertaken using Sample Power 1.20 developed by SPSS Inc., comparing two groups (60 individuals in each) and for α = 0.05 (two-sided).Data collection and OutcomesThe LEEDS trial co-ordinator (LS) collected details of allocated detoxification agent, background history, demographic details and use of opiates from the participant\'s prison medical records.Primary outcomeAbstinence from illicit opiates at five days post detoxification as indicated by a supervised Sure Screen multi panel drugs test negative for opiates. This urine test was taken by a prison nurse who was prompted by LS at the appropriate follow-up time period.Secondary outcomesDuring the period of detoxificationSerious and Adverse Events – As part of routine clinical practice, clinicians and drugs workers noted any adverse events by making an entry in the participant\'s medical records. LS extracted data of adverse events clearly resulting in clinically significant distress to study participants or of major concern to clinicians from medical records, for the period of detoxification, and transcribed these onto a database.Leaving the study early – perceived reasons for withdrawal were recorded.Inappropriate use of prescribed medication – examples of this included intentional overdose, storing, trading, swapping or selling of prescribed medication.Service utilisation – admission to hospital, Accident and Emergency and in-patient stays in prison hospital healthcare wing were recorded.At 1, 3, and 6 months post detoxificationAbstinence status – if the prisoner was still in HMP Leedsthese data were extracted from clinical notes. If the person had been transferred, other prisons were contacted. If the prisoner had been released into the community, evidence of abstinence status was primarily ascertained through local community drugs service or GPs records. There was some, albeit limited, success tracing people via the address or telephone number which they had provided at the point of randomisation.Service utilisation (as above)All data was recorded on a Microsoft Excel spreadsheet.Significant loss to follow-up occurred due to the high turnover of prisoners in HMP Leeds. Being a busy remand prison, the eligibility criteria of "remaining in custody in HMP Leeds for longer than 28 days" was determined so that the primary outcome would be complete for most participants. At the point of randomisation, remand prisoners who were due to appear in court in less than 28 days time were asked the likelihood of returning to HMP Leeds and invited to take part accordingly.AnalysisFollowing data entry, all analyses were undertaken using Review Manager 4.2.8 and SPSS software. The analysis of the primary outcomes was by a simple 2 × 2 table. Dummy tables were constructed for all secondary outcomes. These tables were designed as rigid templates for the final write up of the research, and to facilitate the researchers to collate a full data set and to mitigate against data dredging. Primary outcomes were analysed on an intention-to-treat basis: if the person did not finish the course of detoxification or did not give a urine sample then this was considered as a positive urine test for opiates. Intention-to-treat was used as a replication of the analysis performed in the trial conducted in the community [18] rather than other methods e.g. multiple imputation. Primary outcomes at follow-up were analysed both as per protocol (excluding those lost to follow-up) and intention-to-treat (missing urines assumed positive) with relative risk tests for categorical data and unpaired t-tests for continuous data. Secondary outcome data were analysed using chi square tests.ResultsParticipantsNinety men, that is 64% of those who were eligible and approached to take part in the study, consented to recruitment (Figure 1). These men were imprisoned in HMP Leeds and using illicit opiates prior to their sentence. The average age was 29.8 years (range 19–53) with the mean age for those allocated buprenorphine being 28.9 (SD 4.6) and 29.7 for those allocated dihydrocodeine (SD 6.1). The duration of using opiates overall was 9.3 years (range 1–18) with a mean of 8.9 years for those allocated buprenorphine (SD 3.5) and 9.7 years for those allocated dihydrocodeine (SD 4.6). Forty two men were randomly allocated to buprenorphine and 48 to dihydrocodeine. Variables relating to age, pattern of use and prognosis were evenly distributed between groups (Table 3).Table 3Demographic characteristics and prognostic factorsBuprenorphine(n = 42)Dihydrocodeine(n = 48)Age – mean (SD)28.9 (4.6)29.7 (6.1)Pattern of use\u2003How are opiates taken?\u2003\u2003IV21 (50%)18\u2003\u2003Smoking912\u2003\u2003Methadone maintenance20\u2003\u2003Don\'t know1018Current daily use\u2003minimum – mean (SD)£40.00 (21.10)£42.10 (29.40)\u2003maximum£45.48 (23.39)£45.65 (30.21)Duration taking opiates – mean (SD)8.9 (3.5) years9.70 (4.6) yearsInitial urine\u2003illicit opiates present28/3027/27\u2003other drugs present16/3013/27Prognostic factorsYesNoD/KYesNoD/K\u2003Previous detoxes?27342543\u2003Successful detoxes?119101386Figure 1Flow chart of randomisation outcome.Primary outcomeOverall, 63 men (70%) gave a urine sample at 5 days post detoxification (Table 4), between the two allocated regimens for provision of urine sample (RR 1.18, CI 0.90 – 1.54, z = 1.20, p = 0.43). 27 men (30%) did not provide a urine sample. 18 were released before their urine sample was due, 4 were transferred to another prison and 5 did not complete the prescribed detoxification regime. Of those released or transferred, 11 did not complete the detoxification, 4 completed the regime but left HMP Leeds before their urine test was due and 5 left on the day of the test or afterwards (data unavailable for 2). There was no statistically significant difference in demographic variables at baseline between those who completed detoxification and those who did not.Table 4ResultsBuprenorphine(total = 42)Dihydrocodeine(total = 48)Relative Risk(95% CI)Unpaired t-testP valueBy end of detox\u2003Final urine sample32/4231/481.18 (0.90, 1.54)N/A0.43\u2003Per protocol negative urine24/3217/311.37 (0.94, 1.99)N/A0.10\u2003ITT negative urine24/4217/481.61 (1.02, 2.56)N/A0.04\u2003Leaving early10/4215/480.76 (0.38, 1.51)N/A0.43\u2003Overdose00N/A\u2003Inappropriate use of allocated drug3/291/252.59 (0.29,23.32)N/A0.39\u2003A&E attendance00N/A\u2003Hospital admittance00N/A\u2003Prison doctor visits (mean)1.0 (0.5) n = 281.0 (0.6) n = 23N/At(49) = 0.001.00At 1 months post detoxification\u2003Dead0/330/33N/A\u2003Abstinent (ITT)16/4217/481.08 (0.63, 1.85)N/A0.79\u2003How known?\u2003\u2003Urine test4/102/51.00 (0.27, 3.72)N/A\u2003\u2003Self report12/2115/250.95 (0.58, 1.55)N/A1.00\u2003A&E attendance0/330/33N/A0.84\u2003Hospital attendance0/330/33N/APrison doctor visits (mean)0.4 (0.9) n = 250.6 (1.0) n = 28N/At(51) = 0.760.45Drug worker visits(mean)0.2 (0.4) n = 32 n = 1N/AAt 3 months post detoxification\u2003Dead0/270/23N/A\u2003Abstinent (ITT)13/4212/481.24 (0.64, 2.41N/A0.53\u2003How known?\u2003\u2003Urine test2/81/41.00 (0.13, 8.00)N/A1.00\u2003\u2003Self report11/1811/181.00 (0.59, 1.68)N/A1.00\u2003A&E attendance1/271/230.85 (0.06,12.87)N/A0.91\u2003Hospital attendance2/271/231.70 (0.16,17.60)N/A0.65\u2003Prison doctor visits (mean)0.8 (1.7) n = 171.5 (1.9) n = 17N/At(32) = 0.760.27\u2003Drug worker visits (mean)0No dataN/AAt 6 months post detoxification\u2003Dead0/140/12\u2003Abstinent5/425/481.14 (0.36, 3.68)N/A0.82\u2003How known?\u2003\u2003Urine test1/31/41.33(0.13,13.74)N/A0.81\u2003\u2003Self report4/114/80.73 (0.26, 2.07)N/A0.55\u2003A&E attendance2/141/121.71(0.18,16.65)N/A0.64\u2003Hospital attendance3/142/121.29 (0.26, 6.46)N/A0.76\u2003Prison doctor visits (mean)2.0 (2.2) n = 42.2 (1.5) n = 4N/A\u2003Drug worker visits (mean)No dataN/A*ITT assumption = everybody not returning for final urine test had positive urine* Statistical tests were z (approximation) testsAt the completion of detoxification, by intention to treat analysis, we found a higher proportion of people allocated to buprenorphine provided a urine sample negative for opiates (abstinent) compared with those who received dihydrocodeine (57% vs 35%, RR 1.61 CI 1.02–2.56, z = 2.065, p = 0.04).Secondary outcomesAt one month, follow up data were obtained on 66 participants (73% of the study sample). At three months, follow up data were obtained on 55 participants (61% of the study population). At six months, follow up data were obtained on 26 participants (29% of the study population).At the 1, 3 and 6 month follow-up points, there were no statistically significant differences for urine samples negative for opiates between the two groups. There were also no statistically significant differences for any other of the secondary outcomes of Accident and Emergency attendance, hospital attendance, GP visits or drugs worker visits throughout this post-treatment period (Table 4). No serious adverse events were reported throughout the study.DiscussionThe findingsOur study showed that at five days after completion of the prison detoxification regime, buprenorphine at a total dose of 96 mg was more effective than dihydrocodeine at a total dose of 6660 mg in achieving abstinence from illicit opiates. It also showed that 43% of HMP Leeds\' prisoners with a habit of illicit opiate use, who agreed to be included in the study, continued to acquire and use opiates even through the first few days of imprisonment and prescribed detoxification regimen.It is possible that the research was underpowered to determine the effect of the interventions upon longer term abstinence, as at the secondary follow up points there were no statistically significant differences between the two groups for urine samples negative for opiates. However, it may be that there was clinically no significant difference. To this effect, firm conclusions regarding the effectiveness of buprenorphine and dihydrocodeine detoxification on post release opioid use and other core outcomes can not be conclusively determined. It is well known that post release from prison is a high risk time for relapse into illicit drug use. Therefore, it could be that more meaningful follow up data from prison based detoxification trials could be derived based on the time since release from prison in addition to time since detoxification.A direct comparison can be made between the results of this study and those of the sister trial conducted in the community [18]. As previously stated, the result of the community trial also favoured buprenorphine over dihydrocodeine for opiate detoxification. Most importantly, completion of detoxification and provision of final urine in the prison environment was much higher than in the community (23% vs 70%). Reasons for this are varied but may include inherent characteristics of the treatment setting. For the participants who remained in HMP Leeds, when their urine sample was due, the closed, secure environment meant they were actively traced by prison nurses who took the urine samples. This contrasts with the very different environment of the community where the research team were dependent on the participants returning to their general practice to collect their final prescription so that a urine sample could be taken.It is important to state that the trial did not introduce any new intervention medications into HMP Leeds as dihydrocodeine and buprenorphine were the only detoxification agents available during the period of randomisation [20]. The trial took place for a year from summer 2004, which is important as during this period the first line agent for most UK prisons was dihydrocodeine, with buprenorphine slowly being introduced. It seemed pertinent to compare these two agents, given that they were being prescribed to thousands of prisoners with a history of illicit opiate use every year in UK prisons despite no previous evaluation of their clinical effectiveness. Current policy recommendations are very different, with methadone and buprenorphine now being advocated as first line agents for opiate detoxification [4]. However, anecdotally, a practice of dihydrocodeine prescribing continues in many UK prisons.Whilst there is a paucity of opiate detoxification trials conducted with prisoners, some studies have highlighted prisoners\' subjective experiences of opiate detoxification. One recent qualitative study identified that prisoners in England who had been prescribed dihydrocodeine found that it was often inadequate at relieving acute opiate withdrawal and they were often reduced too quickly [21]. More favourable prison detoxification experiences were noted with buprenorphine and methadone [21]. Other studies have reported prisoners\' sense of inadequacy in relation to short term methadone detoxifications [22,23] where the length of the detoxification is perceived as too short. Length of detoxification has now increased in UK prisons [4] and methadone and buprenorphine have become first line agents in the prison estate [4].Current UK guidelines regarding the treatment of drug misuse in prisons recommend that only licensed opiate agonist medications (such as methadone or buprenorphine) should be used in the pharmacological treatment of opiate detoxification [4]. This recommendation was based on face validity consensus view of experts working in the field. Our findings strengthen and provide empirical support for the current guidelines which do not recommend the routine use of dihydrocodeine as a first line agent for detoxification in the prison setting. Outside of prison, recent clinical guidance from UK\'s National Institute of Clinical Excellence [24] has recommended against the routine use of dihydrocodeine for opiate detoxification based on evidence from the LEEDS trial in the community [18] and unpublished data from this current study. Both suggested no advantage in effectiveness of dihydrocodeine over buprenorphine either in the community or the prison.Methodological issuesLEEDS is only one of a small number of randomised controlled trials to take place in the UK prison estate. [25] The research team encountered barriers when conducting the community trial [18] such as patient preference, clinical equipoise and logistical issues [26]. Patient preference was a difficulty that carried through to the prison setting and was probably the largest hurdle to randomising people into the trial. However, conducting this trial in the prison environment presented many new problems and issues. Most significantly, the research team had to be satisfied that all prisoners gave informed consent and that they understood the processes of the trial. This was sometimes difficult in the noisy and chaotic environment of first night medical reception. Additionally, the reception area has a fast throughput and was not often conducive to the intricacies of a research trial. On some occasions, potential participants were not randomised if it was thought that they did not fully understand the concept of the trial or – more often – the process of randomisation. This was usually the case when they were in physical withdrawal from illicit opiates.One weakness of the study was not recording demographic details of those who declined to participate as we cannot compare this group with those who agreed to be involved. Also this study involved men over the age of 18. Therefore applicability of the findings to women and young people in prison is problematic. Additionally, there are limitations with the intention-to-treat analysis used as this assumes that all missing urines tests are positive for opiates. Whilst we acknowledge this is problematic, this trial was analysed according to statistical convention in the UK and in keeping with the analysis of the sister trial previously conducted in the community.Data collection was difficult when prisoners were transferred to serve their remaining sentence at other establishments across the wider prison estate. Indeed, there was a wide variation of responses to requests for help obtaining important information from other prison healthcare departments, despite having the necessary ethical and governance approvals in place to facilitate this. Whilst some prison healthcare departments at other establishments were willing to share information for the purposes of the trial, despite our best efforts, others refused. This sometimes led to a loss of follow up data from prisoners who were participating in the trial who had been transferred to certain unhelpful establishments.As far as the research team are aware, this study is the only opiate detoxification randomised controlled trial in a prison setting which has taken abstinence from opiates (as indicated by a urine test) as the primary outcome. For studies assessing efficacy of opiate detoxification agents, an accurate and independent measure of abstinence status is important Cf [27]. The only other prison trial with which to compare is Howells et al (2002) [19]. In this UK study of 74 male prisoners with opiate addiction, lofexidine was compared with methadone with the primary outcome being self-reported withdrawal symptom severity during the detoxification period. Variously, other trials comparing agents for opiate detoxification in a variety of settings have used intensity/symptoms of withdrawal, retention in treatment, completion of treatment, nature of adverse effects [16,28] and relapse rate [28]. We believe that our first line method of ascertaining abstinence status via a urine test represents the most robust and binary manner in which to answer a clinical research question pertaining to the efficacy of detoxification medications.We undertook this study on a minimal budget (one half time research assistant post for co-ordination and data collection over 19 months). Prison doctors (NW and HE) randomised in addition to their everyday clinical roles and responsibilities (approximately 5 to 8 minutes per participant). The research team believed this trial is imperative in order to ascertain whether a randomised controlled trial with drug using prisoners, which recorded abstinence, was feasible in UK prisons. The high throughput of large numbers of prisoners in an environment that is recognised as a high risk for overdose, self-harm and suicide [29] certainly presents significant logistical barriers to the smooth running of a research project. However, we do acknowledge that the very low follow up rate of this study is problematic and it may be pertinent for future studies to examine more rigorously whether buprenorphine was superior to dihydrocodeine at post release.Future researchThis study raises further research questions. Since completion of this trial, the issue of buprenorphine abuse in the UK prison estate has been highlighted [30]. Therefore it could be that whilst our findings would suggest that dihydrocodeine should not routinely be used for detoxification in the prison setting, there could be other more effective agents than buprenorphine. In particular it is possible that methadone mixture is the pharmacological agent that is both most clinically effective and least amenable to diversion in the prison setting. Currently the Department of Health is supporting the research team to undertake a multi-prison trial comparing methadone with buprenorphine regimens for opiate detoxification. After a lengthy period completing the necessary approvals [31], recruitment for this trial began in January 2006. Randomisation and data collection for this research is currently ongoing, with almost 300 prisoners recruited to date across three prisons in the North of England. Methadone and buprenorphine are now the two first line detoxification medications within the British prison estate and a comparison is therefore fundamental to inform the current knowledge and evidence base.The research team believe that conducting qualitative work around this trial may strengthen and give depth to the findings, particularly in relation to those people who were not abstinent at the primary outcome stage. It would have been interesting to understand how prisoners viewed the experience of their detoxification and how issues peculiar to the nature of prison life and drug use were worked out and overcome. Consequently, we would recommend that future randomised controlled trials (in a variety of settings) incorporate a qualitative element into their design in order to understand the holistic experience of simultaneously being a patient and research participant.ConclusionThis study suggests that buprenorphine may be more effective than dihydrocodeine for adult men undergoing opiate detoxification in the prison environment. However, it also demonstrates the high level of illicit opiate use within the prison estate even for those entered into a detoxification programme, with over 40% of prisoners in this study showing evidence of illicit opiates in their urine. The results of this trial reinforce current guidelines which do not recommend dihydrocodeine is prescribed as a first line agent for the management of opiate misuse. The high rate of relapse into opiate use post-intervention would also suggest a greater role for opiate maintenance in the prison estate as abstinence is not a realistic goal for many drug users within this environment. There is an emerging evidence base for the effectiveness of opiate maintenance programmes in the prison setting [32].The research team encountered novel methodological issues and problems when randomising in the prison environment, the most crucial being informed consent. Data collection was also problematic once prisoners had been released or transferred to other establishments. In outlining our research experience, we hope to inform other research teams of the logistical issues of conducting a clinical trial in the British prison estate. Most significantly, this research demonstrates that a pragmatic randomised controlled trial can be undertaken in this difficult and challenging environment.Notes1. Category B refers to a prison which is high but not maximum security. HMP Leeds is classed as a local prison in that it predominantly accepts men from the local area which is the county of West Yorkshire.Competing interestsThe authors declare that they have no competing interests.Authors\' contributionsNW and CA designed the study and offered project supervision. NW was principal investigator. CA centrally managed the randomisation process. LS co-ordinated and managed the project, assisted during randomisation clinics and collected follow up data. HE and NW randomised participants into the trial. RL conducted statistical analysis. All authors drafted the manuscript.AcknowledgementsWe are grateful to all participants who participated in the trial at HMP Leeds. We would particularly like to thank all medical staff who were involved and assisted us with randomisation and data collection. We also thank Leeds Primary Care Trusts Research Consortium Priorities and Needs Funding who funded the project.ShewanDStoverHDolanKPates R, McBride A, Arnold KInjecting in PrisonsInjecting Illicit Drugs2005Oxford, BlackwellFarrellMHowsSTaylorCLewisGJenkinsRBebbingtonPJarvisMBrughaTGillBMeltzerHSubstance misuse and psychiatric co morbidity: an overview of the OPCS National Psychiatric Morbidity surveyAddictive Behaviors199823909918980172510.1016/S0306-4603(98)00075-6Health Protection Agency, Health Protection Scotland, National Public Health Service for Wales, CDSC Northern Ireland, CRDHB, the UASSGShooting Up: Infections among Injecting Drug Users in the United Kingdom London2006Department of HealthClinical Management of Drug Dependence in the Adult Prison Setting London2006HekGUnlocking potential: challenges for primary health care researchers in the prison settingPrimary Health Care Research and Development20067919410.1191/1463423606pc277edHM Prison ServicePSO 3550: Standard for the 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26/03/08SheardLTompkinsCWrightNAdamsCNon-commercial clinical trials of a medicinal product: can they survive the current process of research approvals in the UK?Journal of Medical Ethics2006324304341681604610.1136/jme.2005.015180KinlockTGordonMSchwartzRO\'GradyKFitzgeraldTWilsonMA randomized clinical trial of methadone maintenance for prisoners: Results at 1 month post releaseDrug and Alcohol Dependence2007912202271762835110.1016/j.drugalcdep.2007.05.022', 'title': 'The Leeds Evaluation of Efficacy of Detoxification Study (LEEDS) prisons project: a randomised controlled trial comparing dihydrocodeine and buprenorphine for opiate detoxification.', 'date': '2009-02-07'}, '17210079': {'article_id': '17210079', 'content': 'BMC Fam PractBMC Family Practice1471-2296BioMed CentralLondon1721007917745691471-2296-8-310.1186/1471-2296-8-3Research ArticleBuprenorphine versus dihydrocodeine for opiate detoxification in primary care: a randomised controlled trialWrightNat MJ1n.wright@leeds.ac.ukSheardLaura1l.sheard@leeds.ac.ukTompkinsCharlotte NE1c.tompkins@leeds.ac.ukAdamsClive E2ceadams@cochrane-sz.orgAllgarVictoria L1v.l.allgar@leeds.ac.ukOldhamNicola S3l.sheard@leeds.ac.uk1Centre for Research in Primary Care, 71-75 Clarendon Road, Leeds, LS2 9PL, UK2Department of Psychiatry, 15 Hyde Terrace, Leeds, LS2 9L, UK3Formerly of NFA Health Centre for Homeless People, 68 York Street, Leeds, LS9 8AA, UK20078120078331652006812007Copyright © 2007 Wright et al; licensee BioMed Central Ltd.2007Wright et al; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.BackgroundMany drug users present to primary care requesting detoxification from illicit opiates. There are a number of detoxification agents but no recommended drug of choice. The purpose of this study is to compare buprenorphine with dihydrocodeine for detoxification from illicit opiates in primary care.MethodsOpen label randomised controlled trial in NHS Primary Care (General Practices), Leeds, UK. Sixty consenting adults using illicit opiates received either daily sublingual buprenorphine or daily oral dihydrocodeine. Reducing regimens for both interventions were at the discretion of prescribing doctor within a standard regimen of not more than 15 days. Primary outcome was abstinence from illicit opiates at final prescription as indicated by a urine sample. Secondary outcomes during detoxification period and at three and six months post detoxification were recorded.ResultsOnly 23% completed the prescribed course of detoxification medication and gave a urine sample on collection of their final prescription. Risk of non-completion of detoxification was reduced if allocated buprenorphine (68% vs 88%, RR 0.58 CI 0.35–0.96, p = 0.065). A higher proportion of people allocated to buprenorphine provided a clean urine sample compared with those who received dihydrocodeine (21% vs 3%, RR 2.06 CI 1.33–3.21, p = 0.028). People allocated to buprenorphine had fewer visits to professional carers during detoxification and more were abstinent at three months (10 vs 4, RR 1.55 CI 0.96–2.52) and six months post detoxification (7 vs 3, RR 1.45 CI 0.84–2.49).ConclusionInformative randomised trials evaluating routine care within the primary care setting are possible amongst drug using populations. This small study generates unique data on commonly used treatment regimens.BackgroundIn the United Kingdom (UK), policy directives have highlighted the importance of offering either maintenance or detoxification to illicit opiate users within an agreed plan of care [1]. This is in response to routine practice by some treatment providers of \'gradual reduction\' of opiate maintenance treatment – a regimen without a supporting evidence base [2]. Opiate detoxification, using one of various therapeutic agents, remains an important part of drug management for some illicit opiate users. However, neither the evidence base nor UK national guidelines recommend a \'drug of choice\' [1]. Understandably, there has been a call for randomised controlled trials (RCTs) in this area [3]. In primary care, methadone is commonly used, with reductions in the dose over 7–21 days [4]. Methadone has a long half life [5,6] and patients often report distressing withdrawal symptoms in the latter stages of detoxification [6]. This has meant increasing use of alternative agents such as clonidine, lofexidine, dihydrocodeine and, more recently, buprenorphine. The hypotensive effects of clonidine [4] have make it unacceptable for use in primary care and the reduced ability of lofexidine to control withdrawal, coupled with its high cost have resulted in limited clinical uptake [4].The use of sublingual buprenorphine is relatively new in the UK for opiate detoxification and there have been only two randomised controlled trials (RCTs) comparing it with methadone for this purpose [7,8]. Buprenorphine has been more commonly used as a drug of comparison in trials of opiate maintenance [9-16]. A recent Cochrane review assessing methadone and buprenorphine for the management of opioid withdrawal found no significant difference between these two agents [17]. In this context, buprenorphine has a good safety profile, better retention in treatment and lower withdrawal severity [18-22]. Sublingual buprenorphine is increasingly being prescribed by General Practitioners (GPs) for opiate detoxification [23] despite limited clinical and research evidence.Dihydrocodeine has a shorter half life than methadone and has been widely used in both primary care and prison drug treatment settings for opiate detoxification. Whilst some commentators have documented success with dihydrocodeine [24,25] others have expressed concerns regarding its effects, particularly the potential diversion into the street economy [26]. Despite routine use, dihydrocodeine has rarely been studied for the purposes of opiate detoxification [24] but has been compared in a randomised controlled trial with buprenorphine for postoperative pain [27].When comparing methadone, dihydrocodeine and buprenorphine it is important to note several factors which may impact upon prescribing and use of these agents. Dihydrocodeine is cheaper than methadone and both methadone and dihydrocodeine are substantially cheaper than buprenorphine. The latter has been subject to heavy pharmaceutical marketing. Buprenorphine and dihydrocodeine have a better safety profile than methadone, which has a high toxicity which (rarely) can result in death [28]. All three agents have the potential for street diversion but dihydrocodeine is the hardest to control, with consumption usually being unsupervised. Methadone is the easiest to manage and buprenorphine seems to be somewhere in-between.The care of people using illicit opiates has changed over recent years. Strang et al (2005) [29] surveyed GPs and found that half had seen at least one opiate user in a four week period, compared to only 19% in a 1986 survey [30]. There has been a significant increase in the number of GPs becoming involved in the care of drug users [31]. Consequently, many short term opiate detoxifications are now undertaken in primary care. The absence of robust evidence underpinning many of the clinical decisions made within primary care has already been highlighted [32]. LEEDS (Leeds Evaluation of Efficacy of Detoxification Study) is a response to this challenge and compared dihydrocodeine with buprenorphine for opiate detoxification within the UK primary care setting.MethodsDesign and settingLEEDS was conducted in ten general practices (6 of which randomised participants) in Leeds, UK (population ~750,000). We used a randomised controlled trial design to compare open giving of oral dihydrocodeine tartrate with open giving of sublingual buprenorphine. Randomisation was by random block size, stratified by practice, using Microsoft Excel RAND function. This was undertaken by the Department of Psychiatry, University of Leeds, and was concealed from clinicians prescribing interventions. The name of the allocated intervention was obscured within fully opaque sealed envelopes [33]. All envelopes were opened in strict order, confirmed by an investigator independent of the clinical interface. The outside of the randomisation envelope contained a brief information form to be completed which requested the patient\'s practice number, date of birth, contact telephone number and date of first prescription. Two questions also served to rate the severity of addiction of the participant from the view of the GP. Once the GP/drug worker opened the LEEDS envelope both practitioner and patient knew the intervention, standard clinical care resumed and the patient made subsequent appointments with the GP and/or drugs worker. To detect with 80% power a difference in treatment effectiveness of 25% between groups (50% versus 25%) at 5% level of significance, it was calculated that 120 participants would be needed in the study. However within the time frame for recruitment we were only able to recruit 60 participants. Randomisation took place between August 2002 and May 2004. Full methods are reported elsewhere [33].The Leeds Teaching Hospitals Local NHS Research Ethics Committee (LREC) approved the study in April 2002. Informed written consent was obtained from each patient following receipt of a participant information leaflet prior to their involvement in the trial.InterventionsBuprenorphine was prescribed on an FP10 MDA prescription. This allows daily dispensing under supervision of a pharmacist. Daily supervised administration of dihydrocodeine tablets is not possible in the UK as it cannot be prescribed on FP10 MDA prescriptions. As such, buprenorphine was dispensed either as 8 mg, 2 mg or 0.4 mg sublingual tablet preparation under daily supervision. Dihydrocodeine was dispensed as 30 mg rapid release tablet preparation in take home installments. Each installment was for a minimum of three and a maximum of 4 daily doses. The reducing regimens for both interventions were at the discretion of the prescribing doctor and within the standard regimen which was approximately 15 days (Tables 1 and 2). However, clinicians were free to titrate doses against withdrawal symptoms. What was being randomised was the open giving of the drugs even if that meant that participants were not given in the opinion of the prescribing doctor pharmacologically equivalent dosages.Table 1Standard buprenorphine detoxificationDayDose (mg)16283846566473.683.292.8102.4112.0121.6131.2140.8150.4Table 2Standard dihydrocodeine detoxificationDayNumber of 30 mg tabletsMorningMiddayEveningNight-time1185445220555531854454164444514433461233337103223892223982222107212211621121251112134111114311115211Inclusion and exclusion criteriaPatients were eligible for the study if they were: aged 18 years or over, using street opiates as confirmed by a urine sample taken at first assessment, wishing to detoxify through the standard monitored process, willing to remain abstinent from opiates and to give informed consent. Patients were excluded if they had contra-indications to dihydrocodeine or buprenorphine or had been randomised into the trial previously.OutcomesThe primary outcome was abstinence from illicit heroin at final prescription, as indicated by urine test. A priori we classed unsuccessful detoxification as: the final urine tested positive for metabolic breakdown products of heroin (morphine or 6-mono-acetyl morphine); urine tested positive for opiates commonly found in street heroin (codeine); the patient did not provide a final urine sample; did not finish detoxification or reported using street opiates during the period of detoxification. We recorded the secondary outcomes of inappropriate use of prescribed medication, overdose and admission to hospital or Accident and Emergency (A&E) and number of GP/drug worker visits during the detoxification period. At three and six month post detoxification, follow up data were recorded. These outcomes were: whether the person was still alive, abstinent from opiates, in receipt of sickness certification and their pattern of service use.Statistical analysisOutcome data were analysed using Epi Info v 3.3.2 and SPSS software with relative risk tests for categorical data and unpaired t-tests for continuous data.ResultsSixty people using illicit opiates took part in LEEDS (Figure 1). This comprised of 42 men and 18 women, with an average age of 28 years. 58% were homeless or unstably housed. There were no significant differences for those allocated to one regimen or the other (Table 3).Figure 1Table 3Demographic characteristics and prognostic factorsBuprenorphine (total 28)Dihydrocodeine (total 32)Age mean (SD)29.9 (5.1)29.0 (7.3)Sex19 M 9 F23 M 9 FPattern of use\u2003How are opiates taken?\u2003\u2003IV14 (50%)24 (75%)\u2003\u2003Smoking13 (46%)8 (25%)\u2003\u2003Both1 (4%)0Current daily use (minimum) (£) mean17.1 (8.1)15.6 (7.2)Current daily use maximum (£) mean23.2 (12.1)18.1 (9.0)Duration taking opiates (years) mean8.8 (4.9)7.0 (3.7)\u2003Illicit opiates in initial urine23 (82%)27 (84%)\u2003Other drugs in initial urine18 (64%)12 (37%)Prognostic factors\u2003\'Severely dependent\'8 (28%)10 (31%)\u2003GP\'s prediction of whether would be off opiates by end of detoxDefinitely notNot sureVery sureDefinitely notNot sureVery sure022 (78%)6 (21%)2 (6%)22 (69%)8 (25%)YesNoD/KYesNoD/K\u2003Previous detoxes?24 (87%)3 (11%)1 (4%)25 (78%)6 (19%)1 (3%)\u2003Successful detoxes?15 (63%)9 (38%)015 (60%)9 (36%)1 (4%)\u2003Employed?4 (14%)19 (68%)5 (18%)4 (13%)19 (59%)9 (28%)\u2003MED-3?6 (21%)8 (29%)14 (50%)5 (16%)13 (41%)14 (44%)\u2003Non using friends?12 (43%)5 (18%)11 (39%)13 (41%)3 (9%)16 (50%)\u2003Anyone supportive of detox?22 (79%)4 (14%)2 (7%)24 (75%)1 (3%)7 (22%)Overall, only 13 people (23%) completed the prescribed course of detoxification medication and gave a urine sample on collection of their final prescription (Table 4). There was an increased chance of completing the prescribing regime if allocated buprenorphine though this finding was of borderline statistical significance (68% vs 88%, RR 0.58 CI 0.35–0.96, p = 0.065). At completion of detoxification, by intention to treat analysis we found a higher proportion of people allocated to buprenorphine provided a urine sample negative for opiates (abstinent) compared with those who received dihydrocodeine (21% vs 3%, RR 2.06 CI 1.33–3.21, p = 0.028). This suggestion of an enhanced therapeutic effect with buprenorphine was negated if we assumed that the proportions of those returning with clean urine per group were representative of those who did not return. Had all the medication been both prescribed and dispensed according to the standard regimes, an expected mean prescribed dose for each dihydrocodeine detoxification would be 4560 mg and 56 mg for each buprenorphine dose. The actual amount of milligrams (mean) and duration of detoxification in days (mean) prescribed for each dihydrocodeine detoxification was 4111 mg (90% of expected dose) over 12 days and 32.9 mg (59% of expected dose) of buprenorphine over 9 days (both rounded to nearest day). This would indicate under-prescribing by doctors for both regimes as 4290 mg (94% of expected dose) would have expected to be prescribed over 12 days for dihydrocodeine and 47.6 mg (85% of expected dose) over 9 days for buprenorphine.Table 4ResultsBuprenorphine (total 28)Dihydrocodeine (total 32)Odds Ratio (95% CI)Relative Risk (95% CI)P valueBy end of detox\u2003Final urine sample9 (32%)4 (13%)3.32 (0.77–15.22)1.71 (1.04–2.83)0.065\u2003Non-ITT Clean urine6/9 (67%)1/4 (25%)6.00 (0.28–246)1.71 (0.73–4.03)0.164\u2003ITT-1* clean urine6/28 (21%)1/32 (3%)8.45 (0.89–200)2.06 (1.33–3.21)0.028\u2003ITT-2* clean urine6+3/281+8/321.21 (0.35–4.21)1.11 (0.63–1.95)0.735\u2003Leaving early19 (68%)28 (88%)0.30 (0.07–1.30)0.58 (0.35–0.96)0.065\u2003Overdose00Not applicable\u2003Inappropriate use of allocated drug00Not applicable\u2003A&E attendance00Not applicable\u2003Admitted00Not applicable\u2003Overdose00Not applicable\u2003GP visits – mean2.2 (1.05)2.8 (1.33)0.06\u2003Drug worker visits – mean0.17 (0.47)1.31 (0.59)0.343At 3 months post detoxification\u2003Abstinent10/27 (37%)4/24 (17%)2.94 (0.67–13.78)1.55 (0.96–2.52)0.104\u2003Dead0/270/28Not applicable\u2003On Med 3 sick note10/16 (63%)6/14 (43%)2.22 (0.41–12.65)1.46 (0.71–2.98)0.282\u2003A&E attendance2/27 (7%)2/28 (7%)1.04 (0.09–11.46)1.06 (0.38–2.94)0.970\u2003Hospital attendance1/27 (4%)2/28 (7%)0.5 (0.02–7.75)0.67 (0.13–3.38)0.574\u2003GP visits – mean5.04 (4.85)4.61 (4.10)0.724\u2003Drug worker visits – mean1.22 (1.67)1.14 (1.53)0.855At 6 months post detoxification\u2003Abstinent7/22 (32%)3/19 (16%)2.49 (0.45–15.15)1.45 (0.84–2.49)0.233\u2003Dead0/230/20Not applicable\u2003On Med 3 sick note3/11 (27%)2/11 (18%)1.69 (0.16–20.05)1.27 (0.53–3.06)0.611\u2003A&E attendance0/220/20Not applicable\u2003Hospital attendance0/222/20 (10%)0.16 (0.01–3.64)0.129\u2003GP visits – mean7.54 (6.71)6.48 (6.07)0.582\u2003Drug worker visits – mean1.74 (2.40)2.65 (2.89)0.265• Assumption 1 = everybody not returning for final urine test had not clean urine• Assumption 2 = everybody not returning for final urine test had same proportion of not clean urine as those who didThere was no statistically significant differences for any other outcomes although throughout the trial people allocated to buprenorphine did better than those on dihydrocodeine. For example people allocated to buprenorphine had fewer visits to the GP and drugs worker during detoxification, and more were abstinent at the three month (10 vs 4, RR 1.55 CI 0.96–2.52) and six month (7 vs 3, RR 1.45 CI 0.84–2.49) follow up. These findings were of borderline statistical significance. No serious adverse events were reported for any participants.DiscussionCommentators have listed significant barriers to conducting randomised controlled trials in the primary care setting [34,35]. Barriers certainly may include lack of clinical equipoise towards interventions and patient preference for a particular treatment, [36] as well as logistical problems (principally the busy primary care workplace as not being conducive to practitioner participation) and over-optimism regarding recruitment [37]. This study, however, was at the outset designed collaboratively between primary care and secondary care researchers to be conducted specifically in the primary care setting. It did not greatly complicate routine treatment and recorded clear and concrete outcomes of relevance to the primary care drug treatment field [33]. The LEEDS project team sought GPs experience of being involved in the trial through a cross sectional survey. Details of the practicalities of conducting LEEDS (including recruitment issues and equipoise) have been fully described elsewhere [38].LEEDS is the first randomised controlled trial to compare buprenorphine and dihydrocodeine for opiate detoxification. Sixty people with problems of opiate dependence agreed to take part in this randomised trial. Thirty five of these people were recruited from a medical centre for the homeless. Recruitment of practitioners was problematic though recruitment of participants was not a substantial problem for practitioners committed to recruiting into the trial. This study ran on a very low budget (50% research assistant time). LEEDS illustrates how such studies, undertaken in the context of routine care, even with such potentially problematic clientele, are both possible and feasible.One limitation of LEEDS was that it was underpowered to detect with confidence clear differences for secondary outcomes between regimens. Selecting a data collection point for the primary outcome at completion of detoxification could be seen as a limitation of the study. However, this outcome was selected after careful consideration. Ideally urine collection would be several days post-detoxification to allow for all prescribed opiates to be clear from the test. We thought, however, many users would not attend primary care after completion of detoxification simply to provide a urine test, particularly as much of the recruitment was from a homeless population who have been traditionally difficult to engage and retain in treatment services [39]. Indeed, only 23% of participants provided a final urine sample. Reasons for this are varied and multiple (Figure 1). Fourteen people did not collect their final prescription and therefore were not available at this time point to provide a urine sample. Five people never returned to the GP practice to collect any prescriptions after their first consultation with the GP or drugs worker. Additionally, 24 people failed to collect a prescription somewhere between the second and penultimate. The high numbers of people who did not provide a urine sample demonstrates the difficulty in retaining injecting drug users in treatment services. This pragmatic, low budget study only sought to record contact with GPs and drugs workers and did not have sufficient capacity to make personal contact during the detoxification period to obtain abstinence status independent of that recorded through medical contact.The main objectives of LEEDS were to have some indication of whether one regimen was associated with better odds of completing detoxification and to test methods for larger studies. We recognize that these are limited goals but found no indication from the literature or even experts in the field that data was known for these outcomes. Of course, retention in treatment services post-detoxification is an important part of the whole treatment package offered to drug users so we also recorded the frequency of medical service utlisation by participants.An additional limitation of the study is that we were unable to collect data on the numbers and demographics of those people who declined to participate. This was due to the busy nature of the primary care treatment setting.Currently many drug users arrested for crimes related to drug misuse are offered a choice of legally mandated treatment (referred to by some as \'coerced\' treatment) [40] or a custodial sentence. No participant in LEEDS had been legally mandated to enter treatment from the criminal justice system. Consequently, all participants expressed self motivation to undergo detoxification. Yet, regardless of which detoxification drug people were randomised to, completion rates were poor. This study suggests that even in this relatively self motivated group of people, completion rates were between only 13% and 32%. In secondary care others have reported completion rates in the range of 33% [41]. However comparisons with study retention rates from trials undertaken in secondary care should be made with caution as it is possible that participants were not equivalent in terms of motivation and self-efficacy. More evaluation of treatment effects in different health settings would therefore seem prudent and we have nearly completed a larger study in the prison setting. The results of this current study, however, are generalisable to those patients presenting for detoxification from illicit opiates in primary care. We would be less confident of generalising our findings to the residential or inpatient setting.This trial suggests that buprenorphine may be able to deliver 20% more completion than dihydrocodeine. If completion of detoxification is associated with remaining abstinent, use of buprenorphine as an agent of opiate detoxification could be a very important step forward. Whilst clinicians prescribing the interventions were not blinded beyond the point of randomisation, the difference favouring buprenorphine could be due to increased professional input for that intervention. However there was no evidence to suggest that this was the case. Rather, there was no suggestion of a difference in GP/drug worker visits between the two groups. LEEDS was a "real-world" trial with a pragmatic rather than explanatory design. As such it randomised interventions which are used in everyday clinical practice. Previous commentators have spoken about the need to balance issues of methodological rigour (commonly referred to as internal validity) versus the feasibility of conducting trials in the real world clinical environment (commonly referred to as external validity) [42]. Inevitably there is a trade off between rigour and feasibility. For example in this case whilst the use of dummy pills was considered at the design stage, it was deemed unfeasible as it would both add to the cost of the research and also limit the independence of the trial from pharmaceutical company funding.It could also be argued that the superior percentage of those achieving abstinence as a result of the buprenorphine intervention was because mean buprenorphine and dihydrocodeine doses were not equivalent in terms of the pharmacological opiate effect. However this is not possible to verify as the two interventions are not identical in terms of action on opiate receptors. Buprenorphine has the unusual property of being both a partial MU receptor (one of a number of opiate receptors) agonist and partial opiate antagonist whereas dihydrocodeine is a full opiate receptor agonist.ConclusionOnly 23% of participants completed their detoxification and gave a final urine sample. This finding suggests a high non-completion rate of primary care opiate detoxifications. A higher proportion of people randomised to buprenorphine provided a final urine sample negative for illicit opiates compared with those who received dihydrocodeine. Those allocated buprenorphine made fewer visits to the GP and drugs worker during detoxification. Additionally, more of those allocated buprenorphine were abstinent at three and six months post detoxification when compared to the dihydrocodeine group.Currently in some treatment services in the UK the open giving of dihydrocodeine has continued despite an absence of evidence to support its clinical effectiveness. More recently, there has been a marked increase in the prescribing of buprenorphine in the UK [23]. Such an increase is in line with emerging best practice primary care guidance based primarily upon face validity for opiate detoxification. This guidance supports the use of buprenorphine but not dihydrocodeine for opiate detoxification in the primary care setting [43]. The LEEDS findings begin to support this guidance with good evidence but there is some way to go before fully confident recommendations can be made.The findings will also have relevance to any review of current Department of Health best practice guidelines for the treatment of substance misuse [4]. Launched in 1999, they argued that GP prescribing of buprenorphine requires a greater level of clinical experience than the prescribing of dihydrocodeine. The guidelines recommend buprenorphine should only be given by a "specialist general practitioner" and dihydrocodeine by an "experienced" GP [4]. LEEDS provides little evidence to support the continued prescribing of dihydrocodeine as a first line agent for opiate detoxification by less experienced GPs in primary care, but larger, well designed, conducted and reported trials are necessary.Competing interestsThe author(s) declare that they have no competing interests.Authors\' contributionsNW and CA designed the study, offered project supervision and drafted the manuscript. NW was principal investigator. CA centrally managed the randomisation process and conducted statistical analysis. LS coordinated and managed the project during the latter stages, collected data and drafted the manuscript. CT conducted data collection and drafted the manuscript. VA conducted statistical analysis and commented on the results section. NO was the initial project coordinator, who assisted in the design of the study and collected data. All authors have read and approved the final manuscript.Funding bodyLeeds Primary Care Trusts Research Consortium Priorities and Needs Funding.Ethics committeeLeeds Teaching Hospitals Local Research Ethics Committee.Pre-publication historyThe pre-publication history for this paper can be accessed here:AcknowledgementsWe are grateful to all patients at surgeries in Leeds who participated in the trial. We would particularly like to thank Drs Paul Glynn, Sally Read and Will Bolland, drug workers and reception.Staff who form the LEEDS project collaborative. We also thank Leeds Primary Care Trusts Research Consortium Priorities and Needs Funding who funded the project.National Treatment AgencyModels of Care: for Adult Drug Misusers2002Department of Health, LondonGossopMMarsdenJStewartDTreacyS"Outcomes after methadone maintenance and methadone reduction treatments: two year follow up results from the National Treatment Outcome Research Study"Drug and Alcohol Dependence2001622552641129533010.1016/S0376-8716(00)00211-8MacLeodJWhittakerARobertsonR"Changes in opiate treatment during attendance at a community drug service – findings from a clinical audit"Drug and Alcohol Review19981719251620346510.1080/09595239800187561Department of Health, Scottish Office Department of Health, Welsh Office, & Department of Health and Social Services, N. IDrug Misuse and Dependence – Guidelines on Clinical Management1999The Stationary Office, LondonLowinsonJBerleBLangrodJ"Detoxification of long-term methadone patients: problems and prospects"International Journal of the Addictions197611100910181025030SeivewrightNCommunity Treatment of Drug Misuse: More than Methadone2000Cambridge University Press, CambridgeBickelWStitzerMBigelowGLiebsonIJasinskiDJohnsonR"A clinical trial of buprenorphine: comparison with methadone in the detoxification of heroin addicts"Clinical Pharmacology and Therapeutics19884372783275523SeifertJMetznerCPaetzoldWBorsutzkyMPassieTRollnikJWieseBEmrichHSchneiderU"Detoxification of opiate addicts with multiple drug abuse: a comparison of buprenorphine vs. methadone"Pharmacopsychiatry2002351591641223778610.1055/s-2002-34115FischerGGombasWEderHJagschRPeternellAStuhlingerGPezawasLAschauerHKasperS"Buprenorphine versus methadone maintenance for the treatment of opioid dependence"Addiction199994133713471061571910.1046/j.1360-0443.1999.94913376.xJohnsonRChutuapeMStrainEWalshSStitzerMBigelowE"A comparison of levomethadyl acetate, buprenorphine and methadone for opioid dependence"New England Journal of Medicine2000343129012971105867310.1056/NEJM200011023431802KostenTSchottenfieldRZiedonisDFalcioniJ"Buprenorphine versus methadone maintenance for opioid dependence "Journal of Nervous and Mental Disease1993181358364850145710.1097/00005053-199306000-00004LingWWessonDCharuvastraCKlettC"A controlled trial comparing buprenorphine and methadone maintenance in opioid dependence"Archives of General Psychiatry1996534014078624183MattickRAliRWhiteJO\'BrienSWolkSDanzC"Buprenorphine versus methadone maintenance therapy: a randomised double blind trial with 405 opioid dependent patients"Addiction2003984414521265381410.1046/j.1360-0443.2003.00335.xPaniPMaremmaniIPirastuRTagliamonteAGessaG"Buprenorphine: a controlled clinical trial in the treatment of opioid dependence"Drug and Alcohol Dependence20006039501082198810.1016/S0376-8716(99)00140-4PetitjeanSStohlerRDeglonJLivotiSWaldvogelDUehlingerCLadewigD"Double blind randomized trial of buprenorphine and methadone in opiate dependence"Drug and Alcohol Dependence200162971041117317310.1016/S0376-8716(00)00163-0WhiteRAlcornRFeinmannC"Two methods of community detoxification from opiates: an open label comparison of lofexidine and buprenorphine"Drug and Alcohol Dependence20016577831171459210.1016/S0376-8716(01)00149-1GowingLAliRWhiteJ"Buprenorphine for the management of opioid withdrawal"The Cochrane Database of Systematic Reviews2006CheskinLFudalaPJohnsonR"A controlled comparison of buprenorphine and clonidine for acute detoxification from opioids"Drug and Alcohol Dependence199436115121785127810.1016/0376-8716(94)90093-0LintzerisNBammerGJolleyDRushworthL"A randomised controlled trial of buprenorphine in the management of short term ambulatory heroin withdrawal"Addiction200211139514041241078010.1046/j.1360-0443.2002.00215.xNigamARayRTripathiB"Buprenorphine in opiate withdrawal: a comparison with clonidine"Journal of Substance Abuse Treatment199310391394825755110.1016/0740-5472(93)90024-VO\'ConnorPCarrollKShiJSchottenfieldRKostenTRounsavilleB"Three methods of opioid detoxification in a primary care setting: a randomized trial"Annals of Internal Medicine19971275265309313020SimoensSMathesonCBondCInksterKLudbrookA"The effectiveness of community maintenance with methadone or buprenorphine for treating opiate dependence"British Journal of General Practice20055513914615720937de WetCReedLBearnJ"The rise of buprenorphine prescribing in England: analysis of NHS regional data, 2001–03"Addiction20051004954991578406410.1111/j.1360-0443.2005.01039.xBanberyJWolffKRaistrickD"Dihydrocodeine. 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| 1
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Psychiatry & Neurology
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92
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Is the likelihood of treatment retention higher, lower, or the same when comparing dihydrocodeine (DHC) to buprenorphine?
|
no difference
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low
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yes
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['19196468', '17210079']
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{'19196468': {'article_id': '19196468', 'content': 'Subst Abuse Treat Prev PolicySubstance Abuse Treatment, Prevention, and Policy1747-597XBioMed Central1919646826490651747-597X-4-110.1186/1747-597X-4-1ResearchThe Leeds Evaluation of Efficacy of Detoxification Study (LEEDS) prisons project: a randomised controlled trial comparing dihydrocodeine and buprenorphine for opiate detoxificationSheardLaura1l.sheard@leeds.ac.ukWrightNat MJ2n.wright@leeds.ac.ukEl-SayehHany G3hany.el-sayeh@nyypct.nhs.ukAdamsClive E4clive.adams@nottingham.ac.ukLiRyan5ryan.li@ucl.ac.ukTompkinsCharlotte NE1c.tompkins@leeds.ac.uk1Leeds Institute of Health Sciences, Charles Thackrah Building, 101 Clarendon Road, Leeds, LS2 9LJ, UK2HMP Leeds and Leeds PCT based at Leeds Institute of Health Sciences, Charles Thackrah Building, 101 Clarendon Road, Leeds, LS2 9LJ, UK3North Yorkshire and York Primary Care Trust, The Briary Wing, Harrogate District Hospital, Lancaster Park Road, Harrogate HG2 7SX, UK4Mental Health Services Research, Division of Psychiatry, University of Nottingham Duncan MacMillan House, Portchester Road, Nottingham, NG3 6AA, UK5Department of Mental Health Sciences, University College London Holborn Union Building, Highgate Hill, London, N19 5LW, England, UK20095220094111792008522009Copyright © 2009 Sheard et al; licensee BioMed Central Ltd.2009Sheard et al; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.BackgroundMany opiate users entering British prisons require prescribed medication to help them achieve abstinence. This commonly takes the form of a detoxification regime. Previously, a range of detoxification agents have been prescribed without a clear evidence base to recommend a drug of choice. There are few trials and very few in the prison setting. This study compares dihydrocodeine with buprenorphine.MethodsOpen label, pragmatic, randomised controlled trial in a large remand prison in the North of England. Ninety adult male prisoners requesting an opiate detoxification were randomised to receive either daily sublingual buprenorphine or daily oral dihydrocodeine, given in the context of routine care. All participants gave written, informed consent. Reducing regimens were within a standard regimen of not more than 20 days and were at the discretion of the prescribing doctor. Primary outcome was abstinence from illicit opiates as indicated by a urine test at five days post detoxification. Secondary outcomes were collected during the detoxification period and then at one, three and six months post detoxification. Analysis was undertaken using relative risk tests for categorical data and unpaired t-tests for continuous data.Results64% of those approached took part in the study. 63 men (70%) gave a urine sample at five days post detoxification. At the completion of detoxification, by intention to treat analysis, a higher proportion of people allocated to buprenorphine provided a urine sample negative for opiates (abstinent) compared with those who received dihydrocodeine (57% vs 35%, RR 1.61 CI 1.02–2.56). At the 1, 3 and 6 month follow-up points, there were no significant differences for urine samples negative for opiates between the two groups. Follow up rates were low for those participants who had subsequently been released into the community.ConclusionThese findings would suggest that dihydrocodeine should not be routinely used for detoxification from opiates in the prison setting. The high relapse rate amongst those achieving abstinence would suggest the need for an increased emphasis upon opiate maintenance programmes in the prison setting.Trial registrationCurrent Controlled Trials ISRCTN07752728BackgroundPrison populations include a high proportion of people who use illicit substances and are dependent upon illicit opiates [1]. Levels of drug use among prisoners tend to be much higher than in the general population [2]. In the United Kingdom (UK) almost two thirds of injecting drug users have spent some time in prison [3] and repeat drug-related offending and re-incarceration is common [3]. Illicit opiate users who enter the prison estate in the UK are typically offered pharmacological interventions of opiate maintenance treatment, or an opiate detoxification regime complimented by psychosocial support according to individual health need [4].Historically, healthcare provision for injecting drug users in prisons in England and Wales has not been equivalent to that offered in community settings. There has recently been a phased re-organisation in prison healthcare with responsibility in England and Wales being transferred from the Home Office to individual National Health Service (NHS) Primary Care Trusts (PCT) [5]. Alongside this, current developments in drug policy have been designed to facilitate a change in prison based clinical practice to enable it to become equivalent to that offered in the community [6-9]. In support of this policy directive, financial resource is being provided to prisons to supply an integrated system for drug maintenance or detoxification treatment within nationally agreed clinical guidelines [4]. Consequently, all prisoners whose urine tests are positive for illicit opiates should be offered an opiate detoxification of equivalent standard to that in the community.As many drug users reduce or cease illicit drug use whilst in prison, providing treatment for opiate detoxification is a core function of prison healthcare provision [4]. However, during the period when the current research was conducted (2004/2005) the evidence base and the national guidelines on the clinical management of drug misuse [10] did not stipulate a \'drug of choice\' for opiate detoxification. In the absence of this evidence base, a wide variety of agents for opiate detoxification have previously been prescribed at the discretion of prison clinicians. Such medications include methadone, dihydrocodeine, buprenorphine, lofexidine and clonidine. Historically within UK prisons, the most commonly used drug for opiate detoxification has been dihydrocodeine. Anecdotally this was partly due to a reluctance to prescribe methadone following a small number of methadone related deaths in the prison setting. Dihydrocodeine has been attractive to clinicians as it has a shorter half-life than methadone, and seems equally acceptable to users. Robertson et al (2006) found that there was no significant difference in retention in treatment between dihydrocodeine and methadone for maintenance treatment in the community [11]. Towards the end of the study period (late 2005), there was a national move away from prescribing dihydrocodeine in the British prison setting due to its potential for diversion by prisoners into the shadow economy.Buprenorphine, in the form of sub-lingual tablets, has the potential advantage of having a good safety profile, better retention in treatment and lower withdrawal severity when compared to methadone, lofexidine or clonidine [12-16]. Comparatively, it has been increasingly prescribed in the community for the purpose of opiate detoxification [17]. The latest Department of Health guidelines recommend either buprenorphine or methadone as first line agents for prisoners requesting an opiate detoxification, subject to clinician discretion [4].Recently, the results of the Leeds Evaluation of Efficacy of Detoxification Study (LEEDS) were published [18]. The study was a randomised controlled trial (RCT) comparing buprenorphine and dihydrocodeine for opiate detoxification in the community drug treatment setting and showed that participants were more likely to achieve abstinence from illicit opiates at completion of detoxification with buprenorphine. However there are potentially differences in the demographics, drug histories and structuring of drug treatment in the community compared to the prison which limits the external validity of these findings in the prison treatment setting. Consequently, the research team considered it imperative that the same detoxification agents were compared within the prison estate. Additionally, there appears to be a paucity of clinical trials conducted worldwide in the prison setting which have evaluated medication for opiate detoxification. Whilst one British study evaluated the withdrawal severity of methadone versus lofexidine, the rates of completion were not sufficient to detect a statistically significant difference between the medications [19]. Given the dearth of randomised controlled trials for opiate detoxification in this environment, we felt it appropriate to introduce this methodology to answer an important research question which could inform clinical policy, decision making and prison policy directives [20]. This paper reports the findings of a trial comparing dihydrocodeine and buprenorphine for opiate detoxification in the UK prison setting.MethodsSettingHer Majesty\'s Prison Leeds. This is a large category B local remand prison1 in the North of England, with over 1200 bed spaces. It accepts over 6000 adult male prisoners per year, primarily from the West Yorkshire area.DesignPragmatic open label randomised controlled trial comparing two detoxification interventions – oral dihydrocodeine and sublingual buprenorphine. Randomisation sequence, with random block size, was generated using Microsoft Excel RAND function, by CEA in the Department of Psychiatry at the University of Leeds. CEA prepared sealed opaque consecutively numbered envelopes concealing the name of the allocated intervention. CEA had no contact with eligible participants.The Multi Centre Research Ethics Committee for Wales (MREC Wales) approved the study in May 2004, and the Research Governance Organisation (Bradford South and West PCT) in April 2004.EligibilityInclusion criteria1. Male (since research only took place in the male estate, thereby implicitly excluding women)2. 18 – 65 years3. Using illicit opiates as confirmed by a urine test taken at first assessment4. Expressing a wish to detoxify through the standard monitored process and remain abstinent from opiates5. Willing to give informed consent after receiving the participant information sheet6. Remaining in custody in HMP Leeds for longer than 28 daysExclusion criteria1. Contraindications to dihydrocodeine or buprenorphine2. Co-existing acute medical conditions requiring emergency admission for hospital care so precluding detoxification in the prison setting3. Currently undergoing detoxification from other illicit drugs whereby concurrent detoxification from opiates would not be clinically indicated4. Previous randomisation into the trialRecruitmentParticipants were recruited from the medical reception area on arrival into HMP Leeds. On their first night in HMP Leeds, those with a current history of illicit opiate use (as confirmed by a Sure Screen multi panel drugs test) are routinely offered a detoxification regime. When prisoners who fulfilled the inclusion criteria approached the prison doctor, the purpose and rationale of the trial was explained to them. If they provided informed consent, the prison doctor (NW or HE) randomised them by opening the next pre-prepared opaque envelope and prescribing the intervention named within. Up to the point of opening the envelope both prisoner and doctor were blind to the intervention; once the envelope was open both prisoner and doctor knew the allocated intervention. On the opening of the envelope, the prison nursing staff and the prison pharmacist were informed of the allocated intervention for each participant. Standard clinical care continued from this point onwards.Randomisation took place between July 2004 and July 2005. Some prisoners may have chosen to enter the trial as during this period, the standard detoxification choices offered to prisoners were dihydrocodeine and buprenorphine. This was regardless of whether they entered the trial or not, so it was only strong patient preference which predominantly meant people declined to take part. Recruitment was disappointing during the first five months of the trial (See Table 1 for breakdown of the actual rates of recruitment per month and also anticipated recruitment). So, in September 2004 (following MREC approval) the research team decided to provide an incentive of £5 which was credited to the prisoners\' phone accounts (operated by a PIN number). The incentive was credited upon entry to the trial and prisoners were aware that they could withdraw at any time, yet keep the accredited incentive. We felt this incentive was an appropriate gratitude for prisoners to provide the voluntary urine samples and information that were required as part of taking part in the study. After introduction of the incentive, recruitment rates remained static but then increased in December and fluctuated somewhat. Ideally, it would have been beneficial to be able to provide incentives for urine samples at the secondary outcome points in order to increase the follow up rates.Table 1Rates of recruitment per month versus anticipated recruitmentActual recruitmentAnticipated recruitmentJul 2004110Aug 2004210Sep 2004210Oct 2004210Nov 2004010Dec 2004710Jan 20051910Feb 20051710Mar 20051310Apr 2005410May 20051210Jun 2005310Jul 2005810InterventionsDihydrocodeine was given openly in the context of the standard prison doctor and drugs worker support. It was prescribed as a 30 mg oral tablet preparation "in-possession" medication. The medication was administered once a day to the participant who held the supply of medication to take in four daily divided doses.Buprenorphine was given openly, in the context of the standard prison doctor and drugs worker support. It was dispensed either as 8 mg, 2 mg or 0.4 mg sublingual tablet preparation under daily supervised consumption.The reducing regimen of both medications was at the discretion of the prescribing doctor. However, in practice, the detoxification regimes were subject to a protocol so as to fit into the high volume, busy nature of the prison regime. The dose prescribed did not exceed the standard regimes (Table 2). Therefore, the total dose administered was 96 mg of buprenorphine over 20 days and 6660 mg of dihydrocodeine over 20 days.Table 2Detoxification regimensBuprenorphineDihydrocodeineDayDose (mg)morningevening162 × 1202 × 120282 × 1202 × 120382 × 1202 × 120482 × 1202 × 120582 × 1202 × 120682 × 1202 × 120782 × 1202 × 120881 × 120, 1 × 901 × 120, 1 × 90961 × 120, 1 × 901 × 120, 1 × 901062 × 902 × 901142 × 902 × 90123.61 × 90, 1 × 601 × 90, 1 × 60133.21 × 90, 1 × 601 × 90, 1 × 60142.82 × 602 × 60152.42 × 602 × 60162.01 × 602 × 60171.61 × 602 × 60181.21 × 601 × 60190.81 × 601 × 60200.4XXXX1 × 60Sample sizeAs no randomised controlled trials relevant to these comparisons have been previously undertaken in the prison setting, there was no comparable study on which to base the sample size calculation. The only other controlled trial comparing agents for detoxification (methadone and lofexidine) in a UK prison randomised 74 prisoners [19]. However, the project team completed a detoxification trial in the homeless community comparing dihydrocodeine with buprenorphine [20]. From this, we estimated that with a sample size of 60 we would have a finding of clinical and statistical significance for differences in the primary outcome. Due to loss of follow-up we determined a sample size of 120 would have sufficient power (i.e 80%) to determine a difference in the secondary outcomes between the two arms of 70% versus 45% [OR 1.56; α = 0.05 (two-sided)]. The power calculation was undertaken using Sample Power 1.20 developed by SPSS Inc., comparing two groups (60 individuals in each) and for α = 0.05 (two-sided).Data collection and OutcomesThe LEEDS trial co-ordinator (LS) collected details of allocated detoxification agent, background history, demographic details and use of opiates from the participant\'s prison medical records.Primary outcomeAbstinence from illicit opiates at five days post detoxification as indicated by a supervised Sure Screen multi panel drugs test negative for opiates. This urine test was taken by a prison nurse who was prompted by LS at the appropriate follow-up time period.Secondary outcomesDuring the period of detoxificationSerious and Adverse Events – As part of routine clinical practice, clinicians and drugs workers noted any adverse events by making an entry in the participant\'s medical records. LS extracted data of adverse events clearly resulting in clinically significant distress to study participants or of major concern to clinicians from medical records, for the period of detoxification, and transcribed these onto a database.Leaving the study early – perceived reasons for withdrawal were recorded.Inappropriate use of prescribed medication – examples of this included intentional overdose, storing, trading, swapping or selling of prescribed medication.Service utilisation – admission to hospital, Accident and Emergency and in-patient stays in prison hospital healthcare wing were recorded.At 1, 3, and 6 months post detoxificationAbstinence status – if the prisoner was still in HMP Leedsthese data were extracted from clinical notes. If the person had been transferred, other prisons were contacted. If the prisoner had been released into the community, evidence of abstinence status was primarily ascertained through local community drugs service or GPs records. There was some, albeit limited, success tracing people via the address or telephone number which they had provided at the point of randomisation.Service utilisation (as above)All data was recorded on a Microsoft Excel spreadsheet.Significant loss to follow-up occurred due to the high turnover of prisoners in HMP Leeds. Being a busy remand prison, the eligibility criteria of "remaining in custody in HMP Leeds for longer than 28 days" was determined so that the primary outcome would be complete for most participants. At the point of randomisation, remand prisoners who were due to appear in court in less than 28 days time were asked the likelihood of returning to HMP Leeds and invited to take part accordingly.AnalysisFollowing data entry, all analyses were undertaken using Review Manager 4.2.8 and SPSS software. The analysis of the primary outcomes was by a simple 2 × 2 table. Dummy tables were constructed for all secondary outcomes. These tables were designed as rigid templates for the final write up of the research, and to facilitate the researchers to collate a full data set and to mitigate against data dredging. Primary outcomes were analysed on an intention-to-treat basis: if the person did not finish the course of detoxification or did not give a urine sample then this was considered as a positive urine test for opiates. Intention-to-treat was used as a replication of the analysis performed in the trial conducted in the community [18] rather than other methods e.g. multiple imputation. Primary outcomes at follow-up were analysed both as per protocol (excluding those lost to follow-up) and intention-to-treat (missing urines assumed positive) with relative risk tests for categorical data and unpaired t-tests for continuous data. Secondary outcome data were analysed using chi square tests.ResultsParticipantsNinety men, that is 64% of those who were eligible and approached to take part in the study, consented to recruitment (Figure 1). These men were imprisoned in HMP Leeds and using illicit opiates prior to their sentence. The average age was 29.8 years (range 19–53) with the mean age for those allocated buprenorphine being 28.9 (SD 4.6) and 29.7 for those allocated dihydrocodeine (SD 6.1). The duration of using opiates overall was 9.3 years (range 1–18) with a mean of 8.9 years for those allocated buprenorphine (SD 3.5) and 9.7 years for those allocated dihydrocodeine (SD 4.6). Forty two men were randomly allocated to buprenorphine and 48 to dihydrocodeine. Variables relating to age, pattern of use and prognosis were evenly distributed between groups (Table 3).Table 3Demographic characteristics and prognostic factorsBuprenorphine(n = 42)Dihydrocodeine(n = 48)Age – mean (SD)28.9 (4.6)29.7 (6.1)Pattern of use\u2003How are opiates taken?\u2003\u2003IV21 (50%)18\u2003\u2003Smoking912\u2003\u2003Methadone maintenance20\u2003\u2003Don\'t know1018Current daily use\u2003minimum – mean (SD)£40.00 (21.10)£42.10 (29.40)\u2003maximum£45.48 (23.39)£45.65 (30.21)Duration taking opiates – mean (SD)8.9 (3.5) years9.70 (4.6) yearsInitial urine\u2003illicit opiates present28/3027/27\u2003other drugs present16/3013/27Prognostic factorsYesNoD/KYesNoD/K\u2003Previous detoxes?27342543\u2003Successful detoxes?119101386Figure 1Flow chart of randomisation outcome.Primary outcomeOverall, 63 men (70%) gave a urine sample at 5 days post detoxification (Table 4), between the two allocated regimens for provision of urine sample (RR 1.18, CI 0.90 – 1.54, z = 1.20, p = 0.43). 27 men (30%) did not provide a urine sample. 18 were released before their urine sample was due, 4 were transferred to another prison and 5 did not complete the prescribed detoxification regime. Of those released or transferred, 11 did not complete the detoxification, 4 completed the regime but left HMP Leeds before their urine test was due and 5 left on the day of the test or afterwards (data unavailable for 2). There was no statistically significant difference in demographic variables at baseline between those who completed detoxification and those who did not.Table 4ResultsBuprenorphine(total = 42)Dihydrocodeine(total = 48)Relative Risk(95% CI)Unpaired t-testP valueBy end of detox\u2003Final urine sample32/4231/481.18 (0.90, 1.54)N/A0.43\u2003Per protocol negative urine24/3217/311.37 (0.94, 1.99)N/A0.10\u2003ITT negative urine24/4217/481.61 (1.02, 2.56)N/A0.04\u2003Leaving early10/4215/480.76 (0.38, 1.51)N/A0.43\u2003Overdose00N/A\u2003Inappropriate use of allocated drug3/291/252.59 (0.29,23.32)N/A0.39\u2003A&E attendance00N/A\u2003Hospital admittance00N/A\u2003Prison doctor visits (mean)1.0 (0.5) n = 281.0 (0.6) n = 23N/At(49) = 0.001.00At 1 months post detoxification\u2003Dead0/330/33N/A\u2003Abstinent (ITT)16/4217/481.08 (0.63, 1.85)N/A0.79\u2003How known?\u2003\u2003Urine test4/102/51.00 (0.27, 3.72)N/A\u2003\u2003Self report12/2115/250.95 (0.58, 1.55)N/A1.00\u2003A&E attendance0/330/33N/A0.84\u2003Hospital attendance0/330/33N/APrison doctor visits (mean)0.4 (0.9) n = 250.6 (1.0) n = 28N/At(51) = 0.760.45Drug worker visits(mean)0.2 (0.4) n = 32 n = 1N/AAt 3 months post detoxification\u2003Dead0/270/23N/A\u2003Abstinent (ITT)13/4212/481.24 (0.64, 2.41N/A0.53\u2003How known?\u2003\u2003Urine test2/81/41.00 (0.13, 8.00)N/A1.00\u2003\u2003Self report11/1811/181.00 (0.59, 1.68)N/A1.00\u2003A&E attendance1/271/230.85 (0.06,12.87)N/A0.91\u2003Hospital attendance2/271/231.70 (0.16,17.60)N/A0.65\u2003Prison doctor visits (mean)0.8 (1.7) n = 171.5 (1.9) n = 17N/At(32) = 0.760.27\u2003Drug worker visits (mean)0No dataN/AAt 6 months post detoxification\u2003Dead0/140/12\u2003Abstinent5/425/481.14 (0.36, 3.68)N/A0.82\u2003How known?\u2003\u2003Urine test1/31/41.33(0.13,13.74)N/A0.81\u2003\u2003Self report4/114/80.73 (0.26, 2.07)N/A0.55\u2003A&E attendance2/141/121.71(0.18,16.65)N/A0.64\u2003Hospital attendance3/142/121.29 (0.26, 6.46)N/A0.76\u2003Prison doctor visits (mean)2.0 (2.2) n = 42.2 (1.5) n = 4N/A\u2003Drug worker visits (mean)No dataN/A*ITT assumption = everybody not returning for final urine test had positive urine* Statistical tests were z (approximation) testsAt the completion of detoxification, by intention to treat analysis, we found a higher proportion of people allocated to buprenorphine provided a urine sample negative for opiates (abstinent) compared with those who received dihydrocodeine (57% vs 35%, RR 1.61 CI 1.02–2.56, z = 2.065, p = 0.04).Secondary outcomesAt one month, follow up data were obtained on 66 participants (73% of the study sample). At three months, follow up data were obtained on 55 participants (61% of the study population). At six months, follow up data were obtained on 26 participants (29% of the study population).At the 1, 3 and 6 month follow-up points, there were no statistically significant differences for urine samples negative for opiates between the two groups. There were also no statistically significant differences for any other of the secondary outcomes of Accident and Emergency attendance, hospital attendance, GP visits or drugs worker visits throughout this post-treatment period (Table 4). No serious adverse events were reported throughout the study.DiscussionThe findingsOur study showed that at five days after completion of the prison detoxification regime, buprenorphine at a total dose of 96 mg was more effective than dihydrocodeine at a total dose of 6660 mg in achieving abstinence from illicit opiates. It also showed that 43% of HMP Leeds\' prisoners with a habit of illicit opiate use, who agreed to be included in the study, continued to acquire and use opiates even through the first few days of imprisonment and prescribed detoxification regimen.It is possible that the research was underpowered to determine the effect of the interventions upon longer term abstinence, as at the secondary follow up points there were no statistically significant differences between the two groups for urine samples negative for opiates. However, it may be that there was clinically no significant difference. To this effect, firm conclusions regarding the effectiveness of buprenorphine and dihydrocodeine detoxification on post release opioid use and other core outcomes can not be conclusively determined. It is well known that post release from prison is a high risk time for relapse into illicit drug use. Therefore, it could be that more meaningful follow up data from prison based detoxification trials could be derived based on the time since release from prison in addition to time since detoxification.A direct comparison can be made between the results of this study and those of the sister trial conducted in the community [18]. As previously stated, the result of the community trial also favoured buprenorphine over dihydrocodeine for opiate detoxification. Most importantly, completion of detoxification and provision of final urine in the prison environment was much higher than in the community (23% vs 70%). Reasons for this are varied but may include inherent characteristics of the treatment setting. For the participants who remained in HMP Leeds, when their urine sample was due, the closed, secure environment meant they were actively traced by prison nurses who took the urine samples. This contrasts with the very different environment of the community where the research team were dependent on the participants returning to their general practice to collect their final prescription so that a urine sample could be taken.It is important to state that the trial did not introduce any new intervention medications into HMP Leeds as dihydrocodeine and buprenorphine were the only detoxification agents available during the period of randomisation [20]. The trial took place for a year from summer 2004, which is important as during this period the first line agent for most UK prisons was dihydrocodeine, with buprenorphine slowly being introduced. It seemed pertinent to compare these two agents, given that they were being prescribed to thousands of prisoners with a history of illicit opiate use every year in UK prisons despite no previous evaluation of their clinical effectiveness. Current policy recommendations are very different, with methadone and buprenorphine now being advocated as first line agents for opiate detoxification [4]. However, anecdotally, a practice of dihydrocodeine prescribing continues in many UK prisons.Whilst there is a paucity of opiate detoxification trials conducted with prisoners, some studies have highlighted prisoners\' subjective experiences of opiate detoxification. One recent qualitative study identified that prisoners in England who had been prescribed dihydrocodeine found that it was often inadequate at relieving acute opiate withdrawal and they were often reduced too quickly [21]. More favourable prison detoxification experiences were noted with buprenorphine and methadone [21]. Other studies have reported prisoners\' sense of inadequacy in relation to short term methadone detoxifications [22,23] where the length of the detoxification is perceived as too short. Length of detoxification has now increased in UK prisons [4] and methadone and buprenorphine have become first line agents in the prison estate [4].Current UK guidelines regarding the treatment of drug misuse in prisons recommend that only licensed opiate agonist medications (such as methadone or buprenorphine) should be used in the pharmacological treatment of opiate detoxification [4]. This recommendation was based on face validity consensus view of experts working in the field. Our findings strengthen and provide empirical support for the current guidelines which do not recommend the routine use of dihydrocodeine as a first line agent for detoxification in the prison setting. Outside of prison, recent clinical guidance from UK\'s National Institute of Clinical Excellence [24] has recommended against the routine use of dihydrocodeine for opiate detoxification based on evidence from the LEEDS trial in the community [18] and unpublished data from this current study. Both suggested no advantage in effectiveness of dihydrocodeine over buprenorphine either in the community or the prison.Methodological issuesLEEDS is only one of a small number of randomised controlled trials to take place in the UK prison estate. [25] The research team encountered barriers when conducting the community trial [18] such as patient preference, clinical equipoise and logistical issues [26]. Patient preference was a difficulty that carried through to the prison setting and was probably the largest hurdle to randomising people into the trial. However, conducting this trial in the prison environment presented many new problems and issues. Most significantly, the research team had to be satisfied that all prisoners gave informed consent and that they understood the processes of the trial. This was sometimes difficult in the noisy and chaotic environment of first night medical reception. Additionally, the reception area has a fast throughput and was not often conducive to the intricacies of a research trial. On some occasions, potential participants were not randomised if it was thought that they did not fully understand the concept of the trial or – more often – the process of randomisation. This was usually the case when they were in physical withdrawal from illicit opiates.One weakness of the study was not recording demographic details of those who declined to participate as we cannot compare this group with those who agreed to be involved. Also this study involved men over the age of 18. Therefore applicability of the findings to women and young people in prison is problematic. Additionally, there are limitations with the intention-to-treat analysis used as this assumes that all missing urines tests are positive for opiates. Whilst we acknowledge this is problematic, this trial was analysed according to statistical convention in the UK and in keeping with the analysis of the sister trial previously conducted in the community.Data collection was difficult when prisoners were transferred to serve their remaining sentence at other establishments across the wider prison estate. Indeed, there was a wide variation of responses to requests for help obtaining important information from other prison healthcare departments, despite having the necessary ethical and governance approvals in place to facilitate this. Whilst some prison healthcare departments at other establishments were willing to share information for the purposes of the trial, despite our best efforts, others refused. This sometimes led to a loss of follow up data from prisoners who were participating in the trial who had been transferred to certain unhelpful establishments.As far as the research team are aware, this study is the only opiate detoxification randomised controlled trial in a prison setting which has taken abstinence from opiates (as indicated by a urine test) as the primary outcome. For studies assessing efficacy of opiate detoxification agents, an accurate and independent measure of abstinence status is important Cf [27]. The only other prison trial with which to compare is Howells et al (2002) [19]. In this UK study of 74 male prisoners with opiate addiction, lofexidine was compared with methadone with the primary outcome being self-reported withdrawal symptom severity during the detoxification period. Variously, other trials comparing agents for opiate detoxification in a variety of settings have used intensity/symptoms of withdrawal, retention in treatment, completion of treatment, nature of adverse effects [16,28] and relapse rate [28]. We believe that our first line method of ascertaining abstinence status via a urine test represents the most robust and binary manner in which to answer a clinical research question pertaining to the efficacy of detoxification medications.We undertook this study on a minimal budget (one half time research assistant post for co-ordination and data collection over 19 months). Prison doctors (NW and HE) randomised in addition to their everyday clinical roles and responsibilities (approximately 5 to 8 minutes per participant). The research team believed this trial is imperative in order to ascertain whether a randomised controlled trial with drug using prisoners, which recorded abstinence, was feasible in UK prisons. The high throughput of large numbers of prisoners in an environment that is recognised as a high risk for overdose, self-harm and suicide [29] certainly presents significant logistical barriers to the smooth running of a research project. However, we do acknowledge that the very low follow up rate of this study is problematic and it may be pertinent for future studies to examine more rigorously whether buprenorphine was superior to dihydrocodeine at post release.Future researchThis study raises further research questions. Since completion of this trial, the issue of buprenorphine abuse in the UK prison estate has been highlighted [30]. Therefore it could be that whilst our findings would suggest that dihydrocodeine should not routinely be used for detoxification in the prison setting, there could be other more effective agents than buprenorphine. In particular it is possible that methadone mixture is the pharmacological agent that is both most clinically effective and least amenable to diversion in the prison setting. Currently the Department of Health is supporting the research team to undertake a multi-prison trial comparing methadone with buprenorphine regimens for opiate detoxification. After a lengthy period completing the necessary approvals [31], recruitment for this trial began in January 2006. Randomisation and data collection for this research is currently ongoing, with almost 300 prisoners recruited to date across three prisons in the North of England. Methadone and buprenorphine are now the two first line detoxification medications within the British prison estate and a comparison is therefore fundamental to inform the current knowledge and evidence base.The research team believe that conducting qualitative work around this trial may strengthen and give depth to the findings, particularly in relation to those people who were not abstinent at the primary outcome stage. It would have been interesting to understand how prisoners viewed the experience of their detoxification and how issues peculiar to the nature of prison life and drug use were worked out and overcome. Consequently, we would recommend that future randomised controlled trials (in a variety of settings) incorporate a qualitative element into their design in order to understand the holistic experience of simultaneously being a patient and research participant.ConclusionThis study suggests that buprenorphine may be more effective than dihydrocodeine for adult men undergoing opiate detoxification in the prison environment. However, it also demonstrates the high level of illicit opiate use within the prison estate even for those entered into a detoxification programme, with over 40% of prisoners in this study showing evidence of illicit opiates in their urine. The results of this trial reinforce current guidelines which do not recommend dihydrocodeine is prescribed as a first line agent for the management of opiate misuse. The high rate of relapse into opiate use post-intervention would also suggest a greater role for opiate maintenance in the prison estate as abstinence is not a realistic goal for many drug users within this environment. There is an emerging evidence base for the effectiveness of opiate maintenance programmes in the prison setting [32].The research team encountered novel methodological issues and problems when randomising in the prison environment, the most crucial being informed consent. Data collection was also problematic once prisoners had been released or transferred to other establishments. In outlining our research experience, we hope to inform other research teams of the logistical issues of conducting a clinical trial in the British prison estate. Most significantly, this research demonstrates that a pragmatic randomised controlled trial can be undertaken in this difficult and challenging environment.Notes1. Category B refers to a prison which is high but not maximum security. HMP Leeds is classed as a local prison in that it predominantly accepts men from the local area which is the county of West Yorkshire.Competing interestsThe authors declare that they have no competing interests.Authors\' contributionsNW and CA designed the study and offered project supervision. NW was principal investigator. CA centrally managed the randomisation process. LS co-ordinated and managed the project, assisted during randomisation clinics and collected follow up data. HE and NW randomised participants into the trial. RL conducted statistical analysis. All authors drafted the manuscript.AcknowledgementsWe are grateful to all participants who participated in the trial at HMP Leeds. We would particularly like to thank all medical staff who were involved and assisted us with randomisation and data collection. 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detoxification for opioid dependence: a randomised double blind controlled trial of lofexidine and methadoneDrug and Alcohol Dependence2002671691761209566610.1016/S0376-8716(02)00024-8SheardLAdamsCWrightNEl-SayehHDaltonRTompkinsCThe Leeds Evaluation of Efficacy of Detoxification Study (LEEDS) prisons project pilot study: protocol for a randomised controlled trial comparing dihydrocodeine and buprenorphine for opiate detoxificationTrials2007811721008010.1186/1745-6215-8-1TompkinsCNealeJSheardLWrightNExperiences of prison among injecting drug users in England: A qualitative studyInternational Journal of Prisoner Health2007318920310.1080/17449200701520123Health Research BoardDrug use among prisoners: An exploratory study Dublin2001HughesR"It\'s like having half a sugar when you were used to three" Drug injectors views and experiences of substitute drug prescribing inside English prisonsInternational Journal of Drug Policy2000104556610.1016/S0955-3959(99)00039-0National Institute for Clinical ExcellenceDrug Misuse: Opioid detoxification: NICE guidanceFarringtonDJoliffeDA feasibility study into using a randomised controlled trial to evaluate treatment pilots at HMP Whitemoor London2002SheardLWrightNTompkinsCAdamsCRecruiting opiate users to a randomised controlled trial in primary care: a descriptive study of GP attitudesPrimary Health Care Research and Development2006710611510.1191/1463423606pc274oaFarmerKMethods for measuring and monitoring medication regimen adherence in clinical trials and clinical practiceClinical Therapeutics1999211074901044062810.1016/S0149-2918(99)80026-5AmatoLDavoliMFerriMGowingLPerucciCEffectiveness of interventions on opiate withdrawal treatment: an overview of systematic reviewsDrug and Alcohol Dependence2004732192261503654410.1016/j.drugalcdep.2003.11.002Department of HealthDrug Misuse and Dependence: UK Guidelines on Clinical Management London2007Ministry of JusticeA Survey of Buprenorphine Misuse in Prison2007Accessed 26/03/08SheardLTompkinsCWrightNAdamsCNon-commercial clinical trials of a medicinal product: can they survive the current process of research approvals in the UK?Journal of Medical Ethics2006324304341681604610.1136/jme.2005.015180KinlockTGordonMSchwartzRO\'GradyKFitzgeraldTWilsonMA randomized clinical trial of methadone maintenance for prisoners: Results at 1 month post releaseDrug and Alcohol Dependence2007912202271762835110.1016/j.drugalcdep.2007.05.022', 'title': 'The Leeds Evaluation of Efficacy of Detoxification Study (LEEDS) prisons project: a randomised controlled trial comparing dihydrocodeine and buprenorphine for opiate detoxification.', 'date': '2009-02-07'}, '17210079': {'article_id': '17210079', 'content': 'BMC Fam PractBMC Family Practice1471-2296BioMed CentralLondon1721007917745691471-2296-8-310.1186/1471-2296-8-3Research ArticleBuprenorphine versus dihydrocodeine for opiate detoxification in primary care: a randomised controlled trialWrightNat MJ1n.wright@leeds.ac.ukSheardLaura1l.sheard@leeds.ac.ukTompkinsCharlotte NE1c.tompkins@leeds.ac.ukAdamsClive E2ceadams@cochrane-sz.orgAllgarVictoria L1v.l.allgar@leeds.ac.ukOldhamNicola S3l.sheard@leeds.ac.uk1Centre for Research in Primary Care, 71-75 Clarendon Road, Leeds, LS2 9PL, UK2Department of Psychiatry, 15 Hyde Terrace, Leeds, LS2 9L, UK3Formerly of NFA Health Centre for Homeless People, 68 York Street, Leeds, LS9 8AA, UK20078120078331652006812007Copyright © 2007 Wright et al; licensee BioMed Central Ltd.2007Wright et al; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.BackgroundMany drug users present to primary care requesting detoxification from illicit opiates. There are a number of detoxification agents but no recommended drug of choice. The purpose of this study is to compare buprenorphine with dihydrocodeine for detoxification from illicit opiates in primary care.MethodsOpen label randomised controlled trial in NHS Primary Care (General Practices), Leeds, UK. Sixty consenting adults using illicit opiates received either daily sublingual buprenorphine or daily oral dihydrocodeine. Reducing regimens for both interventions were at the discretion of prescribing doctor within a standard regimen of not more than 15 days. Primary outcome was abstinence from illicit opiates at final prescription as indicated by a urine sample. Secondary outcomes during detoxification period and at three and six months post detoxification were recorded.ResultsOnly 23% completed the prescribed course of detoxification medication and gave a urine sample on collection of their final prescription. Risk of non-completion of detoxification was reduced if allocated buprenorphine (68% vs 88%, RR 0.58 CI 0.35–0.96, p = 0.065). A higher proportion of people allocated to buprenorphine provided a clean urine sample compared with those who received dihydrocodeine (21% vs 3%, RR 2.06 CI 1.33–3.21, p = 0.028). People allocated to buprenorphine had fewer visits to professional carers during detoxification and more were abstinent at three months (10 vs 4, RR 1.55 CI 0.96–2.52) and six months post detoxification (7 vs 3, RR 1.45 CI 0.84–2.49).ConclusionInformative randomised trials evaluating routine care within the primary care setting are possible amongst drug using populations. This small study generates unique data on commonly used treatment regimens.BackgroundIn the United Kingdom (UK), policy directives have highlighted the importance of offering either maintenance or detoxification to illicit opiate users within an agreed plan of care [1]. This is in response to routine practice by some treatment providers of \'gradual reduction\' of opiate maintenance treatment – a regimen without a supporting evidence base [2]. Opiate detoxification, using one of various therapeutic agents, remains an important part of drug management for some illicit opiate users. However, neither the evidence base nor UK national guidelines recommend a \'drug of choice\' [1]. Understandably, there has been a call for randomised controlled trials (RCTs) in this area [3]. In primary care, methadone is commonly used, with reductions in the dose over 7–21 days [4]. Methadone has a long half life [5,6] and patients often report distressing withdrawal symptoms in the latter stages of detoxification [6]. This has meant increasing use of alternative agents such as clonidine, lofexidine, dihydrocodeine and, more recently, buprenorphine. The hypotensive effects of clonidine [4] have make it unacceptable for use in primary care and the reduced ability of lofexidine to control withdrawal, coupled with its high cost have resulted in limited clinical uptake [4].The use of sublingual buprenorphine is relatively new in the UK for opiate detoxification and there have been only two randomised controlled trials (RCTs) comparing it with methadone for this purpose [7,8]. Buprenorphine has been more commonly used as a drug of comparison in trials of opiate maintenance [9-16]. A recent Cochrane review assessing methadone and buprenorphine for the management of opioid withdrawal found no significant difference between these two agents [17]. In this context, buprenorphine has a good safety profile, better retention in treatment and lower withdrawal severity [18-22]. Sublingual buprenorphine is increasingly being prescribed by General Practitioners (GPs) for opiate detoxification [23] despite limited clinical and research evidence.Dihydrocodeine has a shorter half life than methadone and has been widely used in both primary care and prison drug treatment settings for opiate detoxification. Whilst some commentators have documented success with dihydrocodeine [24,25] others have expressed concerns regarding its effects, particularly the potential diversion into the street economy [26]. Despite routine use, dihydrocodeine has rarely been studied for the purposes of opiate detoxification [24] but has been compared in a randomised controlled trial with buprenorphine for postoperative pain [27].When comparing methadone, dihydrocodeine and buprenorphine it is important to note several factors which may impact upon prescribing and use of these agents. Dihydrocodeine is cheaper than methadone and both methadone and dihydrocodeine are substantially cheaper than buprenorphine. The latter has been subject to heavy pharmaceutical marketing. Buprenorphine and dihydrocodeine have a better safety profile than methadone, which has a high toxicity which (rarely) can result in death [28]. All three agents have the potential for street diversion but dihydrocodeine is the hardest to control, with consumption usually being unsupervised. Methadone is the easiest to manage and buprenorphine seems to be somewhere in-between.The care of people using illicit opiates has changed over recent years. Strang et al (2005) [29] surveyed GPs and found that half had seen at least one opiate user in a four week period, compared to only 19% in a 1986 survey [30]. There has been a significant increase in the number of GPs becoming involved in the care of drug users [31]. Consequently, many short term opiate detoxifications are now undertaken in primary care. The absence of robust evidence underpinning many of the clinical decisions made within primary care has already been highlighted [32]. LEEDS (Leeds Evaluation of Efficacy of Detoxification Study) is a response to this challenge and compared dihydrocodeine with buprenorphine for opiate detoxification within the UK primary care setting.MethodsDesign and settingLEEDS was conducted in ten general practices (6 of which randomised participants) in Leeds, UK (population ~750,000). We used a randomised controlled trial design to compare open giving of oral dihydrocodeine tartrate with open giving of sublingual buprenorphine. Randomisation was by random block size, stratified by practice, using Microsoft Excel RAND function. This was undertaken by the Department of Psychiatry, University of Leeds, and was concealed from clinicians prescribing interventions. The name of the allocated intervention was obscured within fully opaque sealed envelopes [33]. All envelopes were opened in strict order, confirmed by an investigator independent of the clinical interface. The outside of the randomisation envelope contained a brief information form to be completed which requested the patient\'s practice number, date of birth, contact telephone number and date of first prescription. Two questions also served to rate the severity of addiction of the participant from the view of the GP. Once the GP/drug worker opened the LEEDS envelope both practitioner and patient knew the intervention, standard clinical care resumed and the patient made subsequent appointments with the GP and/or drugs worker. To detect with 80% power a difference in treatment effectiveness of 25% between groups (50% versus 25%) at 5% level of significance, it was calculated that 120 participants would be needed in the study. However within the time frame for recruitment we were only able to recruit 60 participants. Randomisation took place between August 2002 and May 2004. Full methods are reported elsewhere [33].The Leeds Teaching Hospitals Local NHS Research Ethics Committee (LREC) approved the study in April 2002. Informed written consent was obtained from each patient following receipt of a participant information leaflet prior to their involvement in the trial.InterventionsBuprenorphine was prescribed on an FP10 MDA prescription. This allows daily dispensing under supervision of a pharmacist. Daily supervised administration of dihydrocodeine tablets is not possible in the UK as it cannot be prescribed on FP10 MDA prescriptions. As such, buprenorphine was dispensed either as 8 mg, 2 mg or 0.4 mg sublingual tablet preparation under daily supervision. Dihydrocodeine was dispensed as 30 mg rapid release tablet preparation in take home installments. Each installment was for a minimum of three and a maximum of 4 daily doses. The reducing regimens for both interventions were at the discretion of the prescribing doctor and within the standard regimen which was approximately 15 days (Tables 1 and 2). However, clinicians were free to titrate doses against withdrawal symptoms. What was being randomised was the open giving of the drugs even if that meant that participants were not given in the opinion of the prescribing doctor pharmacologically equivalent dosages.Table 1Standard buprenorphine detoxificationDayDose (mg)16283846566473.683.292.8102.4112.0121.6131.2140.8150.4Table 2Standard dihydrocodeine detoxificationDayNumber of 30 mg tabletsMorningMiddayEveningNight-time1185445220555531854454164444514433461233337103223892223982222107212211621121251112134111114311115211Inclusion and exclusion criteriaPatients were eligible for the study if they were: aged 18 years or over, using street opiates as confirmed by a urine sample taken at first assessment, wishing to detoxify through the standard monitored process, willing to remain abstinent from opiates and to give informed consent. Patients were excluded if they had contra-indications to dihydrocodeine or buprenorphine or had been randomised into the trial previously.OutcomesThe primary outcome was abstinence from illicit heroin at final prescription, as indicated by urine test. A priori we classed unsuccessful detoxification as: the final urine tested positive for metabolic breakdown products of heroin (morphine or 6-mono-acetyl morphine); urine tested positive for opiates commonly found in street heroin (codeine); the patient did not provide a final urine sample; did not finish detoxification or reported using street opiates during the period of detoxification. We recorded the secondary outcomes of inappropriate use of prescribed medication, overdose and admission to hospital or Accident and Emergency (A&E) and number of GP/drug worker visits during the detoxification period. At three and six month post detoxification, follow up data were recorded. These outcomes were: whether the person was still alive, abstinent from opiates, in receipt of sickness certification and their pattern of service use.Statistical analysisOutcome data were analysed using Epi Info v 3.3.2 and SPSS software with relative risk tests for categorical data and unpaired t-tests for continuous data.ResultsSixty people using illicit opiates took part in LEEDS (Figure 1). This comprised of 42 men and 18 women, with an average age of 28 years. 58% were homeless or unstably housed. There were no significant differences for those allocated to one regimen or the other (Table 3).Figure 1Table 3Demographic characteristics and prognostic factorsBuprenorphine (total 28)Dihydrocodeine (total 32)Age mean (SD)29.9 (5.1)29.0 (7.3)Sex19 M 9 F23 M 9 FPattern of use\u2003How are opiates taken?\u2003\u2003IV14 (50%)24 (75%)\u2003\u2003Smoking13 (46%)8 (25%)\u2003\u2003Both1 (4%)0Current daily use (minimum) (£) mean17.1 (8.1)15.6 (7.2)Current daily use maximum (£) mean23.2 (12.1)18.1 (9.0)Duration taking opiates (years) mean8.8 (4.9)7.0 (3.7)\u2003Illicit opiates in initial urine23 (82%)27 (84%)\u2003Other drugs in initial urine18 (64%)12 (37%)Prognostic factors\u2003\'Severely dependent\'8 (28%)10 (31%)\u2003GP\'s prediction of whether would be off opiates by end of detoxDefinitely notNot sureVery sureDefinitely notNot sureVery sure022 (78%)6 (21%)2 (6%)22 (69%)8 (25%)YesNoD/KYesNoD/K\u2003Previous detoxes?24 (87%)3 (11%)1 (4%)25 (78%)6 (19%)1 (3%)\u2003Successful detoxes?15 (63%)9 (38%)015 (60%)9 (36%)1 (4%)\u2003Employed?4 (14%)19 (68%)5 (18%)4 (13%)19 (59%)9 (28%)\u2003MED-3?6 (21%)8 (29%)14 (50%)5 (16%)13 (41%)14 (44%)\u2003Non using friends?12 (43%)5 (18%)11 (39%)13 (41%)3 (9%)16 (50%)\u2003Anyone supportive of detox?22 (79%)4 (14%)2 (7%)24 (75%)1 (3%)7 (22%)Overall, only 13 people (23%) completed the prescribed course of detoxification medication and gave a urine sample on collection of their final prescription (Table 4). There was an increased chance of completing the prescribing regime if allocated buprenorphine though this finding was of borderline statistical significance (68% vs 88%, RR 0.58 CI 0.35–0.96, p = 0.065). At completion of detoxification, by intention to treat analysis we found a higher proportion of people allocated to buprenorphine provided a urine sample negative for opiates (abstinent) compared with those who received dihydrocodeine (21% vs 3%, RR 2.06 CI 1.33–3.21, p = 0.028). This suggestion of an enhanced therapeutic effect with buprenorphine was negated if we assumed that the proportions of those returning with clean urine per group were representative of those who did not return. Had all the medication been both prescribed and dispensed according to the standard regimes, an expected mean prescribed dose for each dihydrocodeine detoxification would be 4560 mg and 56 mg for each buprenorphine dose. The actual amount of milligrams (mean) and duration of detoxification in days (mean) prescribed for each dihydrocodeine detoxification was 4111 mg (90% of expected dose) over 12 days and 32.9 mg (59% of expected dose) of buprenorphine over 9 days (both rounded to nearest day). This would indicate under-prescribing by doctors for both regimes as 4290 mg (94% of expected dose) would have expected to be prescribed over 12 days for dihydrocodeine and 47.6 mg (85% of expected dose) over 9 days for buprenorphine.Table 4ResultsBuprenorphine (total 28)Dihydrocodeine (total 32)Odds Ratio (95% CI)Relative Risk (95% CI)P valueBy end of detox\u2003Final urine sample9 (32%)4 (13%)3.32 (0.77–15.22)1.71 (1.04–2.83)0.065\u2003Non-ITT Clean urine6/9 (67%)1/4 (25%)6.00 (0.28–246)1.71 (0.73–4.03)0.164\u2003ITT-1* clean urine6/28 (21%)1/32 (3%)8.45 (0.89–200)2.06 (1.33–3.21)0.028\u2003ITT-2* clean urine6+3/281+8/321.21 (0.35–4.21)1.11 (0.63–1.95)0.735\u2003Leaving early19 (68%)28 (88%)0.30 (0.07–1.30)0.58 (0.35–0.96)0.065\u2003Overdose00Not applicable\u2003Inappropriate use of allocated drug00Not applicable\u2003A&E attendance00Not applicable\u2003Admitted00Not applicable\u2003Overdose00Not applicable\u2003GP visits – mean2.2 (1.05)2.8 (1.33)0.06\u2003Drug worker visits – mean0.17 (0.47)1.31 (0.59)0.343At 3 months post detoxification\u2003Abstinent10/27 (37%)4/24 (17%)2.94 (0.67–13.78)1.55 (0.96–2.52)0.104\u2003Dead0/270/28Not applicable\u2003On Med 3 sick note10/16 (63%)6/14 (43%)2.22 (0.41–12.65)1.46 (0.71–2.98)0.282\u2003A&E attendance2/27 (7%)2/28 (7%)1.04 (0.09–11.46)1.06 (0.38–2.94)0.970\u2003Hospital attendance1/27 (4%)2/28 (7%)0.5 (0.02–7.75)0.67 (0.13–3.38)0.574\u2003GP visits – mean5.04 (4.85)4.61 (4.10)0.724\u2003Drug worker visits – mean1.22 (1.67)1.14 (1.53)0.855At 6 months post detoxification\u2003Abstinent7/22 (32%)3/19 (16%)2.49 (0.45–15.15)1.45 (0.84–2.49)0.233\u2003Dead0/230/20Not applicable\u2003On Med 3 sick note3/11 (27%)2/11 (18%)1.69 (0.16–20.05)1.27 (0.53–3.06)0.611\u2003A&E attendance0/220/20Not applicable\u2003Hospital attendance0/222/20 (10%)0.16 (0.01–3.64)0.129\u2003GP visits – mean7.54 (6.71)6.48 (6.07)0.582\u2003Drug worker visits – mean1.74 (2.40)2.65 (2.89)0.265• Assumption 1 = everybody not returning for final urine test had not clean urine• Assumption 2 = everybody not returning for final urine test had same proportion of not clean urine as those who didThere was no statistically significant differences for any other outcomes although throughout the trial people allocated to buprenorphine did better than those on dihydrocodeine. For example people allocated to buprenorphine had fewer visits to the GP and drugs worker during detoxification, and more were abstinent at the three month (10 vs 4, RR 1.55 CI 0.96–2.52) and six month (7 vs 3, RR 1.45 CI 0.84–2.49) follow up. These findings were of borderline statistical significance. No serious adverse events were reported for any participants.DiscussionCommentators have listed significant barriers to conducting randomised controlled trials in the primary care setting [34,35]. Barriers certainly may include lack of clinical equipoise towards interventions and patient preference for a particular treatment, [36] as well as logistical problems (principally the busy primary care workplace as not being conducive to practitioner participation) and over-optimism regarding recruitment [37]. This study, however, was at the outset designed collaboratively between primary care and secondary care researchers to be conducted specifically in the primary care setting. It did not greatly complicate routine treatment and recorded clear and concrete outcomes of relevance to the primary care drug treatment field [33]. The LEEDS project team sought GPs experience of being involved in the trial through a cross sectional survey. Details of the practicalities of conducting LEEDS (including recruitment issues and equipoise) have been fully described elsewhere [38].LEEDS is the first randomised controlled trial to compare buprenorphine and dihydrocodeine for opiate detoxification. Sixty people with problems of opiate dependence agreed to take part in this randomised trial. Thirty five of these people were recruited from a medical centre for the homeless. Recruitment of practitioners was problematic though recruitment of participants was not a substantial problem for practitioners committed to recruiting into the trial. This study ran on a very low budget (50% research assistant time). LEEDS illustrates how such studies, undertaken in the context of routine care, even with such potentially problematic clientele, are both possible and feasible.One limitation of LEEDS was that it was underpowered to detect with confidence clear differences for secondary outcomes between regimens. Selecting a data collection point for the primary outcome at completion of detoxification could be seen as a limitation of the study. However, this outcome was selected after careful consideration. Ideally urine collection would be several days post-detoxification to allow for all prescribed opiates to be clear from the test. We thought, however, many users would not attend primary care after completion of detoxification simply to provide a urine test, particularly as much of the recruitment was from a homeless population who have been traditionally difficult to engage and retain in treatment services [39]. Indeed, only 23% of participants provided a final urine sample. Reasons for this are varied and multiple (Figure 1). Fourteen people did not collect their final prescription and therefore were not available at this time point to provide a urine sample. Five people never returned to the GP practice to collect any prescriptions after their first consultation with the GP or drugs worker. Additionally, 24 people failed to collect a prescription somewhere between the second and penultimate. The high numbers of people who did not provide a urine sample demonstrates the difficulty in retaining injecting drug users in treatment services. This pragmatic, low budget study only sought to record contact with GPs and drugs workers and did not have sufficient capacity to make personal contact during the detoxification period to obtain abstinence status independent of that recorded through medical contact.The main objectives of LEEDS were to have some indication of whether one regimen was associated with better odds of completing detoxification and to test methods for larger studies. We recognize that these are limited goals but found no indication from the literature or even experts in the field that data was known for these outcomes. Of course, retention in treatment services post-detoxification is an important part of the whole treatment package offered to drug users so we also recorded the frequency of medical service utlisation by participants.An additional limitation of the study is that we were unable to collect data on the numbers and demographics of those people who declined to participate. This was due to the busy nature of the primary care treatment setting.Currently many drug users arrested for crimes related to drug misuse are offered a choice of legally mandated treatment (referred to by some as \'coerced\' treatment) [40] or a custodial sentence. No participant in LEEDS had been legally mandated to enter treatment from the criminal justice system. Consequently, all participants expressed self motivation to undergo detoxification. Yet, regardless of which detoxification drug people were randomised to, completion rates were poor. This study suggests that even in this relatively self motivated group of people, completion rates were between only 13% and 32%. In secondary care others have reported completion rates in the range of 33% [41]. However comparisons with study retention rates from trials undertaken in secondary care should be made with caution as it is possible that participants were not equivalent in terms of motivation and self-efficacy. More evaluation of treatment effects in different health settings would therefore seem prudent and we have nearly completed a larger study in the prison setting. The results of this current study, however, are generalisable to those patients presenting for detoxification from illicit opiates in primary care. We would be less confident of generalising our findings to the residential or inpatient setting.This trial suggests that buprenorphine may be able to deliver 20% more completion than dihydrocodeine. If completion of detoxification is associated with remaining abstinent, use of buprenorphine as an agent of opiate detoxification could be a very important step forward. Whilst clinicians prescribing the interventions were not blinded beyond the point of randomisation, the difference favouring buprenorphine could be due to increased professional input for that intervention. However there was no evidence to suggest that this was the case. Rather, there was no suggestion of a difference in GP/drug worker visits between the two groups. LEEDS was a "real-world" trial with a pragmatic rather than explanatory design. As such it randomised interventions which are used in everyday clinical practice. Previous commentators have spoken about the need to balance issues of methodological rigour (commonly referred to as internal validity) versus the feasibility of conducting trials in the real world clinical environment (commonly referred to as external validity) [42]. Inevitably there is a trade off between rigour and feasibility. For example in this case whilst the use of dummy pills was considered at the design stage, it was deemed unfeasible as it would both add to the cost of the research and also limit the independence of the trial from pharmaceutical company funding.It could also be argued that the superior percentage of those achieving abstinence as a result of the buprenorphine intervention was because mean buprenorphine and dihydrocodeine doses were not equivalent in terms of the pharmacological opiate effect. However this is not possible to verify as the two interventions are not identical in terms of action on opiate receptors. Buprenorphine has the unusual property of being both a partial MU receptor (one of a number of opiate receptors) agonist and partial opiate antagonist whereas dihydrocodeine is a full opiate receptor agonist.ConclusionOnly 23% of participants completed their detoxification and gave a final urine sample. This finding suggests a high non-completion rate of primary care opiate detoxifications. A higher proportion of people randomised to buprenorphine provided a final urine sample negative for illicit opiates compared with those who received dihydrocodeine. Those allocated buprenorphine made fewer visits to the GP and drugs worker during detoxification. Additionally, more of those allocated buprenorphine were abstinent at three and six months post detoxification when compared to the dihydrocodeine group.Currently in some treatment services in the UK the open giving of dihydrocodeine has continued despite an absence of evidence to support its clinical effectiveness. More recently, there has been a marked increase in the prescribing of buprenorphine in the UK [23]. Such an increase is in line with emerging best practice primary care guidance based primarily upon face validity for opiate detoxification. This guidance supports the use of buprenorphine but not dihydrocodeine for opiate detoxification in the primary care setting [43]. The LEEDS findings begin to support this guidance with good evidence but there is some way to go before fully confident recommendations can be made.The findings will also have relevance to any review of current Department of Health best practice guidelines for the treatment of substance misuse [4]. Launched in 1999, they argued that GP prescribing of buprenorphine requires a greater level of clinical experience than the prescribing of dihydrocodeine. The guidelines recommend buprenorphine should only be given by a "specialist general practitioner" and dihydrocodeine by an "experienced" GP [4]. LEEDS provides little evidence to support the continued prescribing of dihydrocodeine as a first line agent for opiate detoxification by less experienced GPs in primary care, but larger, well designed, conducted and reported trials are necessary.Competing interestsThe author(s) declare that they have no competing interests.Authors\' contributionsNW and CA designed the study, offered project supervision and drafted the manuscript. NW was principal investigator. CA centrally managed the randomisation process and conducted statistical analysis. LS coordinated and managed the project during the latter stages, collected data and drafted the manuscript. CT conducted data collection and drafted the manuscript. VA conducted statistical analysis and commented on the results section. NO was the initial project coordinator, who assisted in the design of the study and collected data. All authors have read and approved the final manuscript.Funding bodyLeeds Primary Care Trusts Research Consortium Priorities and Needs Funding.Ethics committeeLeeds Teaching Hospitals Local Research Ethics Committee.Pre-publication historyThe pre-publication history for this paper can be accessed here:AcknowledgementsWe are grateful to all patients at surgeries in Leeds who participated in the trial. We would particularly like to thank Drs Paul Glynn, Sally Read and Will Bolland, drug workers and reception.Staff who form the LEEDS project collaborative. We also thank Leeds Primary Care Trusts Research Consortium Priorities and Needs Funding who funded the project.National Treatment AgencyModels of Care: for Adult Drug Misusers2002Department of Health, LondonGossopMMarsdenJStewartDTreacyS"Outcomes after methadone maintenance and methadone reduction treatments: two year follow up results from the National Treatment Outcome Research Study"Drug and Alcohol Dependence2001622552641129533010.1016/S0376-8716(00)00211-8MacLeodJWhittakerARobertsonR"Changes in opiate treatment during attendance at a community drug service – findings from a clinical audit"Drug and Alcohol Review19981719251620346510.1080/09595239800187561Department of Health, Scottish Office Department of Health, Welsh Office, & Department of Health and Social Services, N. IDrug Misuse and Dependence – Guidelines on Clinical Management1999The Stationary Office, LondonLowinsonJBerleBLangrodJ"Detoxification of long-term methadone patients: problems and prospects"International Journal of the Addictions197611100910181025030SeivewrightNCommunity Treatment of Drug Misuse: More than Methadone2000Cambridge University Press, CambridgeBickelWStitzerMBigelowGLiebsonIJasinskiDJohnsonR"A clinical trial of buprenorphine: comparison with methadone in the detoxification of heroin addicts"Clinical Pharmacology and Therapeutics19884372783275523SeifertJMetznerCPaetzoldWBorsutzkyMPassieTRollnikJWieseBEmrichHSchneiderU"Detoxification of opiate addicts with multiple drug abuse: a comparison of buprenorphine vs. methadone"Pharmacopsychiatry2002351591641223778610.1055/s-2002-34115FischerGGombasWEderHJagschRPeternellAStuhlingerGPezawasLAschauerHKasperS"Buprenorphine versus methadone maintenance for the treatment of opioid dependence"Addiction199994133713471061571910.1046/j.1360-0443.1999.94913376.xJohnsonRChutuapeMStrainEWalshSStitzerMBigelowE"A comparison of levomethadyl acetate, buprenorphine and methadone for opioid dependence"New England Journal of Medicine2000343129012971105867310.1056/NEJM200011023431802KostenTSchottenfieldRZiedonisDFalcioniJ"Buprenorphine versus methadone maintenance for opioid dependence "Journal of Nervous and Mental Disease1993181358364850145710.1097/00005053-199306000-00004LingWWessonDCharuvastraCKlettC"A controlled trial comparing buprenorphine and methadone maintenance in opioid dependence"Archives of General Psychiatry1996534014078624183MattickRAliRWhiteJO\'BrienSWolkSDanzC"Buprenorphine versus methadone maintenance therapy: a randomised double blind trial with 405 opioid dependent patients"Addiction2003984414521265381410.1046/j.1360-0443.2003.00335.xPaniPMaremmaniIPirastuRTagliamonteAGessaG"Buprenorphine: a controlled clinical trial in the treatment of opioid dependence"Drug and Alcohol Dependence20006039501082198810.1016/S0376-8716(99)00140-4PetitjeanSStohlerRDeglonJLivotiSWaldvogelDUehlingerCLadewigD"Double blind randomized trial of buprenorphine and methadone in opiate dependence"Drug and Alcohol Dependence200162971041117317310.1016/S0376-8716(00)00163-0WhiteRAlcornRFeinmannC"Two methods of community detoxification from opiates: an open label comparison of lofexidine and buprenorphine"Drug and Alcohol Dependence20016577831171459210.1016/S0376-8716(01)00149-1GowingLAliRWhiteJ"Buprenorphine for the management of opioid withdrawal"The Cochrane Database of Systematic Reviews2006CheskinLFudalaPJohnsonR"A controlled comparison of buprenorphine and clonidine for acute detoxification from opioids"Drug and Alcohol Dependence199436115121785127810.1016/0376-8716(94)90093-0LintzerisNBammerGJolleyDRushworthL"A randomised controlled trial of buprenorphine in the management of short term ambulatory heroin withdrawal"Addiction200211139514041241078010.1046/j.1360-0443.2002.00215.xNigamARayRTripathiB"Buprenorphine in opiate withdrawal: a comparison with clonidine"Journal of Substance Abuse Treatment199310391394825755110.1016/0740-5472(93)90024-VO\'ConnorPCarrollKShiJSchottenfieldRKostenTRounsavilleB"Three methods of opioid detoxification in a primary care setting: a randomized trial"Annals of Internal Medicine19971275265309313020SimoensSMathesonCBondCInksterKLudbrookA"The effectiveness of community maintenance with methadone or buprenorphine for treating opiate dependence"British Journal of General Practice20055513914615720937de WetCReedLBearnJ"The rise of buprenorphine prescribing in England: analysis of NHS regional data, 2001–03"Addiction20051004954991578406410.1111/j.1360-0443.2005.01039.xBanberyJWolffKRaistrickD"Dihydrocodeine. A useful tool in the detoxification of methadone-maintained patients"Journal of Substance Abuse Treatment2000193013051102790210.1016/S0740-5472(00)00093-3RobertsonRWitcombJRobertsJEganJ" Misuse of dihydrocodeine tartrate (DF 118) among opiate addicts (letter)"British Medical Journal1990301119SwadiHWellsBPowerR"Misuse of dihydrocodeine tartrate (DF 118) among opiate addicts"British Medical Journal199030013132369664MassonA"Sublingual buprenorphine versus oral dihydrocodeine in post-operative pain"Journal of International Medical Research198195065107319134ZadorDSunjicS"Deaths in methadone maintenance treatment in New South Wales, Australia 1990–1995"Addiction20009577841072383210.1046/j.1360-0443.2000.951778.xStrangJSheridanJHuntCKerrBGeradaCPringleM"The prescribing of methadone and other opioids to addicts: national survey of GPs in England and Wales"British Journal of General Practice20055544445115970068GlanzATaylorC"Findings of a national survey of the role of general practitioners in the treatment of opiate misuse: extent of contact"British Medical Journal19862934274303091145DaviesAHuxleyP"Survey of general practitioners opinions on treatment of opiate users"British Medical Journal199731411739146392HortonR"Evidence and primary care"Lancet19993536091003032410.1016/S0140-6736(99)00056-2OldhamNWrightNAdamsCSheardLTompkinsC"The Leeds Evaluation of Efficacy of Detoxification Study (LEEDS) Project: An open label pragmatic randomised control trial comparing the efficacy of differing therapeutic agents for primary care detoxification from either street heroin or methadone – ISRCTN07752728"BMC Family Practice2004515117415FairhurstKDowrickC"Problems with recruitment in a randomised controlled trial of counselling in general practice: causes and implications"Journal of Health Service Research Policy199617780HethertonJMathesonARobsonM"Recruitment by GPs during consultations in a primary care randomised controlled trial comparing computerised psychological therapy with clinical psychology and routine GP care: problems and possible solutions"Primary Health Care Research and Development2004551010.1191/1463423604pc168oaWardEKingMLloydMBowerPFriedliK"Conducting randomised trials in general practice: methodological and practical issues"British Journal of General Practice19994991992210818663van der WindtDKoesBvan AarstMHeemskerkMBouterL"Practical aspects of conducting a pragmatic randomised trial in primary care: patient recruitment and outcome assessment"British Journal of General Practice20005037137410897533SheardLTompkinsCWrightNAdamsC"Recruiting opiate users to a randomized controlled trial in primary care: A descriptive study of GP attitudes"Primary Health Care Research and Development2006710611510.1191/1463423606pc274oaWrightNTompkinsC"How can health services effectively meet the health needs of homeless people"British Journal of General Practice20065628629316611519AshtonM"Force in the Sunshine State."Drug and Alcohol Findings200042125VanichseniSWongsuwanBChoopanyaKWongpanichK"A controlled trial of methadone maintenance in a population of intravenous drug users in Bangkok: implications for prevention of HIV"The International Journal of the Addictions199126131313201787024CarrolKFarentinosCBallSCrits-ChristophPLibbyBMorgensternJObertJPolcinDWoodyG"MET meets the real world: design issues and clinical strategies in the Clinical Trials Network"Journal of Substance Abuse Treatment20022373801222060410.1016/S0740-5472(02)00255-6Royal College of General PractitionersRCGP Guide to the Management of Substance Misuse in Primary Care2005Royal College of General Practitioners, London', 'title': 'Buprenorphine versus dihydrocodeine for opiate detoxification in primary care: a randomised controlled trial.', 'date': '2007-01-11'}}
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Psychiatry & Neurology
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93
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Is the time to postvoid residual volume of urine ≤ 50 mL higher, lower, or the same when comparing nerve‐sparing radical hysterectomy to standard radical hysterectomy?
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lower
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low
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no
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['22209773', '25872890']
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{'22209773': {'article_id': '22209773', 'content': 'This study evaluated histopathology and clinical outcome of autonomic nerve trauma and vessels removal within the cardinal ligament (CL) during nerve-sparing radical hysterectomy (NSRH) compared with radical hysterectomy (RH).\n25 women with FIGO stage Ib1-IIa cervical cancer underwent RH (n=13) or NSRH (n=12). Removed CLs lengths were measured. Biopsies were collected from the proximal, middle and distal segment of CLs and fixed. Different markers were used for immunohistochemisty analysis: tyrosine hydroxylase for sympathetic nerves; vasoactive intestinal polypeptide for parasympathetic nerves; CD34 for blood vessels; and D2-40 for lymphatic vessels. The volume density (Vv), a parameter of biological stereology, was used to quantitatively measure CL components, while post-operative functions, such as defecation, micturition and two-year disease free survival in RH and NSRH groups were compared.\nThe nerves mainly existed in the middle and distal segments of CLs. The Vv was greater in RH compared with NSRH for both sympathetic and parasympathetic nerve markers (P<0.05), while the Vv of blood and lymphatic vessels were same in the two groups. Average time to achieve residual urine≤50ml and first defecation were shorter in NSRH than in RH (P<0.05).\nLess autonomic nerves within CL are transected in NSRH than in RH, while blood/lymphatic vessels are efficiently removed in both treatments. Compared to RH, NSRH decreases iatrogenic injury, which leads to reduced post-operative co-morbidities, with ensure the same radicality.', 'title': 'Classical and nerve-sparing radical hysterectomy: an evaluation of the nerve trauma in cardinal ligament.', 'date': '2012-01-03'}, '25872890': {'article_id': '25872890', 'content': 'J Gynecol OncolJ Gynecol OncolJGOJournal of Gynecologic Oncology2005-03802005-0399Asian Society of Gynecologic Oncology; Korean Society of Gynecologic Oncology25872890439723810.3802/jgo.2015.26.2.90Original ArticleCervixEfficacy and oncologic safety of nerve-sparing radical hysterectomy for cervical cancer: a randomized controlled trialRohJu-Won1*LeeDong Ock2http://orcid.org/0000-0002-4312-966XSuhDong Hoon3LimMyong Cheol2SeoSang-Soo2ChungJinsoo4LeeSun5ParkSang-Yoon2*1Department of Obstetrics and Gynecology, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang, Korea.2Center for Uterine Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea.3Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.4Department of Urology, Center for Prostate Cancer, National Cancer Center, Goyang, Korea.5Department of Pathology, Kyung Hee University School of Medicine, Seoul, Korea.Correspondence to Sang-Yoon Park. Center for Uterine Cancer, Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 410-769, Korea. parksang@ncc.re.kr*Both authors contributed equally to this work.4201509420152629099242201510320151032015Copyright © 2015. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology2015This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.ObjectiveA prospective, randomized controlled trial was conducted to evaluate the efficacy of nerve-sparing radical hysterectomy (NSRH) in preserving bladder function and its oncologic safety in the treatment of cervical cancer.MethodsFrom March 2003 to November 2005, 92 patients with cervical cancer stage IA2 to IIA were randomly assigned for surgical treatment with conventional radical hysterectomy (CRH) or NSRH, and 86 patients finally included in the analysis. Adequacy of nerve sparing, radicality, bladder function, and oncologic safety were assessed by quantifying the nerve fibers in the paracervix, measuring the extent of paracervix and harvested lymph nodes (LNs), urodynamic study (UDS) with International Prostate Symptom Score (IPSS), and 10-year disease-free survival (DFS), respectively.ResultsThere were no differences in clinicopathologic characteristics between two groups. The median number of nerve fiber was 12 (range, 6 to 21) and 30 (range, 17 to 45) in the NSRH and CRH, respectively (p<0.001). The extent of resected paracervix and number of LNs were not different between the two groups. Volume of residual urine and bladder compliance were significantly deteriorated at 12 months after CRH. On the contrary, all parameters of UDS were recovered no later than 3 months after NSRH. Evaluation of the IPSS showed that the frequency of long-term urinary symptom was higher in CRH than in the NSRH group. The median duration before the postvoid residual urine volume became less than 50 mL was 11 days (range, 7 to 26 days) in NSRH group and was 18 days (range, 10 to 85 days) in CRH group (p<0.001). No significant difference was observed in the 10-year DFS between two groups.ConclusionNSRH appears to be effective in preserving bladder function without sacrificing oncologic safety.Disease-Free SurvivalHysterectomyUrinary Bladder, NeurogenicUterine Cervical NeoplasmsNational Cancer CenterNCC 0310040INTRODUCTIONRadical hysterectomy (RH) is one of the most common surgeries for gynecologic malignancies, especially for early-stage cervical cancer [1]. The quality of life (QoL) is a very important issue because most of the patients can live without disease for long time after the treatment. Although conventional radical hysterectomy (CRH) is an effective approach for the management of early-stage cervical carcinoma and it has shown 5-year survival rates of more than 90%, it has been demonstrated that this procedure frequently causes pelvic organ dysfunction, especially bladder dysfunction up to 85% of cervical cancer survivors [2]. These complications are believed to be the result of surgical trauma to the sympathetic and parasympathetic branches of the pelvic autonomic nervous system [2,3,4,5].Although these autonomic nerves of the pelvic organs and their origins are well described in anatomic textbooks, these structures are rarely visualized and preserved in operating rooms by surgical oncologists until the publications by several pioneer surgeons during the last two decades [6,7,8,9]. They proposed that preserving the pelvic autonomic nerves with the nerve-sparing surgical techniques may reduce the incidence of long-term complications following CRH, without reducing the radicality of the operation. However, a conclusion on this subject could not be made because only a few small randomized trials without a long-term follow-up have been reported [10,11,12].We have developed and performed nerve-sparing radical hysterectomy (NSRH) based on the experiences with Professor M. Höckel and Professor A. Schneider in Germany in 2001 (JWR), and the published articles describing the surgical methods of NSRH in detail [6,7,13,14].After the pilot trial for this new surgical procedure over a 1 year, we designed a prospective randomized controlled trial (RCT) to assess the efficacy of NSRH in prevention of bladder dysfunction and its oncologic safety compared to that of CRH. Here, we present the results with a long-term follow-up.MATERIALS AND METHODS1. Study subjectsThis study was conducted prospectively in patients with cervical cancer the International Federation of Gynecology and Obstetrics (FIGO) stage IB1-IIA. Exclusion criteria included neuroendocrine histology, pathologically proven distant metastasis, history of psychiatric disease, preoperative urinary dysfunction, and another coexisting malignancy. Patients with an adequate follow-up duration of more than one year after the surgery were included in the analysis.Between March 2003 and November 2005, 94 consecutive patients with cervical cancer FIGO stage IB1-IIA were enrolled and 92 patients were randomly assigned to surgical treatment with CRH or NSRH after excluding panic disorder (n=1) and pathologically confirmed supraclavicular lymph node (LN) metastasis (n=1). After random assignment, one patient declined to get included in the CRH group, and one patient with intraoperatively confirmed multiple metastatic LNs was converted to chemoradiation followed by pelvic and para-aortic LND in NSRH group. Two patients in the CRH group who had confirmed neuroendocrine histology in the surgical specimen were excluded from the study, and treated by systemic chemotherapy. One patient in each group was lost to follow-up within one year after the surgery. Eighty-six patients (40 in the CRH group and 46 in the NSRH group) were included in the final analysis (Fig. 1). This prospective study was approved by the Institutional Review Board of the National Cancer Center of Korea.2. Surgical procedureAll operations were performed by either or both surgeons (JWR and SYP) who were skilled in CRH and already had experience with NSRH for one year before this study in the pilot trial. Laparotomy through hypogastric midline incision and left circumcision of the umbilicus was performed for the procedure. A schematic three-dimensional (3D)-illustration of the nervous system of the pelvis and key steps in the surgical procedure are presented in Fig. 2. The key for the nerve-sparing during RH included four steps. The first step was to identify the superior hypogastric plexus (SHP) at the aortic bifurcation and mobilize it from the sacral promontary, which would be the starting point of the nerve-sparing procedure (Fig. 2B). The second step was, after entering the retroperitoneal pelvic space and completion of pelvic LND, the hypogastric nerves (HN) originating from the SHP and the upper part of the inferior hypogastric plexus (IHP) were exposed along the lateral border of the mesorectum (Fig. 2C). The third step was for the IHP (Fig. 2D). The vascular part of the paracervix was ligated at the level where uterine vessels branch from the internal iliac vessels. After incision of the rectouterine peritoneal fold, separation of the anterior mesorectum from the proximal vagina and lateral mobilization of the IHP, which was HN fused with the pelvic splanchnic nerves from S2 to S4, were performed before transaction of the uterosacral ligament. After an anterior incision between the bladder and the cervix, the medial aspect of the distal ureter was exposed by separation of the uterine vessels, lymphatics, and a few small LNs from the bladder mesentery. For complete removal of the paracervical tissues, liposuction was performed with Hercules aspirator (Wells Johnson Co., Tucson, AZ, USA) below the vascular part of the paracervix.The last part of nerve-sparing was for the bladder branch of the IHP (Fig. 2E). The vesicovaginal venous connection and anterior condensed ligamentous portion crossing the ureters were ligated and transected, and then the vagina at a level 2 to 3 cm distal to the tumor was clamped while saving the posterior part of the vesicouterine ligament which contained the bladder branch of the IHP.After the insertion of two Jackson-Pratt closed suction drains, suprapubic cystostomy was performed. Bladder emptying with suprapubic catheterization was performed for one week, and then self-voiding was attempted after clamping of the suprapubic catheter. Residual urine (RU) volume was recorded by declamping the catheter immediately after the self-voiding. The suprapubic catheter was removed when the RU measured less than 50 mL at least two times in a low. The duration of bladder catheterization after the surgery was recorded and compared.For the quantification of nerve fibers retained in the resected paracervix, longitudinal paracervical tissues were marked at 2 cm lateral to the isthmus of the resected uterus at the operating theater (Supplementary Fig. 1). Microscopic section of full length of the labeled paracervix was stained with a general nerve marker, S-100 protein, in order to quantify the nerve fibers. Nerve fibers larger than 100 µm on both sides were counted by the pathologist (SL) without any clinical information and surgical protocol.Postoperative external radiotherapy (RT) was employed when the final pathologic report revealed LN metastasis or histologically confirmed parametrial invasion, and intracavitary RT was added when the vaginal resection margin was involved by tumor.3. Evaluation of urinary functionUrodynamic studies (UDSs) were carried out before the operation and at 1, 3, and 12 months after the operation. UDS were carried out using the Duet MultiP (Medtronic Inc., Minneapolis, MN, USA) and air-charged urethral and abdominal sensors. All procedures were performed in a sitting erect position on a toilet seat with room-temperature sterile water. The filling rate was 30 mL/min unless this provoked urinary urgency. Abdominal leak point pressures were measured at 200 cm3, with the urethral catheter in place, unless otherwise specified. The abdominal pressure transducer was placed rectally. Provocative maneuvers, including water stimulation and cough, were used in an effort to provoke detrusor overactivity. Urethral pressure profile was performed using a mechanical puller at a rate of 1 mm/sec. Both static and dynamic profiles were performed at cystometric capacity. Recorded urodynamic parameters in addition to the urodynamic tracings were from the uroflowmetry (voided volume, postvoid RU, maximal flow rate, voiding time), cystometrogram (first sensation, first desire to void, capacity, filling rate, detrusor overactivity, urodynamic stress incontinence, abdominal leak point pressure at 200 cm3), and urethral pressure profile. One urologist (JSC) reviewed each case without any clinical information.Subjective bladder dysfunction was evaluated with a standard questionnaire of the Korean version of International Prostate Symptom Score (IPSS). The scoring system for voiding function described above was based on a 0 to 5 scale, as follows; 0, not at all; 1, less than one time in five; 2, less than half the time; 3, about half the time; 4, more than half the time; and 5, almost always. Questionnaires were analyzed and divided into emptying, frequency, intermittency, urgency, weak stream, straining, and nocturia. Total IPSS score was calculated by adding the score of each item. It can be expected that the greater is the increase in the IPSS, the lesser is the urinary function.4. Evaluation of oncologic safetyAll enrolled patients were followed up every 3 months for the first 2 years after the surgery and every 6 months thereafter with a physical gynecological examination, vaginal cytology, chest X-ray, tumor markers (squamous cell carcinoma antigen and carcinoembryonic antigen), and other imaging modality including computed tomography (CT), magnetic resonance imaging, positron emission tomography (PET), and PET/CT if indicated.Disease-free survival (DFS) and overall survival (OS) were calculated as time, in months, from the date of the primary surgery to the time of confirmed recurrence of cervical cancer and death, respectively. DFS and OS were compared between the two groups by survival analysis with a long-term follow-up.5. Statistical analysisContinuous variables were assessed for normal distribution (Kolmogorov-Smirnov test) and expressed as appropriate (mean with SD or median with range). Categorical variables were evaluated with the use of the Fisher exact test. For paired data, such as postoperative changes in UDS or IPSS score compared with preoperative baseline, Wilcoxon singed rank test was used for analysis. A p<0.05 was considered statistically significant. DFS and OS were evaluated by Kaplan-Meier analysis. IBM SPSS ver. 20.0 (IBM Co., Armonk, NY, USA) was used for all statistical analyses.RESULTS1. Clinicopathologic characteristics and surgical outcomesThe detailed clinical and pathologic characteristics of the enrolled patients and the surgical outcomes in both groups are detailed in Table 1. The general characteristics of the patients, including age, BMI, FIGO stage, histologic distribution, tumor size, operating time, estimated blood loss, adjuvant RT, and LN metastasis were not different in the two groups. With respect to the evaluation of radicality of NSRH, surgical outcomes such as the width and length of the resected paracervix, length of safety margin of the resected vagina, and the number of harvested LNs were also similar between the two groups. Average count of resected nerve bundles stained with S-100 in the removed paracervix was significantly lower in the NSRH (12; range, 6 to 21) compared to CRH (30; range, 17 to 45; p<0.001).2. Evaluation of urinary functionThe median duration before the postvoid RU volume became less than 50 mL was 11 days (range, 7 to 26 days) among the patients in the NSRH group and was 18 days (range, 10 to 85 days) among the patients in the CRH group (p<0.001). No significant difference in the preoperative data of UDS was found between the two groups (p>0.05). Postoperative changes in UDS compared with preoperative data are shown in Table 2. At postoperative 1 month, almost all parameters of UDS were significantly changed in the CRH group, and several parameters including maximal flow rate, voided volume, RU, compliance, and maximal urethral pressure were also changed in the NSRH group. All changed parameters of USD in the NSRH group were recovered at postoperative 3 months examination, while changes in many parameters of USD in the CRH group were maintained 3 months later. One year after the operation, changes of bladder compliance and RU were still persistent in the CRH group (Fig. 3). For the evaluation of subjective urinary symptoms, postoperative IPSS scores were compared with preoperative IPSS scores (Table 3).There were changes in every item for urinary symptoms, emptying, frequency, intermittency, urgency, weak stream, straining, and nocturia, after CRH and these changes were persistent for more than a year. On the contrary, there were no changes in all urinary symptoms except for intermittency in the NSRH group after a year, although four items for frequency, intermittency, weak stream, and straining indicated deterioration immediately after the operation.3. Evaluation of oncologic safetyThe median duration of follow-up was 101 months (range, 13 to 137 months) in the CRH group and 111 months (range, 13 to 139 months) in the NSRH group. Ten-year DFS of the patients in the CRH and NSRH groups was 94.9% and 92.4%, respectively (Fig. 4). During the follow-up, two patients in the CRH group and three patients in the NSRH group developed recurrence. Three out of the five patients developed recurrence within 2 years, and one patient was diagnosed with pulmonary metastasis at 7-year follow-up. Four out of the five patients had systemic metastatic diseases, and only one patient was diagnosed para-aortic LN metastasis and was treated by laparoscopic resection followed by RT. One patient in the NSRH group was died with systemic metastatic lesions at 21 months after the initial diagnosis. The clinicopathologic features of the recurred cases are summarized in Supplementary Table 1. The 10-year DFS and OS were not different between the two groups.DISCUSSIONThis was an RCT with the greatest number of cases enrolled and the longest duration of follow-up for the evaluation of efficacy and oncologic safety of NSRH till date. This means that the results of this prospective study strongly support the efficacy of NSRH in preventing urinary dysfunction without sacrifice of oncologic safety.Ideal surgical management of cervical cancer should reduce early and late morbidity without compromising oncological disease control. Although CRH has been confirmed to be a standard treatment modality resulting in reduced risk of pelvic recurrence for FIGO stage IB1-IIA cervical cancer, it has been criticized for its high rate of postoperative pelvic organ dysfunction, especially urinary dysfunction. According to the literatures, urinary dysfunction (sensory loss, storing and voiding dysfunctions, urinary incontinence, and detrusor instability) is the most common long-term complication following CRH. The incidence has been reported to occur in 70% to 85% of reported studies [2,15,16]. Nowadays, postoperative QoL has become a more important issue, considering that more than 90% of the patients with cervical cancer could survive for a long time [2]. Deterioration of QoL after the surgery is believed to be the result of nerve injury during the procedure. In general, sympathetic branches of the hypogastric nerve and the vesical branch of the pelvic plexus stimulate the urethral sphincter and inhibit the detrusor muscle of the bladder, while parasympathetic branches of the pelvic splanchnic nerve and the vesical branch of the pelvic plexus relax the urethral sphincter and stimulate the detrusor muscle of the bladder. In order to maintain bladder function, those nerve networks should be preserved intact as much as possible unless these attempts sacrifice the therapeutic role of surgery. Although various attempts have been made to prevent pelvic organ dysfunction via autonomic nerve preservation, most of these studies provide either subjective or objective UDS data for a relatively short-time after the surgery [17,18,19,20].It has been reported that RH is also associated with significant urodynamic changes and that these alterations may persist for at least 1 year following surgery [15,21,22]. Immediately after the operation, many factors including postoperative inflammation, local edema, temporary electrical injury, and decreased blood supply may influence the voiding function irrespective of nerve injury. Also, the bladder function after RH could be improved by 12 months after the operation [11,23,24]. Therefore, reliable data should be obtained for a long-time period of at least 1 year. The strong point of this study is in assessing the efficacy of NSRH in preserving voiding function. Both objective and subjective evaluations of voiding function using both UDS and IPSS were performed preoperative and at 1, 3, and 12 months after the surgery. In our study, increased RU volume and decreased compliance were maintained over a one year after the CRH. These results were compatible with those in the previous reports [15,21]. Differences in subjective urinary symptoms by questionnaire-based IPSS were more significant than that on UDS. Subjective voiding dysfunction seems to be strengthened because all parameters should be coordinated to maintain normal urination and even a malfunctioning detail could affect the general sense of normal voiding. The results from this study support the claim that NSRH is very effective method for increasing the QoL of cervical cancer survivors.In terms of postoperative chronic morbidity, many literatures including this study have provided evidence of favorable outcomes for urinary function after NSRH compared with CRH [10,11,25], and a recent meta-analysis also showed that NSRH is associated with less bladder dysfunction and fewer complications [26]. Nevertheless, NSRH has not yet become popular among gynecologic surgeons. The most important barrier to the widespread use of this concept is the lack of sufficient survival data comparing the oncologic outcomes of NSRH with CRH. Although a lot of studies have already reported the results of NSRH, they had various limitations in ensuring the oncologic safety. Most of the studies were retrospective analysis without control or non-randomized historical comparison, and they mainly focused on the comparison of urinary dysfunctions between CRH and NSRH without longterm survival results.For relevant survival analysis, well-designed RCTs with sufficient number of cases and adequate duration of follow-up are the basic prerequisites for drawing a conclusion. Till date, only three small-scale RCTs have reported the clinical data of NSRH [10,11,12], and two of them only focused on the efficacy of NSRH in reducing the postoperative morbidity without survival results [11,12], and the other study reported only the 2-year DFS rate for a small number of patients [10]. A recently published systematic review of oncological outcomes of NSRH concluded that the evidence addressing the oncologic safety of NSRH over that of CRH is neither adequate nor statistically relevant [27]. The authors emphasized that properly designed, prospective randomized noninferiority trial with more than five hundred cases in each arm is needed to assess the equality of survival [27].Although the number of enrolled patients in this study were not enough to assess the noninferior oncologic outcome of NSRH compared to that of CRH, long-term follow-up duration of over 10-year period compensated for this limitation to some extent, and this study provided the evidence for the safety of NSRH. Late recurrence after 5 years occurs occasionally in patients with cervical cancer, although more than two-thirds of recurrences develop within 2 years after diagnosis. Therefore, 10-year DFS has been reported to show the total outcome of treatment for cervical cancer [28,29]. In fact, one out of the five recurred cases in this study was diagnosed with recurrence at the 7-year follow-up.In conclusion, the results of this study provided evidence that NSRH should be regarded as a very effective modality to improve the QoL of cervical cancer survivors without sacrificing oncologic safety. A well-designed, large-scale prospective noninferiority trial should be conducted in near future to ensure the safety of NSRH.ACKNOWLEDGMENTSI (JWR) would like to thank Professor Dr. M. Höckel (Leipzig, Germany) and Professor Dr. A. Schneider (Berlin, Germany) for their excellent guidance and hospitality during my training in Germany. Artistic 3D-illustration of nervous system of pelvis was provided by HealthBreeze (Seoul, Korea). This work was supported by a grant from National Cancer Center of Korea (NCC 0310040).CONFLICT OF INTEREST: No potential conflict of interest relevant to this article was reported.1DonatoDMSurgical management of stage IB-IIA cervical carcinomaSemin Surg Oncol199916232235102253012ZulloMAManciNAngioliRMuziiLPaniciPBVesical dysfunctions after radical hysterectomy for cervical cancer: a critical reviewCrit Rev Oncol Hematol200348287293146933413ErcoliADelmasVGadonneixPFanfaniFVilletRPaparellaPClassical and nerve-sparing radical hysterectomy: an evaluation of the risk of injury to the autonomous pelvic nervesSurg Radiol Anat200325200206129103824MaasCPTrimbosJBDeRuiterMCvan de VeldeCJKenterGGNerve sparing radical hysterectomy: latest developments and historical perspectiveCrit Rev Oncol Hematol200348271279146933395LandoniFManeoACormioGPeregoPMilaniRCarusoOClass II versus class III radical hysterectomy in stage IB-IIA cervical cancer: a prospective randomized studyGynecol Oncol200180312111365616HockelMKonerdingMAHeusselCPLiposuction-assisted nerve-sparing extended radical hysterectomy: oncologic rationale, surgical anatomy, and feasibility studyAm J Obstet Gynecol199817897197696095697PossoverMStoberSPlaulKSchneiderAIdentification and preservation of the motoric innervation of the bladder in radical hysterectomy type IIIGynecol Oncol200079154157110636378TrimbosJBMaasCPDeruiterMCPetersAAKenterGGA nerve-sparing radical hysterectomy: guidelines and feasibility in Western patientsInt J Gynecol Cancer200111180186114379229YabukiYAsamotoAHoshibaTNishimotoHNishikawaYNakajimaTRadical hysterectomy: an anatomic evaluation of parametrial dissectionGynecol Oncol2000771551631073970510ChenCLiWLiFLiuPZhouJLuLClassical and nerve-sparing radical hysterectomy: an evaluation of the nerve trauma in cardinal ligamentGynecol Oncol20121252452512220977311WuJLiuXHuaKHuCChenXLuXEffect of nerve-sparing radical hysterectomy on bladder function recovery and quality of life in patients with cervical carcinomaInt J Gynecol Cancer2010209059092060654212ChenLZhangWNZhangSMYangZHZhangPEffect of laparoscopic nerve-sparing radical hysterectomy on bladder function, intestinal function recovery and quality of sexual life in patients with cervical carcinomaAsian Pac J Cancer Prev20141510971109752560521113HockelMHornLCHentschelBHockelSNaumannGTotal mesometrial resection: high resolution nerve-sparing radical hysterectomy based on developmentally defined surgical anatomyInt J Gynecol Cancer2003137918031467531614PossoverMTechnical modification of the nerve-sparing laparoscopy-assisted vaginal radical hysterectomy type 3 for better reproducibility of this procedureGynecol Oncol2003902452471289318315ScottiRJBergmanABhatiaNNOstergardDRUrodynamic changes in urethrovesical function after radical hysterectomyObstet Gynecol198668111120372524116FishmanIJShabsighRKaplanALLower urinary tract dysfunction after radical hysterectomy for carcinoma of cervixUrology198628462468378791817RaspagliesiFDittoAFontanelliRSolimaEHanozetFZanaboniFNerve-sparing radical hysterectomy: a surgical technique for preserving the autonomic hypogastric nerveGynecol Oncol2004933073141509993818FujiiSTakakuraKMatsumuraNHiguchiTYuraSMandaiMAnatomic identification and functional outcomes of the nerve sparing Okabayashi radical hysterectomyGynecol Oncol20071074131790514019CharoenkwanKSrisomboonJSuprasertPTantipalakornCKietpeerakoolCNerve-sparing class III radical hysterectomy: a modified technique to spare the pelvic autonomic nerves without compromising radicalityInt J Gynecol Cancer200616170517121688439020KatahiraANiikuraHKaihoYNakagawaHKurokawaKAraiYIntraoperative electrical stimulation of the pelvic splanchnic nerves during nerve-sparing radical hysterectomyGynecol Oncol2005984624661597969521LinLYWuJHYangCWSheuBCLinHHImpact of radical hysterectomy for cervical cancer on urodynamic findingsInt Urogynecol J Pelvic Floor Dysfunct2004154184211554926122KanaoHFujiwaraKEbisawaKHadaTOtaYAndouMVarious types of total laparoscopic nerve-sparing radical hysterectomies and their effects on bladder functionJ Gynecol Oncol2014251982052504543223RalphGTamussinoKLichteneggerWUrological complications after radical abdominal hysterectomy for cervical cancerBaillieres Clin Obstet Gynaecol19882943952322906224TodoYKuwabaraMWatariHEbinaYTakedaMKudoMUrodynamic study on postsurgical bladder function in cervical cancer treated with systematic nerve-sparing radical hysterectomyInt J Gynecol Cancer2006163693751644566025PlottiFZulloMAMonteraRAngioliRPierluigiBPBladder function after laparoscopic nerve-sparing radical hysterectomyGynecol Oncol20111203152112976926LongYYaoDSPanXWOuTYClinical efficacy and safety of nerve-sparing radical hysterectomy for cervical cancer: a systematic review and meta-analysisPLoS One20149e941162474801527BasaranDDusekLMajekOCibulaDOncological outcomes of nerve-sparing radical hysterectomy for cervical cancer: a systematic reviewAnn Surg Oncol2015123http://dx.doi.org/10.1245/s10434-015-4377-728YeungARAmdurRJMorrisCGMorganLSMendenhallWMLong-term outcome after radiotherapy for FIGO stage IIIB and IVA carcinoma of the cervixInt J Radiat Oncol Biol Phys200767144514501723436229LiuJLiuJLiJChenYGuanXWuXTumor-stroma ratio is an independent predictor for survival in early cervical carcinomaGynecol Oncol2014132818624219981SUPPLEMENTARY MATERIALSSupplementary Fig. 1(A) Longitudinal section of the paracervical tissue at 2 cm apart from the isthmus was fixed for nerve staining. (B) Immunohistochemical staining with S-100 protein for quantification of nerve fibers after conventional radical hysterectomy, and (C) nerve-sparing radical hysterectomy (×40).Supplementary Table 1Summary of clinicopathologic characteristics of recurred casesCase no.GroupAge (yr)PathologyFIGO stageSite of recurrenceDuration from surgery (mo)Treatment modality for recurrenceCurrent status1CRH43AdenocarcinomaIB1PALN13Laparoscopic operation→RTNED2NSRH45AdenocarcinomaIB1Lung90ChemotherapyNED3CRH51SCCAIB1Lung15Resection→chemotherapyNED4NSRH47SCCAIIALung, liver19ChemotherapyDOD5NSRH47AdenocarcinomaIB2Pelvis38Pelvic exenteration→RTAlive with diseaseLung47Resection→chemotherapyCRH, conventional radical hysterectomy; DOD, death of disease; FIGO, International Federation of Gynecology and Obstetrics; NED, no evidence of disease; NSRH, nerve-sparing radical hysterectomy; PALN, para-aortic lymph node; RT, radiotherapy; SCCA, squamous cell carcinoma.Fig. 1Flow diagram of the patients enrolled in this study. CRH, conventional radical hysterectomy; LN, lymph node; NSRH, nerve-sparing radical hysterectomy.Fig. 2Three-dimensional (3D) illustration and key steps in nerve-sparing radical hysterectomy. (A) Schematic 3D-illustration of the nervous system of the pelvis which should be preserved during nerve-sparing radical hysterectomy. (B) Separation and preservation of the superior hypogastric plexus on the sacral promontory (arrow, SHP). (C) Isolation and tracing of the hypogastric nerve on the lateral border of the rectum (arrow, HN). (D) Identification and preservation of the inferior hypogastric plexus composed of the hypogastric nerve and pelvic splanchnic nerve below the vascular part of the paracervix (arrow, IHP). (E) Vesical branch of the inferior hypogastric plexus during dissection of the vesicouterine ligament (arrow, vesical branch of IHP). B, bladder; HN, hypogastric nerve; IHP, inferior hypogastric plexus; R, rectum; SHP, superior hypogastric plexus; U, ureter; Ut, uterus.Fig. 3(A) Bladder compliance and (B) volume of residual urine were evaluated by urodynamic study preoperatively, and at 1, 3, and 12 months after conventional radical hysterectomy (CRH) or nervesparing radical hysterectomy (NSRH). (C) Subjective urinary symptoms were evaluated with the International Prostate Symptom Score (IPSS). Postoperative results were compared with preoperative basal values by Wilcoxon signed rank test. *p<0.05.Fig. 4(A) Disease-free survival and (B) overall survival in patients with cervical cancer treated by conventional radical hysterectomy (CRH) or nerve-sparing radical hysterectomy (NSRH).Table 1Clinicopathologic characteristics and surgical outcomesCharacteristicCRH (n=40)NSRH (n=46)p-valueAge (yr)49.5±9.146.7±9.4NS*BMI (kg/m2)25.4±3.224.3± 2.2NS*FIGO stageNS†\u2003IB131 (77.5)34 (74.0)\u2003IB23 (7.5)6 (13.0)\u2003IIA6 (15.0)6 (13.0)Tumor size (cm)2.5±1.12.1±1.3NS*Histologic typeNS†\u2003Squamous cell carcinoma33 (82.5)35 (76.0)\u2003Adenocarcinoma6 (15.0)11 (23.9)\u2003Adenosquamous carcinoma1 (2.5)0Operation time (min)278 (244-321)297 (256-368)NS‡Estimated blood loss (mL)520.8±239.8478.9±206.5NS*Radicality\u2003Paracervical length, right (cm)4.7±1.44.2±0.9NS*\u2003Paracervical width, right (cm)3.6±0.83.7±1.0NS*\u2003Paracervical length, left (cm)4.8±1.44.2±1.0NS*\u2003Paracervical width, left (cm)3.3±0.83.6±0.9NS*\u2003Vaginal length (cm)3.0±0.83.0±0.6NS*\u2003No. of harvested pelvic LN25.8±7.826.9±8.1NS*\u2003No. of harvested para-aortic LN5.9±4.76.2±4.8NS*LN involvement2 (5.0)4 (8.7)NS†No. of dissected nerve fibers30 (17-45)12 (6-21)<0.001‡Postoperative complication3 (7.5)2 (4.3)NS†\u2003Incisional hernia11\u2003Infected lymphocele21No. of cases of CIC3 (7.5)0<0.001†Days for RU <50 mL18 (10-85)11 (7-26)<0.001‡Postoperative radiotherapy15 (37.5)14 (31.1)NS†Follow-up duration (mo)101 (13-137)111 (13-139)NS*Recurrence2 (5.0)3 (6.5)NS†10-Year DFS (%)94.992.4NS§Values are presented as mean±SD, number (%), or median (range).BMI, body mass index; CIC, clean intermittent catheterization; CRH, conventional radical hysterectomy; DFS, disease-free survival; FIGO, International Federation of Gynecology and Obstetrics; LN, lymph node; NS, not significant; NSRH, nerve-sparing radical hysterectomy; RU, residual urine.*Student t-test. †Fisher exact test. ‡Mann-Whitney test. §Kaplan-Meier survival analysis.Table 2Postoperative changes in the parameters of urodynamic study compared to preoperative basal valuesVariableConventional radical hysterectomyNerve-sparing radical hysterectomyBasal1 mo3 mo12 moBasal1 mo3 mo12 moMFR (mL/sec)18.5 (8.9-63.9)10.5 (4,4-21,1)*16.5 (5.6-40.8)16.0 (8.3-25.2)18.5 (9.3-39.3)14.5 (5.0-49.5)*15.8 (6.7-35.2)15.5 (9.0-46.5)AFR (mL/sec)8.7 (2.5-47.0)4.7 (1.0-11.3)*6.9 (3.4-46.6)6.1 (2.2-12.8)8,1 (2.2-65.0)6.4 (3.10-71.0)6.6 (2.6-56.0)7.2 (3.2-21.0)VV (mL)368.5 (115.0-677.0)259.5 (56.0-604.0)*330.0 (85.0-564.0)380.0 (230.0-566.0)356.5 (142.0-779.0)308.5 (32.0-606.0)*407.5 (97.0-813.0)350.0 (120.0-566.0)MDP (cmH2O)61.0 (23.0-181.0)54.5 (0-199.0)*53.5 (17.0-90.0)60.5 (1.0-143.0)44.0 (20.0-113.0)45.0 (16.0-106.0)43.0 (18.0-126.0)55.0 (22.0-144.0)RU (mL)16.5 (0-80.0)70.0 (0-181.0)*51.5 (0-220.0)*51.0 (0-120.0)*10.0 (0-100.0)20.0 (0-100.0)*18.0 (0-120.0)20.0 (0-75.0)Compliance (mL/cmH2O)93.8 (34.6-159.6)29.1 (3.5-82.4)*30.3 (4.5-95.6)*61.9 (6.5-194.3)*83.0 (32.1-169.9)52.5 (21.6-125.3)*80.4 (34.0-138.0)59.7 (4.9-294.3)FVS (mL)209.5 (98.0-414.0)207.5 (90.0-343.0)242.0 (44.0-508.0)235.5 (109.0-312.0)193.5 (90.0-430.0)185.0 (129.0-461.0)212.0 (51.0-448.0)248.0 (80.0-389.0)Urgency (mL)411.0 (190.0-659.0)371.9 (210.0-550.0)356.8 (97.0-630.0)*369.0 (302.0-450.0)375.5 (214.0-606.0)348.5 (230.0-584.0)400.0 (240.0-600.0)370.0 (176.0-550.0)Capacity (mL)443.0 (206.0-674.0)395.3 (220.0-550.0)*376.1 (99.0-630.0)401.0 (330.0-462.0)415.0 (273.0-608.0)355.0 (240.0-586.0)429.0 (269.0-612.0)410.0 (181.0-550.0)MUP (cmH2O)88.0 (36.0-158.0)73.5 (38.0-123.0)*76.5 (37.0-193.0)*76.5 (11.0-109.0)*97.0 (44.0-183.0)85.0 (43.0-151.0)*79.0 (19.0-143.0)96.0 (19.0-132.0)MCP (cmH2O)88.0 (36.0-159.0)74.1 (34.0-122.0)*78.0 (37.0-194.0)*77.0 (12.0-111.0)95.5 (45.0-148.0)85.0 (43.0-148.0)84.0 (20.0-143.0)97.0 (19.0-116.0)FUL (mm)92.0 (35.0-197.0)86.5 (36.0-218.0)89.5 (23.0-193.0)80.0 (27.0-117.0)85.0 (34.0-250.0)79.0 (27.0-214.0)76.5 (25.5-232.0)97.0 (56.0-132.0)Values are presented as median (range).AFR, average flow rate; FUL, functional urethral length; FVS, first voiding sense; MCP, maximal closure pressure; MDP, maximal detrusor pressure; MFR, maximal flow rate; MUP, maximal urethral pressure; RU, residual urine; VV, voided volume.*p<0.05, compared with preoperative basal data by Wilcoxon signed rank test.Table 3Postoperative changes of International Prostate Symptom ScoreVariableConventional radical hysterectomyNerve-sparing radical hysterectomyBasal1 mo3 mo12 moBasal1 mo3 mo12 moEmptying1 (0-5)2 (0-5)*3 (0-5)*2 (0-5)*1 (0-5)2 (0-5)1 (0-4)1 (0-5)Frequency1 (0-5)3 (0-5)*3 (0-5)*2 (0-5)*1 (0-3)2 (0-5)*1 (0-3)1 (0-4)Intermittency0 (0-5)4 (0-5)*3 (0-5)*3 (0-5)*0 (0-1)2 (1-5)*1 (0-4)*1 (0-5)*Urgency0 (0-5)1 (0-5)*2 (0-5)*2 (0-5)*1 (0-5)1 (0-5)1 (0-2)0 (0-5)Weak stream0 (0-5)3 (0-5)*2 (0-5)*1 (0-5)*1 (0-4)2 (0-5)*1 (0-4)1 (0-5)Straining0 (0-1)2 (0-5)*1 (0-5)*1 (0-5)*0 (0-1)1 (0-5)*1 (0-1)*0 (0-5)Nocturia1 (0-3)2 (1-4)*2 (0-3)*2 (0-3)*1 (0-3)1 (0-5)1 (0-3)1 (0-3)Total3 (0-28)20 (3-28)*17 (3-26)*14 (3-33)*3 (0-20)11 (3-33)*9 (1-16)6 (0-24)Values are presented as median (range).*p<0.05 compared with preoperative basal data by Wilcoxon signed rank test.', 'title': 'Efficacy and oncologic safety of nerve-sparing radical hysterectomy for cervical cancer: a randomized controlled trial.', 'date': '2015-04-16'}}
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Is the likelihood of disease-free survival higher, lower, or the same when comparing nerve‐sparing radical hysterectomy to standard radical hysterectomy?
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no difference
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very low
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no
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['25872890']
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{'25872890': {'article_id': '25872890', 'content': 'J Gynecol OncolJ Gynecol OncolJGOJournal of Gynecologic Oncology2005-03802005-0399Asian Society of Gynecologic Oncology; Korean Society of Gynecologic Oncology25872890439723810.3802/jgo.2015.26.2.90Original ArticleCervixEfficacy and oncologic safety of nerve-sparing radical hysterectomy for cervical cancer: a randomized controlled trialRohJu-Won1*LeeDong Ock2http://orcid.org/0000-0002-4312-966XSuhDong Hoon3LimMyong Cheol2SeoSang-Soo2ChungJinsoo4LeeSun5ParkSang-Yoon2*1Department of Obstetrics and Gynecology, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang, Korea.2Center for Uterine Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea.3Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.4Department of Urology, Center for Prostate Cancer, National Cancer Center, Goyang, Korea.5Department of Pathology, Kyung Hee University School of Medicine, Seoul, Korea.Correspondence to Sang-Yoon Park. Center for Uterine Cancer, Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 410-769, Korea. parksang@ncc.re.kr*Both authors contributed equally to this work.4201509420152629099242201510320151032015Copyright © 2015. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology2015This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.ObjectiveA prospective, randomized controlled trial was conducted to evaluate the efficacy of nerve-sparing radical hysterectomy (NSRH) in preserving bladder function and its oncologic safety in the treatment of cervical cancer.MethodsFrom March 2003 to November 2005, 92 patients with cervical cancer stage IA2 to IIA were randomly assigned for surgical treatment with conventional radical hysterectomy (CRH) or NSRH, and 86 patients finally included in the analysis. Adequacy of nerve sparing, radicality, bladder function, and oncologic safety were assessed by quantifying the nerve fibers in the paracervix, measuring the extent of paracervix and harvested lymph nodes (LNs), urodynamic study (UDS) with International Prostate Symptom Score (IPSS), and 10-year disease-free survival (DFS), respectively.ResultsThere were no differences in clinicopathologic characteristics between two groups. The median number of nerve fiber was 12 (range, 6 to 21) and 30 (range, 17 to 45) in the NSRH and CRH, respectively (p<0.001). The extent of resected paracervix and number of LNs were not different between the two groups. Volume of residual urine and bladder compliance were significantly deteriorated at 12 months after CRH. On the contrary, all parameters of UDS were recovered no later than 3 months after NSRH. Evaluation of the IPSS showed that the frequency of long-term urinary symptom was higher in CRH than in the NSRH group. The median duration before the postvoid residual urine volume became less than 50 mL was 11 days (range, 7 to 26 days) in NSRH group and was 18 days (range, 10 to 85 days) in CRH group (p<0.001). No significant difference was observed in the 10-year DFS between two groups.ConclusionNSRH appears to be effective in preserving bladder function without sacrificing oncologic safety.Disease-Free SurvivalHysterectomyUrinary Bladder, NeurogenicUterine Cervical NeoplasmsNational Cancer CenterNCC 0310040INTRODUCTIONRadical hysterectomy (RH) is one of the most common surgeries for gynecologic malignancies, especially for early-stage cervical cancer [1]. The quality of life (QoL) is a very important issue because most of the patients can live without disease for long time after the treatment. Although conventional radical hysterectomy (CRH) is an effective approach for the management of early-stage cervical carcinoma and it has shown 5-year survival rates of more than 90%, it has been demonstrated that this procedure frequently causes pelvic organ dysfunction, especially bladder dysfunction up to 85% of cervical cancer survivors [2]. These complications are believed to be the result of surgical trauma to the sympathetic and parasympathetic branches of the pelvic autonomic nervous system [2,3,4,5].Although these autonomic nerves of the pelvic organs and their origins are well described in anatomic textbooks, these structures are rarely visualized and preserved in operating rooms by surgical oncologists until the publications by several pioneer surgeons during the last two decades [6,7,8,9]. They proposed that preserving the pelvic autonomic nerves with the nerve-sparing surgical techniques may reduce the incidence of long-term complications following CRH, without reducing the radicality of the operation. However, a conclusion on this subject could not be made because only a few small randomized trials without a long-term follow-up have been reported [10,11,12].We have developed and performed nerve-sparing radical hysterectomy (NSRH) based on the experiences with Professor M. Höckel and Professor A. Schneider in Germany in 2001 (JWR), and the published articles describing the surgical methods of NSRH in detail [6,7,13,14].After the pilot trial for this new surgical procedure over a 1 year, we designed a prospective randomized controlled trial (RCT) to assess the efficacy of NSRH in prevention of bladder dysfunction and its oncologic safety compared to that of CRH. Here, we present the results with a long-term follow-up.MATERIALS AND METHODS1. Study subjectsThis study was conducted prospectively in patients with cervical cancer the International Federation of Gynecology and Obstetrics (FIGO) stage IB1-IIA. Exclusion criteria included neuroendocrine histology, pathologically proven distant metastasis, history of psychiatric disease, preoperative urinary dysfunction, and another coexisting malignancy. Patients with an adequate follow-up duration of more than one year after the surgery were included in the analysis.Between March 2003 and November 2005, 94 consecutive patients with cervical cancer FIGO stage IB1-IIA were enrolled and 92 patients were randomly assigned to surgical treatment with CRH or NSRH after excluding panic disorder (n=1) and pathologically confirmed supraclavicular lymph node (LN) metastasis (n=1). After random assignment, one patient declined to get included in the CRH group, and one patient with intraoperatively confirmed multiple metastatic LNs was converted to chemoradiation followed by pelvic and para-aortic LND in NSRH group. Two patients in the CRH group who had confirmed neuroendocrine histology in the surgical specimen were excluded from the study, and treated by systemic chemotherapy. One patient in each group was lost to follow-up within one year after the surgery. Eighty-six patients (40 in the CRH group and 46 in the NSRH group) were included in the final analysis (Fig. 1). This prospective study was approved by the Institutional Review Board of the National Cancer Center of Korea.2. Surgical procedureAll operations were performed by either or both surgeons (JWR and SYP) who were skilled in CRH and already had experience with NSRH for one year before this study in the pilot trial. Laparotomy through hypogastric midline incision and left circumcision of the umbilicus was performed for the procedure. A schematic three-dimensional (3D)-illustration of the nervous system of the pelvis and key steps in the surgical procedure are presented in Fig. 2. The key for the nerve-sparing during RH included four steps. The first step was to identify the superior hypogastric plexus (SHP) at the aortic bifurcation and mobilize it from the sacral promontary, which would be the starting point of the nerve-sparing procedure (Fig. 2B). The second step was, after entering the retroperitoneal pelvic space and completion of pelvic LND, the hypogastric nerves (HN) originating from the SHP and the upper part of the inferior hypogastric plexus (IHP) were exposed along the lateral border of the mesorectum (Fig. 2C). The third step was for the IHP (Fig. 2D). The vascular part of the paracervix was ligated at the level where uterine vessels branch from the internal iliac vessels. After incision of the rectouterine peritoneal fold, separation of the anterior mesorectum from the proximal vagina and lateral mobilization of the IHP, which was HN fused with the pelvic splanchnic nerves from S2 to S4, were performed before transaction of the uterosacral ligament. After an anterior incision between the bladder and the cervix, the medial aspect of the distal ureter was exposed by separation of the uterine vessels, lymphatics, and a few small LNs from the bladder mesentery. For complete removal of the paracervical tissues, liposuction was performed with Hercules aspirator (Wells Johnson Co., Tucson, AZ, USA) below the vascular part of the paracervix.The last part of nerve-sparing was for the bladder branch of the IHP (Fig. 2E). The vesicovaginal venous connection and anterior condensed ligamentous portion crossing the ureters were ligated and transected, and then the vagina at a level 2 to 3 cm distal to the tumor was clamped while saving the posterior part of the vesicouterine ligament which contained the bladder branch of the IHP.After the insertion of two Jackson-Pratt closed suction drains, suprapubic cystostomy was performed. Bladder emptying with suprapubic catheterization was performed for one week, and then self-voiding was attempted after clamping of the suprapubic catheter. Residual urine (RU) volume was recorded by declamping the catheter immediately after the self-voiding. The suprapubic catheter was removed when the RU measured less than 50 mL at least two times in a low. The duration of bladder catheterization after the surgery was recorded and compared.For the quantification of nerve fibers retained in the resected paracervix, longitudinal paracervical tissues were marked at 2 cm lateral to the isthmus of the resected uterus at the operating theater (Supplementary Fig. 1). Microscopic section of full length of the labeled paracervix was stained with a general nerve marker, S-100 protein, in order to quantify the nerve fibers. Nerve fibers larger than 100 µm on both sides were counted by the pathologist (SL) without any clinical information and surgical protocol.Postoperative external radiotherapy (RT) was employed when the final pathologic report revealed LN metastasis or histologically confirmed parametrial invasion, and intracavitary RT was added when the vaginal resection margin was involved by tumor.3. Evaluation of urinary functionUrodynamic studies (UDSs) were carried out before the operation and at 1, 3, and 12 months after the operation. UDS were carried out using the Duet MultiP (Medtronic Inc., Minneapolis, MN, USA) and air-charged urethral and abdominal sensors. All procedures were performed in a sitting erect position on a toilet seat with room-temperature sterile water. The filling rate was 30 mL/min unless this provoked urinary urgency. Abdominal leak point pressures were measured at 200 cm3, with the urethral catheter in place, unless otherwise specified. The abdominal pressure transducer was placed rectally. Provocative maneuvers, including water stimulation and cough, were used in an effort to provoke detrusor overactivity. Urethral pressure profile was performed using a mechanical puller at a rate of 1 mm/sec. Both static and dynamic profiles were performed at cystometric capacity. Recorded urodynamic parameters in addition to the urodynamic tracings were from the uroflowmetry (voided volume, postvoid RU, maximal flow rate, voiding time), cystometrogram (first sensation, first desire to void, capacity, filling rate, detrusor overactivity, urodynamic stress incontinence, abdominal leak point pressure at 200 cm3), and urethral pressure profile. One urologist (JSC) reviewed each case without any clinical information.Subjective bladder dysfunction was evaluated with a standard questionnaire of the Korean version of International Prostate Symptom Score (IPSS). The scoring system for voiding function described above was based on a 0 to 5 scale, as follows; 0, not at all; 1, less than one time in five; 2, less than half the time; 3, about half the time; 4, more than half the time; and 5, almost always. Questionnaires were analyzed and divided into emptying, frequency, intermittency, urgency, weak stream, straining, and nocturia. Total IPSS score was calculated by adding the score of each item. It can be expected that the greater is the increase in the IPSS, the lesser is the urinary function.4. Evaluation of oncologic safetyAll enrolled patients were followed up every 3 months for the first 2 years after the surgery and every 6 months thereafter with a physical gynecological examination, vaginal cytology, chest X-ray, tumor markers (squamous cell carcinoma antigen and carcinoembryonic antigen), and other imaging modality including computed tomography (CT), magnetic resonance imaging, positron emission tomography (PET), and PET/CT if indicated.Disease-free survival (DFS) and overall survival (OS) were calculated as time, in months, from the date of the primary surgery to the time of confirmed recurrence of cervical cancer and death, respectively. DFS and OS were compared between the two groups by survival analysis with a long-term follow-up.5. Statistical analysisContinuous variables were assessed for normal distribution (Kolmogorov-Smirnov test) and expressed as appropriate (mean with SD or median with range). Categorical variables were evaluated with the use of the Fisher exact test. For paired data, such as postoperative changes in UDS or IPSS score compared with preoperative baseline, Wilcoxon singed rank test was used for analysis. A p<0.05 was considered statistically significant. DFS and OS were evaluated by Kaplan-Meier analysis. IBM SPSS ver. 20.0 (IBM Co., Armonk, NY, USA) was used for all statistical analyses.RESULTS1. Clinicopathologic characteristics and surgical outcomesThe detailed clinical and pathologic characteristics of the enrolled patients and the surgical outcomes in both groups are detailed in Table 1. The general characteristics of the patients, including age, BMI, FIGO stage, histologic distribution, tumor size, operating time, estimated blood loss, adjuvant RT, and LN metastasis were not different in the two groups. With respect to the evaluation of radicality of NSRH, surgical outcomes such as the width and length of the resected paracervix, length of safety margin of the resected vagina, and the number of harvested LNs were also similar between the two groups. Average count of resected nerve bundles stained with S-100 in the removed paracervix was significantly lower in the NSRH (12; range, 6 to 21) compared to CRH (30; range, 17 to 45; p<0.001).2. Evaluation of urinary functionThe median duration before the postvoid RU volume became less than 50 mL was 11 days (range, 7 to 26 days) among the patients in the NSRH group and was 18 days (range, 10 to 85 days) among the patients in the CRH group (p<0.001). No significant difference in the preoperative data of UDS was found between the two groups (p>0.05). Postoperative changes in UDS compared with preoperative data are shown in Table 2. At postoperative 1 month, almost all parameters of UDS were significantly changed in the CRH group, and several parameters including maximal flow rate, voided volume, RU, compliance, and maximal urethral pressure were also changed in the NSRH group. All changed parameters of USD in the NSRH group were recovered at postoperative 3 months examination, while changes in many parameters of USD in the CRH group were maintained 3 months later. One year after the operation, changes of bladder compliance and RU were still persistent in the CRH group (Fig. 3). For the evaluation of subjective urinary symptoms, postoperative IPSS scores were compared with preoperative IPSS scores (Table 3).There were changes in every item for urinary symptoms, emptying, frequency, intermittency, urgency, weak stream, straining, and nocturia, after CRH and these changes were persistent for more than a year. On the contrary, there were no changes in all urinary symptoms except for intermittency in the NSRH group after a year, although four items for frequency, intermittency, weak stream, and straining indicated deterioration immediately after the operation.3. Evaluation of oncologic safetyThe median duration of follow-up was 101 months (range, 13 to 137 months) in the CRH group and 111 months (range, 13 to 139 months) in the NSRH group. Ten-year DFS of the patients in the CRH and NSRH groups was 94.9% and 92.4%, respectively (Fig. 4). During the follow-up, two patients in the CRH group and three patients in the NSRH group developed recurrence. Three out of the five patients developed recurrence within 2 years, and one patient was diagnosed with pulmonary metastasis at 7-year follow-up. Four out of the five patients had systemic metastatic diseases, and only one patient was diagnosed para-aortic LN metastasis and was treated by laparoscopic resection followed by RT. One patient in the NSRH group was died with systemic metastatic lesions at 21 months after the initial diagnosis. The clinicopathologic features of the recurred cases are summarized in Supplementary Table 1. The 10-year DFS and OS were not different between the two groups.DISCUSSIONThis was an RCT with the greatest number of cases enrolled and the longest duration of follow-up for the evaluation of efficacy and oncologic safety of NSRH till date. This means that the results of this prospective study strongly support the efficacy of NSRH in preventing urinary dysfunction without sacrifice of oncologic safety.Ideal surgical management of cervical cancer should reduce early and late morbidity without compromising oncological disease control. Although CRH has been confirmed to be a standard treatment modality resulting in reduced risk of pelvic recurrence for FIGO stage IB1-IIA cervical cancer, it has been criticized for its high rate of postoperative pelvic organ dysfunction, especially urinary dysfunction. According to the literatures, urinary dysfunction (sensory loss, storing and voiding dysfunctions, urinary incontinence, and detrusor instability) is the most common long-term complication following CRH. The incidence has been reported to occur in 70% to 85% of reported studies [2,15,16]. Nowadays, postoperative QoL has become a more important issue, considering that more than 90% of the patients with cervical cancer could survive for a long time [2]. Deterioration of QoL after the surgery is believed to be the result of nerve injury during the procedure. In general, sympathetic branches of the hypogastric nerve and the vesical branch of the pelvic plexus stimulate the urethral sphincter and inhibit the detrusor muscle of the bladder, while parasympathetic branches of the pelvic splanchnic nerve and the vesical branch of the pelvic plexus relax the urethral sphincter and stimulate the detrusor muscle of the bladder. In order to maintain bladder function, those nerve networks should be preserved intact as much as possible unless these attempts sacrifice the therapeutic role of surgery. Although various attempts have been made to prevent pelvic organ dysfunction via autonomic nerve preservation, most of these studies provide either subjective or objective UDS data for a relatively short-time after the surgery [17,18,19,20].It has been reported that RH is also associated with significant urodynamic changes and that these alterations may persist for at least 1 year following surgery [15,21,22]. Immediately after the operation, many factors including postoperative inflammation, local edema, temporary electrical injury, and decreased blood supply may influence the voiding function irrespective of nerve injury. Also, the bladder function after RH could be improved by 12 months after the operation [11,23,24]. Therefore, reliable data should be obtained for a long-time period of at least 1 year. The strong point of this study is in assessing the efficacy of NSRH in preserving voiding function. Both objective and subjective evaluations of voiding function using both UDS and IPSS were performed preoperative and at 1, 3, and 12 months after the surgery. In our study, increased RU volume and decreased compliance were maintained over a one year after the CRH. These results were compatible with those in the previous reports [15,21]. Differences in subjective urinary symptoms by questionnaire-based IPSS were more significant than that on UDS. Subjective voiding dysfunction seems to be strengthened because all parameters should be coordinated to maintain normal urination and even a malfunctioning detail could affect the general sense of normal voiding. The results from this study support the claim that NSRH is very effective method for increasing the QoL of cervical cancer survivors.In terms of postoperative chronic morbidity, many literatures including this study have provided evidence of favorable outcomes for urinary function after NSRH compared with CRH [10,11,25], and a recent meta-analysis also showed that NSRH is associated with less bladder dysfunction and fewer complications [26]. Nevertheless, NSRH has not yet become popular among gynecologic surgeons. The most important barrier to the widespread use of this concept is the lack of sufficient survival data comparing the oncologic outcomes of NSRH with CRH. Although a lot of studies have already reported the results of NSRH, they had various limitations in ensuring the oncologic safety. Most of the studies were retrospective analysis without control or non-randomized historical comparison, and they mainly focused on the comparison of urinary dysfunctions between CRH and NSRH without longterm survival results.For relevant survival analysis, well-designed RCTs with sufficient number of cases and adequate duration of follow-up are the basic prerequisites for drawing a conclusion. Till date, only three small-scale RCTs have reported the clinical data of NSRH [10,11,12], and two of them only focused on the efficacy of NSRH in reducing the postoperative morbidity without survival results [11,12], and the other study reported only the 2-year DFS rate for a small number of patients [10]. A recently published systematic review of oncological outcomes of NSRH concluded that the evidence addressing the oncologic safety of NSRH over that of CRH is neither adequate nor statistically relevant [27]. The authors emphasized that properly designed, prospective randomized noninferiority trial with more than five hundred cases in each arm is needed to assess the equality of survival [27].Although the number of enrolled patients in this study were not enough to assess the noninferior oncologic outcome of NSRH compared to that of CRH, long-term follow-up duration of over 10-year period compensated for this limitation to some extent, and this study provided the evidence for the safety of NSRH. Late recurrence after 5 years occurs occasionally in patients with cervical cancer, although more than two-thirds of recurrences develop within 2 years after diagnosis. Therefore, 10-year DFS has been reported to show the total outcome of treatment for cervical cancer [28,29]. In fact, one out of the five recurred cases in this study was diagnosed with recurrence at the 7-year follow-up.In conclusion, the results of this study provided evidence that NSRH should be regarded as a very effective modality to improve the QoL of cervical cancer survivors without sacrificing oncologic safety. A well-designed, large-scale prospective noninferiority trial should be conducted in near future to ensure the safety of NSRH.ACKNOWLEDGMENTSI (JWR) would like to thank Professor Dr. M. Höckel (Leipzig, Germany) and Professor Dr. A. Schneider (Berlin, Germany) for their excellent guidance and hospitality during my training in Germany. Artistic 3D-illustration of nervous system of pelvis was provided by HealthBreeze (Seoul, Korea). This work was supported by a grant from National Cancer Center of Korea (NCC 0310040).CONFLICT OF INTEREST: No potential conflict of interest relevant to this article was reported.1DonatoDMSurgical management of stage IB-IIA cervical carcinomaSemin Surg Oncol199916232235102253012ZulloMAManciNAngioliRMuziiLPaniciPBVesical dysfunctions after radical hysterectomy for cervical cancer: a critical reviewCrit Rev Oncol Hematol200348287293146933413ErcoliADelmasVGadonneixPFanfaniFVilletRPaparellaPClassical and nerve-sparing radical hysterectomy: an evaluation of the risk of injury to the autonomous pelvic nervesSurg Radiol Anat200325200206129103824MaasCPTrimbosJBDeRuiterMCvan de VeldeCJKenterGGNerve sparing radical hysterectomy: latest developments and historical perspectiveCrit Rev Oncol Hematol200348271279146933395LandoniFManeoACormioGPeregoPMilaniRCarusoOClass II versus class III radical hysterectomy in stage IB-IIA cervical cancer: a prospective randomized studyGynecol Oncol200180312111365616HockelMKonerdingMAHeusselCPLiposuction-assisted nerve-sparing extended radical hysterectomy: oncologic rationale, surgical anatomy, and feasibility studyAm J Obstet Gynecol199817897197696095697PossoverMStoberSPlaulKSchneiderAIdentification and preservation of the motoric innervation of the bladder in radical hysterectomy type IIIGynecol Oncol200079154157110636378TrimbosJBMaasCPDeruiterMCPetersAAKenterGGA nerve-sparing radical hysterectomy: guidelines and feasibility in Western patientsInt J Gynecol Cancer200111180186114379229YabukiYAsamotoAHoshibaTNishimotoHNishikawaYNakajimaTRadical hysterectomy: an anatomic evaluation of parametrial dissectionGynecol Oncol2000771551631073970510ChenCLiWLiFLiuPZhouJLuLClassical and nerve-sparing radical hysterectomy: an evaluation of the nerve trauma in cardinal ligamentGynecol Oncol20121252452512220977311WuJLiuXHuaKHuCChenXLuXEffect of nerve-sparing radical hysterectomy on bladder function recovery and quality of life in 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Dysfunct2004154184211554926122KanaoHFujiwaraKEbisawaKHadaTOtaYAndouMVarious types of total laparoscopic nerve-sparing radical hysterectomies and their effects on bladder functionJ Gynecol Oncol2014251982052504543223RalphGTamussinoKLichteneggerWUrological complications after radical abdominal hysterectomy for cervical cancerBaillieres Clin Obstet Gynaecol19882943952322906224TodoYKuwabaraMWatariHEbinaYTakedaMKudoMUrodynamic study on postsurgical bladder function in cervical cancer treated with systematic nerve-sparing radical hysterectomyInt J Gynecol Cancer2006163693751644566025PlottiFZulloMAMonteraRAngioliRPierluigiBPBladder function after laparoscopic nerve-sparing radical hysterectomyGynecol Oncol20111203152112976926LongYYaoDSPanXWOuTYClinical efficacy and safety of nerve-sparing radical hysterectomy for cervical cancer: a systematic review and meta-analysisPLoS One20149e941162474801527BasaranDDusekLMajekOCibulaDOncological outcomes of nerve-sparing radical hysterectomy for cervical cancer: a systematic reviewAnn Surg Oncol2015123http://dx.doi.org/10.1245/s10434-015-4377-728YeungARAmdurRJMorrisCGMorganLSMendenhallWMLong-term outcome after radiotherapy for FIGO stage IIIB and IVA carcinoma of the cervixInt J Radiat Oncol Biol Phys200767144514501723436229LiuJLiuJLiJChenYGuanXWuXTumor-stroma ratio is an independent predictor for survival in early cervical carcinomaGynecol Oncol2014132818624219981SUPPLEMENTARY MATERIALSSupplementary Fig. 1(A) Longitudinal section of the paracervical tissue at 2 cm apart from the isthmus was fixed for nerve staining. (B) Immunohistochemical staining with S-100 protein for quantification of nerve fibers after conventional radical hysterectomy, and (C) nerve-sparing radical hysterectomy (×40).Supplementary Table 1Summary of clinicopathologic characteristics of recurred casesCase no.GroupAge (yr)PathologyFIGO stageSite of recurrenceDuration from surgery (mo)Treatment modality for recurrenceCurrent status1CRH43AdenocarcinomaIB1PALN13Laparoscopic operation→RTNED2NSRH45AdenocarcinomaIB1Lung90ChemotherapyNED3CRH51SCCAIB1Lung15Resection→chemotherapyNED4NSRH47SCCAIIALung, liver19ChemotherapyDOD5NSRH47AdenocarcinomaIB2Pelvis38Pelvic exenteration→RTAlive with diseaseLung47Resection→chemotherapyCRH, conventional radical hysterectomy; DOD, death of disease; FIGO, International Federation of Gynecology and Obstetrics; NED, no evidence of disease; NSRH, nerve-sparing radical hysterectomy; PALN, para-aortic lymph node; RT, radiotherapy; SCCA, squamous cell carcinoma.Fig. 1Flow diagram of the patients enrolled in this study. CRH, conventional radical hysterectomy; LN, lymph node; NSRH, nerve-sparing radical hysterectomy.Fig. 2Three-dimensional (3D) illustration and key steps in nerve-sparing radical hysterectomy. (A) Schematic 3D-illustration of the nervous system of the pelvis which should be preserved during nerve-sparing radical hysterectomy. (B) Separation and preservation of the superior hypogastric plexus on the sacral promontory (arrow, SHP). (C) Isolation and tracing of the hypogastric nerve on the lateral border of the rectum (arrow, HN). (D) Identification and preservation of the inferior hypogastric plexus composed of the hypogastric nerve and pelvic splanchnic nerve below the vascular part of the paracervix (arrow, IHP). (E) Vesical branch of the inferior hypogastric plexus during dissection of the vesicouterine ligament (arrow, vesical branch of IHP). B, bladder; HN, hypogastric nerve; IHP, inferior hypogastric plexus; R, rectum; SHP, superior hypogastric plexus; U, ureter; Ut, uterus.Fig. 3(A) Bladder compliance and (B) volume of residual urine were evaluated by urodynamic study preoperatively, and at 1, 3, and 12 months after conventional radical hysterectomy (CRH) or nervesparing radical hysterectomy (NSRH). (C) Subjective urinary symptoms were evaluated with the International Prostate Symptom Score (IPSS). Postoperative results were compared with preoperative basal values by Wilcoxon signed rank test. *p<0.05.Fig. 4(A) Disease-free survival and (B) overall survival in patients with cervical cancer treated by conventional radical hysterectomy (CRH) or nerve-sparing radical hysterectomy (NSRH).Table 1Clinicopathologic characteristics and surgical outcomesCharacteristicCRH (n=40)NSRH (n=46)p-valueAge (yr)49.5±9.146.7±9.4NS*BMI (kg/m2)25.4±3.224.3± 2.2NS*FIGO stageNS†\u2003IB131 (77.5)34 (74.0)\u2003IB23 (7.5)6 (13.0)\u2003IIA6 (15.0)6 (13.0)Tumor size (cm)2.5±1.12.1±1.3NS*Histologic typeNS†\u2003Squamous cell carcinoma33 (82.5)35 (76.0)\u2003Adenocarcinoma6 (15.0)11 (23.9)\u2003Adenosquamous carcinoma1 (2.5)0Operation time (min)278 (244-321)297 (256-368)NS‡Estimated blood loss (mL)520.8±239.8478.9±206.5NS*Radicality\u2003Paracervical length, right (cm)4.7±1.44.2±0.9NS*\u2003Paracervical width, right (cm)3.6±0.83.7±1.0NS*\u2003Paracervical length, left (cm)4.8±1.44.2±1.0NS*\u2003Paracervical width, left (cm)3.3±0.83.6±0.9NS*\u2003Vaginal length (cm)3.0±0.83.0±0.6NS*\u2003No. of harvested pelvic LN25.8±7.826.9±8.1NS*\u2003No. of harvested para-aortic LN5.9±4.76.2±4.8NS*LN involvement2 (5.0)4 (8.7)NS†No. of dissected nerve fibers30 (17-45)12 (6-21)<0.001‡Postoperative complication3 (7.5)2 (4.3)NS†\u2003Incisional hernia11\u2003Infected lymphocele21No. of cases of CIC3 (7.5)0<0.001†Days for RU <50 mL18 (10-85)11 (7-26)<0.001‡Postoperative radiotherapy15 (37.5)14 (31.1)NS†Follow-up duration (mo)101 (13-137)111 (13-139)NS*Recurrence2 (5.0)3 (6.5)NS†10-Year DFS (%)94.992.4NS§Values are presented as mean±SD, number (%), or median (range).BMI, body mass index; CIC, clean intermittent catheterization; CRH, conventional radical hysterectomy; DFS, disease-free survival; FIGO, International Federation of Gynecology and Obstetrics; LN, lymph node; NS, not significant; NSRH, nerve-sparing radical hysterectomy; RU, residual urine.*Student t-test. †Fisher exact test. ‡Mann-Whitney test. §Kaplan-Meier survival analysis.Table 2Postoperative changes in the parameters of urodynamic study compared to preoperative basal valuesVariableConventional radical hysterectomyNerve-sparing radical hysterectomyBasal1 mo3 mo12 moBasal1 mo3 mo12 moMFR (mL/sec)18.5 (8.9-63.9)10.5 (4,4-21,1)*16.5 (5.6-40.8)16.0 (8.3-25.2)18.5 (9.3-39.3)14.5 (5.0-49.5)*15.8 (6.7-35.2)15.5 (9.0-46.5)AFR (mL/sec)8.7 (2.5-47.0)4.7 (1.0-11.3)*6.9 (3.4-46.6)6.1 (2.2-12.8)8,1 (2.2-65.0)6.4 (3.10-71.0)6.6 (2.6-56.0)7.2 (3.2-21.0)VV (mL)368.5 (115.0-677.0)259.5 (56.0-604.0)*330.0 (85.0-564.0)380.0 (230.0-566.0)356.5 (142.0-779.0)308.5 (32.0-606.0)*407.5 (97.0-813.0)350.0 (120.0-566.0)MDP (cmH2O)61.0 (23.0-181.0)54.5 (0-199.0)*53.5 (17.0-90.0)60.5 (1.0-143.0)44.0 (20.0-113.0)45.0 (16.0-106.0)43.0 (18.0-126.0)55.0 (22.0-144.0)RU (mL)16.5 (0-80.0)70.0 (0-181.0)*51.5 (0-220.0)*51.0 (0-120.0)*10.0 (0-100.0)20.0 (0-100.0)*18.0 (0-120.0)20.0 (0-75.0)Compliance (mL/cmH2O)93.8 (34.6-159.6)29.1 (3.5-82.4)*30.3 (4.5-95.6)*61.9 (6.5-194.3)*83.0 (32.1-169.9)52.5 (21.6-125.3)*80.4 (34.0-138.0)59.7 (4.9-294.3)FVS (mL)209.5 (98.0-414.0)207.5 (90.0-343.0)242.0 (44.0-508.0)235.5 (109.0-312.0)193.5 (90.0-430.0)185.0 (129.0-461.0)212.0 (51.0-448.0)248.0 (80.0-389.0)Urgency (mL)411.0 (190.0-659.0)371.9 (210.0-550.0)356.8 (97.0-630.0)*369.0 (302.0-450.0)375.5 (214.0-606.0)348.5 (230.0-584.0)400.0 (240.0-600.0)370.0 (176.0-550.0)Capacity (mL)443.0 (206.0-674.0)395.3 (220.0-550.0)*376.1 (99.0-630.0)401.0 (330.0-462.0)415.0 (273.0-608.0)355.0 (240.0-586.0)429.0 (269.0-612.0)410.0 (181.0-550.0)MUP (cmH2O)88.0 (36.0-158.0)73.5 (38.0-123.0)*76.5 (37.0-193.0)*76.5 (11.0-109.0)*97.0 (44.0-183.0)85.0 (43.0-151.0)*79.0 (19.0-143.0)96.0 (19.0-132.0)MCP (cmH2O)88.0 (36.0-159.0)74.1 (34.0-122.0)*78.0 (37.0-194.0)*77.0 (12.0-111.0)95.5 (45.0-148.0)85.0 (43.0-148.0)84.0 (20.0-143.0)97.0 (19.0-116.0)FUL (mm)92.0 (35.0-197.0)86.5 (36.0-218.0)89.5 (23.0-193.0)80.0 (27.0-117.0)85.0 (34.0-250.0)79.0 (27.0-214.0)76.5 (25.5-232.0)97.0 (56.0-132.0)Values are presented as median (range).AFR, average flow rate; FUL, functional urethral length; FVS, first voiding sense; MCP, maximal closure pressure; MDP, maximal detrusor pressure; MFR, maximal flow rate; MUP, maximal urethral pressure; RU, residual urine; VV, voided volume.*p<0.05, compared with preoperative basal data by Wilcoxon signed rank test.Table 3Postoperative changes of International Prostate Symptom ScoreVariableConventional radical hysterectomyNerve-sparing radical hysterectomyBasal1 mo3 mo12 moBasal1 mo3 mo12 moEmptying1 (0-5)2 (0-5)*3 (0-5)*2 (0-5)*1 (0-5)2 (0-5)1 (0-4)1 (0-5)Frequency1 (0-5)3 (0-5)*3 (0-5)*2 (0-5)*1 (0-3)2 (0-5)*1 (0-3)1 (0-4)Intermittency0 (0-5)4 (0-5)*3 (0-5)*3 (0-5)*0 (0-1)2 (1-5)*1 (0-4)*1 (0-5)*Urgency0 (0-5)1 (0-5)*2 (0-5)*2 (0-5)*1 (0-5)1 (0-5)1 (0-2)0 (0-5)Weak stream0 (0-5)3 (0-5)*2 (0-5)*1 (0-5)*1 (0-4)2 (0-5)*1 (0-4)1 (0-5)Straining0 (0-1)2 (0-5)*1 (0-5)*1 (0-5)*0 (0-1)1 (0-5)*1 (0-1)*0 (0-5)Nocturia1 (0-3)2 (1-4)*2 (0-3)*2 (0-3)*1 (0-3)1 (0-5)1 (0-3)1 (0-3)Total3 (0-28)20 (3-28)*17 (3-26)*14 (3-33)*3 (0-20)11 (3-33)*9 (1-16)6 (0-24)Values are presented as median (range).*p<0.05 compared with preoperative basal data by Wilcoxon signed rank test.', 'title': 'Efficacy and oncologic safety of nerve-sparing radical hysterectomy for cervical cancer: a randomized controlled trial.', 'date': '2015-04-16'}}
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