Pmed.1001236 1.12

Nevirapine- Versus Lopinavir/Ritonavir-Based InitialTherapy for HIV-1 Infection among Women in Africa: ARandomized Trial Shahin Lockman1,2,3*, Michael Hughes2, Fred Sawe4, Yu Zheng2, James McIntyre5, Tsungai Chipato6, Aida Asmelash3, Mohammed Rassool7, Sylvester Kimaiyo8, Douglas Shaffer4, Mina Hosseinipour9, Lerato Mohapi10, Francis Ssali11, Margret Chibowa12, Farida Amod13, Elias Halvas14, Evelyn Hogg15, Beverly Alston-Smith16, Laura Smith17, Robert Schooley18, John Mellors14, Judith Currier19, the OCTANE (Optimal Combination Therapy After Nevirapine Exposure) ACTG A5208/OCTANE Study 1 Brigham and Women's Hospital, Boston, Massachusetts, United States of America, 2 Harvard School of Public Health, Boston, Massachusetts, United States of America, 3 Botswana Harvard School of Public Health AIDS Initiative Partnership, Gaborone, Botswana, 4 Kenya Medical Research Institute/Walter Reed Project and US Military HIV Research Program, Kericho, Kenya, 5 Anova Health Institute, Johannesburg, South Africa, 6 University of Zimbabwe, Harare, Zimbabwe, 7 University of Witwatersrand, Johannesburg, South Africa, 8 Moi University Faculty of Health Sciences, Eldoret, Kenya, 9 Kamuzu Central Hospital, University of North Carolina Project, Lilongwe, Malawi, 10 Chris Hani Baragwanath Hospital, Johannesburg, South Africa, 11 Joint Clinical Research Centre, Kampala, Uganda, 12 University of Alabama at Birmingham Center for Infectious Disease Research in Zambia, Lusaka, 13 University of Kwazulu-Natal, Durban, South Africa, 14 University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America, 15 Social & Scientific Systems, Silver Spring, Maryland, United States of America, 16 National Institutes of Health, Bethesda, Maryland, United States of America, 17 Frontier Science and Technology Research Foundation, Amherst, Massachusetts, United States of America, 18 University of California San Diego, San Diego, California, United States of America, 19 University of California Los Angeles, Los Angeles, California, United States Background: Nevirapine (NVP) is widely used in antiretroviral treatment (ART) of HIV-1 globally. The primary objectiveof the AA5208/OCTANE trial was to compare the efficacy of NVP-based versus lopinavir/ritonavir (LPV/r)-based initialART.
Methods and Findings: In seven African countries (Botswana, Kenya, Malawi, South Africa, Uganda, Zambia, andZimbabwe), 500 antiretroviral-naı¨ve HIV-infected women with CD4,200 cells/mm3 were enrolled into a two-armrandomized trial to initiate open-label ART with tenofovir (TDF)/emtricitabine (FTC) once/day plus either NVP (n = 249)or LPV/r (n = 251) twice/day, and followed for $48 weeks. The primary endpoint was time from randomization to deathor confirmed virologic failure ([VF]) (plasma HIV RNA,1 log10 below baseline 12 weeks after treatment initiation, or$400 copies/ml at or after 24 weeks), with comparison between treatments based on hazard ratios (HRs) in intention-to-treat analysis. Equivalence of randomized treatments was defined as finding the 95% CI for HR for virological failureor death in the range 0.5 to 2.0. Baseline characteristics were (median): age = 34 years, CD4 = 121 cells/mm3, HIVRNA = 5.2 log10copies/ml. Median follow-up = 118 weeks; 29 (6%) women were lost to follow-up. 42 women (37 VFs,five deaths; 17%) in the NVP and 50 (43 VFs, seven deaths; 20%) in the LPV/r arm reached the primary endpoint (HR0.85, 95% CI 0.56–1.29). During initial assigned treatment, 14% and 16% of women receiving NVP and LPV/rexperienced grade 3/4 signs/symptoms and 26% and 22% experienced grade 3/4 laboratory abnormalities. However,35 (14%) women discontinued NVP because of adverse events, most in the first 8 weeks, versus none for LPV/r(p,0.001). VF, death, or permanent treatment discontinuation occurred in 80 (32%) of NVP and 54 (22%) of LPV/r arms(HR = 1.7, 95% CI 1.2–2.4), with the difference primarily due to more treatment discontinuation in the NVP arm. 13(45%) of 29 women tested in the NVP versus six (15%) of 40 in the LPV/r arm had any drug resistance mutation at timeof VF.
Conclusions: Initial ART with NVP+TDF/FTC demonstrated equivalent virologic efficacy but higher rates of treatmentdiscontinuation and new drug resistance compared with LPV/r+TDF/FTC in antiretroviral-naı¨ve women with CD4,200 cells/mm3.
Trial registration: NCT00089505 Please see later in the article for the Editors' Summary.
Citation: Lockman S, Hughes M, Sawe F, Zheng Y, McIntyre J, et al. (2012) Nevirapine- Versus Lopinavir/Ritonavir-Based Initial Therapy for HIV-1 Infection amongWomen in Africa: A Randomized Trial. PLoS Med 9(6): e1001236. doi:10.1371/journal.pmed.1001236 Academic Editor: Steven G. Deeks, San Francisco General Hospital, United States of America Received September 29, 2011; Accepted May 3, 2012; Published June 12, 2012 Copyright: ß 2012 Lockman et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PLoS Medicine June 2012 Volume 9 Issue 6 e1001236 LPV/r- Versus NVP-Based ART among Women in Africa Funding: This project was supported in part by grants (U01AI068636, AI38838, and Statistical and Data Management Center AI68634) from the National Institute ofAllergy and Infectious Diseases to the AIDS Clinical Trials Group. It also was supported in part by the General Clinical Research Center Units funded by the NationalCenter for Research. J. Currier is supported in part by K24 AI56933. E. Dangaiso, University of Zimbabwe, Parirenyatwa, Harare, Zimbabwe CRS (Site 30313) CTU Grant#U01AI069436. F. Conradie, MD and J. Tsotsotetsi, WITS HIV Research Group, Johannesburg, South Africa (Site 11101) CTU Grant #U01 AI69463-03. KMRI/Walter ReedProject Clinical Research Center; Kericho, Kenya (Site 12501) CTU Grant #IAAY1AI8374. C. Potani and R. Mwausegha, UNC Project, Kamuzu Central Hospital, Lilongwe(Site 12001) CTU Grant #5 U01 AI069518. F. Laher and R. Hen-Boisen, Soweto, South Africa ACTG CRS (Site 12301) CTU Grant # AI69453. A. Siika, K. Wools-Kaloustian,K. Kirwa, and A. Nzioka, Moi University, Eldoret, Kenya CRS (Site 12601) CONTRACT No. AACTG. 50.5208.07, the United States Military HIV Research Program. E. Stringer,Centre for Infectious Disease Research, Kalingalinga; Lusaka, Zambia (Site 12801) CTU Grant #5U01AI069455-03 and # 3U01AI32775-13S5. E. Moko, Botswana (Site12701) CTU Grant #5U01AI069456-03. C. Kityo and S. Rwambuya, JCRC, Kampala, Uganda (Site 12401) CTU Grant #AI-069501. F. Amod, U. Lalloo, and S. Pillay,University of Natal, Durban, South Africa (11201) CTU Grant # AI69426. SDAC (X. Sun) FSTRF (A. Nair, L.M. Smith, J. Tutko, C. Lee), Pharmaceutical Affairs Branch, SSSOps (Y. Delph, N. Gettinger, L. Berman, L. Boone), DAIDS (B. Adedeji). These funding bodies played no role in study design, data collection and analysis, decision topublish, or preparation of the manuscript. The following companies donated study drug: Gilead (tenofovir/emtricitabine), Boehringer-Ingelheim (nevirapine), Abbott(lopinavir/ritonavir), GlaxoSmithKline (zidovudine), Bristol-Myers Squibb (didanosine). Pharmaceutical supporters provided study product but did not fund any otheraspect of study conduct nor data analysis. Pharmaceutical supporters also participated as protocol team members and provided feedback (which the authors couldinclude or exclude at their discretion) on the manuscript, but did not participate in writing the manuscript, in analyzing the data, nor in the decision to publish themanuscript. Abbott Laboratories: William C. Woodward. For Boehringer Ingelheim: Lauren Petrella. Gilead: Audrey L. Shaw, Marianne Poblenz, Sabina Pfister, FaridehSaid, and Howard Jaffe. Bristol-Myers Squibb: Awny Farajallah, Kristy Grimm. GlaxoSmithKline: Navdeep Thoofer, Wendy Snowden.
Competing Interests: M. Hughes reports receiving fees as a member of the data and safety monitoring boards for Boehringer Ingelheim, Medicines Development,Pfizer, Tibotec, and Virionyx and the receipt by his department of financial support from Schering-Plough and Merck for an annual educational workshop; J. McIntyre,receiving financial support from the Abbott Speakers Bureau; M. Hosseinipour, receiving financial support from Abbott Virology for educational presentations (M.
Hosseinipour has given an educational lecture at the 2009 IAS conference and the 2010 INTEREST conference for Abbott virology on the topic of antiretroviralresistance in Malawi); L. Mohapi, receiving reimbursement for travel expenses from Pfizer Laboratories (L. Mohapi received travel, accommodation and registrationassistance for the XVII AIDS Conference in Mexico City, August 2008, from Pfizer); J. Mellors, serving on the scientific advisory board for Gilead Sciences, receivingconsulting fees from Merck, Idenix Pharmaceuticals, Chimerix, RFS Pharmaceuticals, Panacos Pharmaceuticals, and Abbott Laboratories, receiving grant support fromMerck, having stock options in RFS Pharmaceuticals, and receiving reimbursement for travel expenses from Gilead Sciences, Merck, Chimerix, Idenix Pharmaceuticals,RFS Pharmaceuticals, and Panacos Pharmaceuticals; R. Schooley, receiving consulting fees from Glaxo-SmithKline and Abbott Laboratories and reimbursement fortravel expenses from Abbott Laboratories (and serves on the scientific advisory board for Gilead Sciences); and J. Currier, receiving consulting fees fromGlaxoSmithKline and grant support from Merck and Tibotec. All other authors have declared that no competing interests exist.
Abbreviations: ART, antiretroviral treatment; FTC, emtricitabine; HR, hazard ratio; LPV/r, lopinavir/ritonavir; NNRTI, non-nucleoside analog reverse transcriptaseinhibitor; NRTI, nucleoside analog reverse transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor; RLS, resource-limited settings; sdNVP, single dose nevirapine;TDF, tenofovir; VF, virologic failure; WHO, World Health Organization; ZDV, zidovudine.
* E-mail: [email protected] PLoS Medicine June 2012 Volume 9 Issue 6 e1001236 LPV/r- Versus NVP-Based ART among Women in Africa hypothesis that the efficacy of NVP- and LPV/r-based ARTwould be similar. To permit optimal interpretation of trial 1, Most of the 33 million people living with HIV reside in interim trial 2 virologic failure (VF)/death results after partial resource-limited settings (RLS), and more than 5 million are follow-up (through 6 October 2008) were included in the receiving antiretroviral treatment (with the number treated published trial 1 paper [5]. This current report describes detailed continuing to increase). Globally, the vast majority of antiretroviral and final trial 2 results, using data from a substantially longer treatment (ART) is provided by general practitioners (and not period of follow-up (through 30 September 2009).
HIV specialists), using a public health approach. One of the Participants were consenting, HIV-1-infected adult women who primary ART regimens recommended in 2010 by the World were not pregnant or breastfeeding, from ten African sites (three in Health Organization (WHO) for initial treatment of HIV-infected South Africa; two in Kenya; and one each in Zimbabwe, persons is composed of tenofovir (TDF), emtricitabine (FTC), and Botswana, Zambia, Malawi, and Uganda). Participants had nevirapine (NVP) [1]. This particular combination is rapidly screening CD4+ cell count (CD4),200 cells/mm3 and trial 2 becoming one of the most commonly used antiretroviral treatment participants were antiretroviral-naı¨ve, except that up to 10 wk of regimens worldwide, particularly among women. However, prior zidovudine (ZDV) were permitted (as short-course ZDV was minimal data regarding the efficacy of this combination exist.
included in mother-to-child HIV transmission prevention regi- Furthermore, many practitioners have expressed concern about mens in some countries, and is not associated with significant the potency of this particular regimen, given early data emanating development of major drug resistance mutations). Lack of prior from small studies and observational cohorts suggesting possible sdNVP exposure was based on participant recall and self-report, in suboptimal efficacy [2,3]. In addition, the efficacy and toxicity of combination with one or more of the following when available: no initial ART containing NVP have not been compared prospec- prior pregnancy or pregnancy prior to the use of sdNVP in tively with regimens containing lopinavir/ritonavir (LPV/r), the country; HIV diagnosis after pregnancy; pre-delivery/postpartum most commonly available boosted protease inhibitor (PI) in RLS at or other relevant records reviewed and no sdNVP recorded; this time. If initial ART with a PI such as LPV/r were found to be patient confirmation of no prior sdNVP after being shown tablet.
much more effective or better tolerated than ART with the Additional eligibility criteria included estimated creatinine clear- commonly used NVP-based regimens, then first-line treatment ance $60 ml/minute; hemoglobin $7.0 g/dl; absolute neutrophil with a PI could in fact be cost-effective [4]; conversely equivalence count $750 cells/mm3; alanine aminotransferase (ALT), aspartate of NVP and LPV/r would provide some reassurance regarding aminotransferase (AST), alkaline phosphatase, and total bilirubin NVP-based ART as an initial therapy as recommended by WHO (each #2.5 times the upper limit of normal); absence of guidelines. Rigorous data regarding the efficacy (and comparative pregnancy/breastfeeding; absence of serious illness or tuberculosis efficacy) of recommended and frequently used ART regimens is of treatment within the prior 30 d; and Karnofsky score $70.
vital importance to HIV programs worldwide.
Participants were followed until 48 wk after the last enrollment.
A particular concern among women starting ART is that prior exposure to single dose NVP (sdNVP) during labor for preventing Women were randomized to open-label LPV/r (400 mg/ mother-to-child transmission (PMTCT) of HIV may affect the 100 mg) one capsule (or tablet) twice daily plus TDF/FTC relative efficacy of these two regimens. We therefore conducted (300 mg/200 mg) one tablet once daily; or to NVP 200 mg twice A5208/OCTANE, a study consisting of two parallel randomized daily plus TDF/FTC 300/200 mg once daily (after 14-d lead-in trials of initial three-drug ART that included LPV/r versus NVP with NVP 200 mg once daily). TDF/FTC was co-formulated in among women in Africa. For one trial among women with prior Truvada. LPV/r was initially supplied as Kaletra capsules, then sdNVP exposure, we previously reported the superior efficacy of heat-stable Aluvia tablets. Participants could switch from NVP to LPV/r versus NVP [5]. In this report, we present the results from second-line treatment with LPV/r or vice versa (and ZDV and women without prior sdNVP exposure.
didanosine were provided), in cases of VF (at the discretion of localinvestigators/participants) or toxicity. EFV was temporarily substituted for NVP and LPV/r during rifampin-containingtuberculosis treatment. Randomization was computer-generated using balanced block randomization (block size 4) stratified by The study was approved by all overseeing local Institutional screening CD4 count (, or $50 cells/mm3). Randomized Review Boards (IRBs)/Ethics Committees, as well as IRBs at the assignment was provided electronically from a remote, central following US institutions: Harvard School of Public Health, Data Management Center in the US back to each clinical site.
Walter Reed Army Institute of Research, Indiana University, While the study was being conducted, access to the block size and University of North Carolina, Case Western Reserve University, the sequence of treatment assignments was restricted to Data University of Alabama, and University of California San Diego.
Center staff who set up the randomization.
Participants provided written informed consent.
Data Collection, Follow-up, and Laboratory Analyses Study Design, Participants Study visits (with safety laboratory/clinical assessment) occurred OCTANE comprised two concurrent, randomized open-label at 2, 4, 8, 12, 16, and 24 wk after treatment initiation and every ART trials (see Texts S1 and S2 for trial details). Trial 1 was 12 wk thereafter. HIV-1 RNA (Roche Amplicor Monitor V1.5) conducted among 243 women who had ingested sdNVP $6 mo and CD4 were assessed at entry, then every 12 wk. Lipids (fasting prior to enrollment (results published [5]), and was designed to test or non-fasting) were evaluated at entry, 24, and 48 wk, then every the superiority of LPV/r over NVP due to the hypothesis that prior sdNVP exposure would result in persistent NVP drug A random subgroup of 126 pre-therapy samples were tested for resistance. Trial 2, described in this report, was conducted among HIV-1 drug resistance using the ViroSeq HIV-1 Genotyping 502 women without prior sdNVP exposure. Trial 2 was designed System (V2.0), with data analyzed using ViroSeq Genotyping to test the equivalence of LPV/r with NVP on the basis of the Software V2.7 (both Celera Diagnostics). In addition, pre-therapy PLoS Medicine June 2012 Volume 9 Issue 6 e1001236 LPV/r- Versus NVP-Based ART among Women in Africa and time-of-failure samples were tested from all patients experi- Board (DSMB), it was noted that the proportion of women encing virologic failure.
experiencing a primary endpoint might be lower than anticipated(14% versus anticipated 20% with median follow-up of 72 wk).
Protocol-Specified Toxicity Management The sample size was therefore increased to 500, which, with an ART was generally held in the event of potentially treatment- associated increase in expected median follow-up to 108 wk, was related grade $3 toxicity. However, more conservative toxicity expected to provide about 77% probability of completing the management was followed for suspected NVP or TDF toxicity.
study showing equivalence (95% CI for the primary endpoint HR Specifically, the presence of any of the following in combination entirely within the range 0.5–2.0) assuming no true difference with any rash (and no other clear explanation) required permanent between treatments.
discontinuation of NVP: systemic, allergic, or mucosal symptoms; Review by the DSMB occurred every 6–12 mo. The protocol or elevated ALT, AST, creatinine, or eosinophils. NVP was also stated that early termination of the trial for efficacy would permanently discontinued in participants experiencing grade $2 generally only be considered if equivalence was established to a elevations in ALT or AST (or with worsening of LFTs by $1 very high level of evidence, specifically a 99.9% CI unadjusted for grade in combination with hepatitis signs/symptoms). TDF was interim analyses within the narrow range of 0.75–1.33, or if a permanently discontinued if confirmed estimated creatinine difference between randomized arms was established with clearance decreased to ,50 ml/min, in absence of alternate cause.
substantial evidence, specifically a 99.9% CI excluding a HR of Women becoming pregnant after enrollment were continued on one; because trial 2 was not stopped early, standard 95% CIs can study treatment, with ZDV substituted for TDF during pregnancy therefore be used at the end of the study [6]. p-Values are two- unless a contraindication to ZDV existed.
sided, for the test of no difference between randomized treatments.
Statistical Analysis The primary endpoint was time to VF or death. VF was defined A total of 502 women (target 500) enrolled and were as plasma HIV-1 RNA,1 log10 copies/ml below baseline 12 wk randomized to NVP+TDF/FTC versus LPV/r+TDF/FTC from after treatment initiation, or HIV-1 RNA $400 copies/ml at$ November 2005–July 2008 (37–81 participants/site) (Figure 1).
24 wk after initiation; in both cases with confirmation by a Two women (in the NVP arm) never started study treatment and second measurement meeting the respective criterion.
were excluded from all analyses. Therefore, results from 500 The primary analysis was intention to treat, including all follow- women (249 randomized to receive NVP, 251 to LPV/r) were up irrespective of changes in ART (but excluded women failing to included. One participant had previously taken sdNVP but was start study treatment, per protocol). Trial 2 was designed to mistakenly enrolled (in the LPV/r arm); her data are included.
evaluate the equivalence of LPV/r- and NVP-based therapies:equivalence was to be established if the two-sided 95% CI for the Median age, CD4 count, and HIV-1 RNA at baseline were hazard ratio (HR) for VF/death was entirely within the range 0.5– 34 y, 121 cells/mm3, and 5.2 log10 copies/ml, respectively (Table 1), and were similar in both arms. Evidence (in addition The Kaplan-Meier method was used to describe the cumulative to self-report) for lack of prior exposure to sdNVP was available for proportion of participants experiencing VF or death by time. Cox 469 (94%) women (most commonly, no pregnancy or occurrence proportional hazards models, stratified by screening CD4 (,50 of pregnancy prior to local use of sdNVP [n = 272] or HIV versus $50 cells/mm3), were used to estimate the HR (95% CIs) of diagnosis after pregnancy [n = 168]). Seven (1%) women reported reaching an endpoint comparing arms.
prior ZDV for preventing mother-to-child transmission. Of the In secondary analysis, we also evaluated equivalence at each of random sample of 126 pre-therapy samples tested for HIV-1 drug week 48, 96, and 144 with respect to the absolute difference resistance (60 from the NVP and 66 from the LPV/r arms), between randomized treatments in the Kaplan-Meier estimate of baseline NVP resistance (K103N) was detected in only one (0.8%) the percentage of subjects reaching an endpoint by these times, on sample (Table 1). No nucleoside analog reverse-transcriptase the basis of the common definition that the 95% CI for the inhibitor (NRTI) or major protease-resistance mutations were absolute difference was entirely within the range 210% to +10%.
detected at baseline, although minor protease-resistance mutations Adjusted analyses were undertaken by including each of the were present in 100% of samples. Subtype C virus was found in 85 following variables in turn into the proportional hazards model, which also included randomized treatment: existence or not of 20 women (4%; 14 assigned to NVP and six to LPV/r) were lost written documentation of no prior sdNVP exposure, prior ZDV to follow-up without first experiencing a primary endpoint use, site, and baseline age, CD4 count, HIV-1 RNA, and WHO (p = 0.08). Nine additional women were lost to follow-up after stage. Subgroup analyses were undertaken by also including the experiencing VF (two in the NVP and seven in the LPV/r arms), treatment interaction with each of these variables in the model.
leading to overall loss to follow-up of 6%. The median duration of These variables were pre-specified in the analysis plan prior to the follow-up on initial assigned treatment was 109 wk (95 wk in the first interim analysis.
NVP and 119 wk in the LPV/r arms), and the overall median Discontinuation of initial assigned regimen was defined as duration of follow-up in the study was 118 wk. At each scheduled permanent discontinuation of either LPV/r or NVP. In secondary evaluation, completed adherence questionnaires were available for as-treated analysis, VF was considered to have occurred on the $78% of participants. Adherence to initial study treatment was randomized regimen only if the initial failing HIV-1 RNA lowest at week 24, when 84% of women reported not missing any measurement was obtained on or before the day of last dose of medications during the past month (88% versus 81% for the NVP the initial regimen. Analyses of adverse events (AEs) were and LPV/r arms). Adherence was 87%–92% at all other weeks.
restricted to the period during which participants received initialNVP or LPV/r. Linear regression was used to compare changes in Primary Endpoint: VF or Death, Intent-to-Treat Analysis CD4 count and lipids, adjusted for baseline count/level.
HIV-1 RNA results were available from 99.6% of 4,223 The original planned sample size for trial 2 was 400. During expected time points. 92 (18%) women either experienced VF or closed reviews by an independent Data and Safety Monitoring died without prior VF, including 42 (17%) assigned to NVP and PLoS Medicine June 2012 Volume 9 Issue 6 e1001236 LPV/r- Versus NVP-Based ART among Women in Africa Figure 1. Consort diagram. Per protocol, participants were not mandated to switch regimens in instances of VF (this decision was left to thediscretion of study staff and participants). More women experienced VF in the LPV/r arm (43 or 17%) compared with the NVP arm (37 or 15%) in ITTanalysis; however, a higher proportion of women experiencing VF in the NVP arm were switched to LPV/r compared with vice versa.
doi:10.1371/journal.pmed.1001236.g001 50 (20%) to LPV/r (HR 0.85, 95% CI 0.56–1.29, p = 0.43) arm who died, three deaths (due to acute renal failure, severe (Figure 2). This group included 37 (15%) and 43 (17%) women in gastroenteritis, and hepatic encephalopathy) were considered the NVP and LPV/r arms, respectively, who experienced VF; and possibly related to study treatment. The cause of death in the five (2%) and seven (3%) in the NVP and LPV/r arms, other five women in the LPV/r arm was gastroenteritis, respectively, who died without prior VF (one additional woman progressive HIV disease, central nervous system lymphoma, died following confirmed VF). There was no significant evidence bacterial septicemia, and unknown in one woman.
that the HR for the primary endpoint changed with increasing 19 (8%) of the women in the NVP arm experienced disease follow-up time (p = 0.58).
progression (to a higher WHO stage) or died, compared with 26 Based on the 95% CI for the HR (0.56–1.29), the NVP- and (10%) in the LPV/r arm (p = 0.30).
LPV/r-based regimens showed equivalent efficacy for theendpoint of VF or death according to the pre-specified criterion.
Adjusted and Subgroup Analyses The estimated percentage of women experiencing VF/death by The adjusted HRs for the primary endpoint comparing NVP- to week 48 was 14.3% with NVP and 13.7% with LPV/r (absolute LPV/r-based treatment in the whole study population varied difference = 0.6%). The associated 95% CI (25.5% to 6.8%) was between 0.83–0.86 (versus an unadjusted HR = 0.85) and the entirely within the range 210% to +10%. The corresponding associated 95% CIs all remained within the range 0.50–2.00.
results in the NVP and LPV/r arms, respectively, were 16.5% and Baseline HIV-1 RNA was the only tested variable that was 19.6% (difference: 23.1%; 95% CI 210.2% to 4.0%) at week 96, predictive of reaching a primary endpoint, after controlling for and 19.1% and 25.3% (difference: 26.2%; 95% CI 215.0% to randomized regimen (for each log10 copies/ml increase: HR 1.56, 2.7%) at week 144.
95% CI 1.07–2.28).
The primary cause of death in the five women in the NVP arm In subgroup analyses, the only significant finding (interaction was tuberculosis, pneumonia, acute renal failure, pulmonary p,0.05) was for CD4. Specifically, among women with CD4#100 embolus, and unknown (the last patient had headache and prior cells/mm3 (the median for participants reaching a primary renal failure and pleural effusion). The death from acute renal endpoint), 26 (27%) of 96 assigned to NVP versus 19 (21%) of failure (but no other deaths in the NVP arm) was deemed probably 90 assigned to LPV/r experienced a primary endpoint (HR 1.36, related to study treatment. Among the eight women in the LPV/r 95% CI 0.74–2.51). In contrast, for women with baseline PLoS Medicine June 2012 Volume 9 Issue 6 e1001236 LPV/r- Versus NVP-Based ART among Women in Africa Table 1. Selected characteristics of OCTANE trial 2 participants at baseline.
Statistics Categories Age at randomization (y) Median (P10, P90) Baseline CD4 count (cells/mm3) Median (P10, P90) HIV-1 RNA (log10 copies/ml) Median (P10, P90) 5.16 (4.16, $5.88) 5.15 (4.28, 5.82) 5.15 (4.21, 5.86) HIV-1 RNA (copies/ml) Clinical stage II Clinical stage III Clinical stage IV Hepatitis B surface antigen Not tested at entry Pre-entry ZDV (#10 wk) Participant's self-report of prior ingestion of sdNVP Supporting evidence for lack of prior sdNVP exposure Complex recombination Nevirapine resistance Percentages use number of participants with a result as the denominator.
aRace was collected as it could potentially be related to treatment response and was reported by the site investigators.
bAll women had screening CD4,200 cells/mm3, but at study entry, 58 women had CD4$200 cells/mm3.
doi:10.1371/journal.pmed.1001236.t001 CD4.100 cell/mm3, the numbers were 16 (11%) of 153 and 31 (n = 15). Among the 35 women discontinuing NVP due to AEs, 20 (19%) of 161, respectively (HR 0.55, 95% CI 0.30–1.01) (p = 0.034 did so following hepatic events, three following the development of for interaction).
both a hepatic event and a rash, and 12 following rashes (77% ofthese 35 women discontinued NVP during the first 8 wk on VF or Death, As-Treated Analysis treatment). For all 35 women, the site investigators considered the In the as-treated analysis, 30 (12%) women in the NVP arm and association of the AE to be potentially related to study treatment.
48 (19%) in the LPV/r arm experienced a primary endpoint (HR The reasons for discontinuation from LPV/r-based treatment 0.71, 95% CI 0.45–1.13). The proportions of women in the NVP included death (n = 8), VF (n = 4), and other reasons (n = 11); no versus LPV/r arms experiencing a primary endpoint in the as- women discontinued LPV/r due to an AE.
treated analysis were 12.2% versus 13.4% at 48 wk (difference: Therefore, more women discontinued NVP (compared with 21.2%; 95% CI 27.3% to 4.9%), 13.6% versus 18.8% at week 96 LPV/r) in first line, because of either VF or to an AE, despite (difference: 25.2%; 95% CI 212.2 to 1.9%), and 15.5% versus similar numbers of participants experiencing primary endpoints or 24.5% at week 144 (difference: 29.1%; 95% CI 217.8% to grade 3 or higher AEs in both arms (described below). Only four of the 43 women experiencing VF in the LPV/r arm discontinuedLPV/r for VF, compared with 15 of 37 women experiencing VF Discontinuation of NVP or LPV/r for Any Reason in the NVP arm. The decision of whether or not to switch a 93 women discontinued their initial randomized regimen— regimen when protocol-defined VF occurred was left to the site significantly more women in the NVP (70, 28%) compared with investigator and participant, who usually elected to intensify the LPV/r (23, 9%) arm (HR 3.45, 95% CI 2.15–5.52, p,0.001) adherence counseling and support and continue the initial regimen, with site clinicians being less likely to switch LPV/r The reasons for discontinuation from NVP-based treatment compared with NVP, following HIV-1 RNA.400 cp/ml occur- included death (n = 5), AEs (n = 35), VF (n = 15), and other reasons ring on treatment.
PLoS Medicine June 2012 Volume 9 Issue 6 e1001236 LPV/r- Versus NVP-Based ART among Women in Africa Figure 2. Kaplan-Meier plot of time to primary endpoint (VF or death) by randomized treatment arm.
doi:10.1371/journal.pmed.1001236.g002 More women also discontinued NVP (compared with LPV/r) Toxicity and Diagnoses Occurring during Initial Assigned because of a clinical or laboratory abnormality. As described below, more women in the NVP arm experienced rash and/or 75 (15%) of the 500 women experienced $grade 3 signs or liver test abnormality, and the protocol-mandated threshold for symptoms through the date of the last dose of initial study permanently discontinuing a study drug after the occurrence of treatment (Table 2): 34 (14%) in the NVP and 41 (16%) in the these events was lower in the NVP arm compared with the LPV/r LPV/r arms (seven and eight women, respectively, experienced grade 4 signs/symptoms). 64 (26%) women in the NVP versus 54 We also conducted a pre-specified analysis on the basis of a (22%) in the LPV/r arm experienced $grade 3 laboratory treatment failure composite endpoint, defined as time to the first of abnormalities. More women in the LPV/r arm had $grade 3 protocol-defined VF, death, or permanent discontinuation of elevation in creatinine (eight versus two), while more women in the initial randomized regimen. In this analysis, 80 (32%) of the 249 NVP arm had $grade 3 elevation in liver function tests (18 versus women randomized to NVP reached the composite endpoint nine). At 24, 48, and 96 wk after entry, participants in the LPV/r compared with 54 (22%) of the 251 women randomized to LPV/r arm experienced significantly greater increases in total cholesterol (HR 1.68, 95% CI 1.18–2.40). The occurrence of significantly and in low-density lipoprotein (LDL) (but smaller increases in more composite treatment failure endpoints among women in the high-density lipoprotein [HDL]) than participants in the NVP arm NVP arm was entirely due to a higher rate of treatment (while triglycerides increased in women in the LPV/r arm but discontinuation in the NVP arm (and not due to higher rates of decreased in women in the NVP arm) (Table 2).
VF or death).
25 women switched from NVP or LPV/r to EFV during rifampin-containing tuberculosis treatment, including 14 assigned Changes in CD4 Cell Count NVP and 11 assigned LPV/r. 47 women became pregnant during At least 98% of expected CD4 cell counts were obtained at each the study, including 21 assigned NVP and 26 assigned LPV/r scheduled measurement time. In intent-to-treat analyses, mean change in CD4 was 183 cells/mm3 in each arm at week 48(p = 0.99), 245 for NVP versus 279 cells/mm3 for LPV/r at week 96 (p = 0.045) and 303 for NVP versus 345 cells/mm3 for LPV/r HIV-1 drug resistance testing was attempted on samples from at week 144 (p = 0.15).
pre-therapy and failure time points among the 80 participants PLoS Medicine June 2012 Volume 9 Issue 6 e1001236 LPV/r- Versus NVP-Based ART among Women in Africa Figure 3. Kaplan-Meier plot of time to early discontinuation of initial randomized treatment for any reason (toxicity, intolerance,VF, death), by randomized treatment arm.
doi:10.1371/journal.pmed.1001236.g003 experiencing VF, with genotypes available for 69 baseline-failure LPV/r arm (HR 0.71, 95% CI 0.45–1.13). However, significantly pairs (Table 3). Genotypes from time of VF revealed that 13 (45%) more women discontinued NVP than LPV/r (28% versus 9%, of 29 women in NVP arm and six (15%) of 40 women in the LPV/ p,0.001) including 14% versus none due to AEs. Consequently, r arm had any resistance mutation (excluding minor PI mutations).
analysis of overall regimen failure (VF, death, or discontinuation 13 (45%) women in the NVP versus three (8%) women in the due to AEs) revealed lower rates of these combined endpoints in LPV/r arm had $1 non-NRTI (NNRTI)-associated mutation at the LPV/r arm. The proportions of women experiencing $grade VF, and nine (31%) versus five (13%) (respectively) had NRTI- 3 signs, symptoms, or laboratory abnormalities did not differ associated mutations (most often K65R and M184V). New significantly between arms, but total cholesterol and triglyceride (compared to pre-therapy) minor protease mutations were increases were significantly larger in the LPV/r arm. Therefore, detected in five participants (two in the NVP and three in the the higher rate of permanent discontinuation of NVP was LPV/r arms); no major PI mutations were found.
primarily driven by protocol-mandated thresholds for permanentdiscontinuation of NVP compared with LPV/r, rather than higher rates of severe or life-threatening toxicities in the NVP arm.
Overall, these data support the WHO recommendation of NVP/ Among African treatment-naı¨ve women with CD4 count ,200 TDF/FTC as an initial affordable and effective HIV treatment cells/mm3, initial ART with NVP+TDF/FTC showed equivalent regimen in RLS, and provide reassurance regarding the efficacy of efficacy compared with LPV/r+TDF/FTC in intention-to-treat this regimen. However, these results also underscore the impor- analysis of the primary endpoint of VF or death (83% versus 80% tance of early toxicity monitoring with NVP-based regimens. The of women were alive and had not experienced VF after a median treatment failure (due to VF or treatment discontinuation) follow-up of more than 2 y; HR 0.85, 95% CI 0.56–1.29, which observed in both arms also highlights the importance of access was within the pre-specified range of equivalence from 0.5 to 2.0).
to effective second treatment options, as well as consideration of Equivalence was not established in the as-treated analysis, with other effective, better-tolerated first-line regimens (including lower rates of VF/death in the NVP arm compared with the among women of reproductive potential).
PLoS Medicine June 2012 Volume 9 Issue 6 e1001236 LPV/r- Versus NVP-Based ART among Women in Africa Table 2. Signs/symptoms, laboratory abnormalities, diagnoses, and lipid results among participants on their first randomizedtreatment regimens.
NVP Arm (n = 249) LPV/r Arm (n = 251) Unadjusted p-Value Grade 3 or higher sign or symptom: General body (pain, fatigue, weight loss, fever) Gastrointestinal (diarrhea, nausea/vomiting) Grade 3 or higher laboratory abnormality: Chemistry (any abnormality) Alkaline phosphatase Liver/hepatic (any abnormality)a Hematology (any abnormality) Absolute neutrophil count Number of participants with new diagnoses Number of participants with pregnancy on-study Change in lipids from baseline to 48 wk(mg/dl; standard error) Total cholesterol Subcolumns may not add up to total number of signs/symptoms or laboratory abnormalities, as participants can experience more than one event.
aIn the NVP and LPV/r arms, respectively, three and 12 participants experienced grade 2 or higher creatinine elevation, and 34 and 19 of participants experienced grade2 or higher liver test abnormalities.
HDL, high-density lipoprotein; LDL, low-density lipoprotein; SGOT, serum glutamic oxaloacetic transaminase; SGPT, serum glutamic pyruvic transaminase.
doi:10.1371/journal.pmed.1001236.t002 The overall and relative efficacy and toxicity of NVP-based one of only a small number of studies to compare the efficacy of versus PI-based ART are relevant in RLS. Globally, NVP is the ART using NVP versus any boosted PI [7,8]. This is also one of most frequently used antiretroviral in combination with two the largest randomized treatment trials to be conducted in HIV- NRTIs, due primarily to its low cost, lack of teratogenicity, and infected women, who may experience different toxicities or heat stability; and regimens including TDF+NVP (with either response compared with men, but who are often underrepre- 3TC or FTC) are recommended by the WHO and increasingly sented in trials. In one previous study (‘‘ARTEN'' [8]), 569 used [1]. However, prior small studies of first-line ART treatment-naive patients were randomized to initiate NVP or composed of NVP+TDF/FTC demonstrated rather high rates atazanavir/ritonavir, each in combination with Truvada.
of early VF on this regimen, raising concern about its use [2,3].
Similar proportions achieved virologic suppression with both If LPV/r were found to be significantly more (or more durably) treatments, although more patients stopped treatment due to potent or less toxic than NVP in first-line treatment, then it AEs in the NVP (14%) than the atazanavir (4%) arm [8]. These could potentially represent a cost-effective choice for initial findings are qualitatively similar to the OCTANE Trial 2 regimen in RLS (as reported in a previous cost-effectiveness results, but are in contrast to those of an observational analysis comparing these regimens among women with prior European study, in which patients were more likely to stop sdNVP exposure [4]), although this has yet to be modeled in first-line NVP because of treatment failure but less likely to do ARV-naive patients. To our knowledge, this is the first direct so because of toxicity or patient/provider choice, compared comparison of the efficacy of NVP- and LPV/r-based ART, and with EFV or LPV/r [7].
PLoS Medicine June 2012 Volume 9 Issue 6 e1001236 LPV/r- Versus NVP-Based ART among Women in Africa Table 3. Summary of drug resistance mutations at time of virologic failure.
n (%) NVP Arm, n = 37a n (%) LPV/r Arm, n = 43 Samples with VF events Genotype available at VF No sample available for testing No sequence available (unable to amplify) Samples with any mutation Samples with NRTI-associated mutations Samples with NVP or EFV mutations Samples with any new protease mutations Major protease mutations Minor protease mutationsb Samples with .1 NRTI mutation Samples with .1 NNRTI mutation Samples with $1 NRTI+$1 NNRTI mutation aPercent mutation per treatment arm calculated as the number of patients with mutation divided by number of patients with genotype results available.
bNew minor protease-resistance mutations detected for NVP arm were L10I/V and L63P and for LPV/r arm were K20R and K20M (data not shown).
doi:10.1371/journal.pmed.1001236.t003 Genotype analysis in our study of samples at the time of failure higher versus lower CD4 counts) identified would not be revealed NNRTI- or NRTI-resistance mutations in nearly one- significant with adjustment for multiple comparisons and so could half of women in the NVP arm. This frequency of resistance is plausibly be a chance finding. We could not compare long-term lower than that reported in other studies of failure of initial therapy morbidity and mortality between regimens because of the study [9–11], and may be related to more rapid regimen switch (in the duration. This was an open-label trial, and the lack of blinding context of careful HIV-1 RNA monitoring) or to premature constitutes another potential limitation. Finally, patient outcomes discontinuation of therapy for suspected toxicity. In the LPV/r in a closely monitored clinical trial setting, including ramifications arm, major PI resistance mutations were not detected at failure of toxicity, may be better than those expected in a routine (similar to findings from other studies of LPV/r [9,12]), and treatment setting in RLS.
NRTI-associated mutations were less frequent (13%) than in the We conclude that in antiretroviral-naı¨ve women with CD4 NVP arm (31%). The occurrence of the K65R mutation in 28% of count ,200 cells/mm3, initial ART with LPV/r/TDF/FTC and participants failing NVP+TDF/FTC is notable. These resistance with NVP+TDF/FTC is equivalent in achieving and maintaining findings have implications for selection of first-line and subsequent virologic suppression and preventing mortality, but that treatment ART regimens to optimize long-term clinical outcomes and cessation due to toxicity concerns, and drug resistance at the time reduce spread of drug resistance.
of VF, are higher with NVP-based ART. Our findings suggest that Strengths of our study included its randomized nature and very NVP (with careful early toxicity monitoring) remains an accept- high visit and data completeness. Limitations include the able choice for first-line ART in RLS, until better tolerated and possibility that some participants may have had previous sdNVP potentially more efficacious regimens become accessible.
exposure. However, the accuracy of our sdNVP exposureascertainment is supported by a low rate (0.8%) of baseline NVP Supporting Information resistance, and by results from trial 1 (which demonstrated higher Trial protocol.
rates of VF/death with NVP versus LPV/r treatment among women with prior sdNVP exposure [5]). Subgroup analyses needto be interpreted with caution given the number of subgroup CONSORT checklist.
analyses considered; the one difference (between women with PLoS Medicine June 2012 Volume 9 Issue 6 e1001236 LPV/r- Versus NVP-Based ART among Women in Africa Data and Safety Monitoring BoardWe would also like to acknowledge the Data and Safety Monitoring We would like to acknowledge the study participants, and the following Board members (who were not members of the A5208/OCTANE study members of the OCTANE (Optimal Combination Therapy After team, with the exception of Tsungai Chipato): Susan S. Ellenberg (Chair), Nevirapine Exposure) ACTG A5208/OCTANE Study Team: Francesca Rena G. Boss-Victoria, Tsungai Chipato, Alex Dodoo, Jerrold Ellner, Conradie, Elizabeth Dangaiso, Elizabeth Stringer, Abraham Siika, Kara Scott Emerson, David Harrington, Anatoli Kamali, Elly Tebasoboke Wools-Kaloustian, Eva Purcelle-Smith, Ann Walawander, Apsara Nair, Katabira, Carl Jacobus Lombard, Chewe Luo, Mary Faith Marshall, Beth Zwickl, Cissy Kityo Mutuluuza, Sandra Rwambuya, Christine Joseph Mfutso-Bengo, Lucky Mokgatlhe, Peter Mwaba, Alwyn Mwinga, Kaseba, Charles Maponga, Heather Watts, Daniel Kuritzkes, Thomas B.
Andrew Nunn, Haroon Saloojee, Merle Sande, Johannes Feuth Schoe- Campbell, Lynn Kidd-Freeman, Monica Carten, Jane Hitti, Mary man, Jerome Amir Singh, as well as DAIDS Liaisons for the DSMB Marovich, Peter Mugyenyi, Sandra Rwambuya, Ian Sanne, Beverly Sandra Lehrman and Rebecca DerSimonian.
Putnam, Cheryl Marcus, Carolyn Wester, Robin DiFrancesco, AnnieBeddison, Sandra Lehrman, Francesca Aweeka, Betty Dong, Peter Author Contributions Ndhleni Ziba, Michael Saag, William Holmes, Scott Hammer, CharityPotani, Regina Mwausegha, Fatima Laher, Reinet Hen-Boisen, Agnes Conceived and designed the experiments: SL MHu FSa JMc TC AA DS Nzioka, Evans Moko, Farida Amod, Umesh Lalloo, Sandy Pillay, Apsara MHo LM FA EHa BAS RS JMe JC. Analyzed the data: MHu EZ. Wrote Nair, Laura M. Smith, James Tutko, Christine Lee, Eva Purcelle Smith, the first draft of the manuscript: SL. Contributed to the writing of themanuscript: SL MHu EHo JMe JC. Elaine Ferguson, Ana Martinez, Yvette Delph, Nikki Gettinger, Linda Berman, Linda Boone, Bola Adedeji.
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Ciaranello AL, Lockman S, Freedberg KA, Hughes M, Chu J, et al. (2011) First- 10. Orrell C, Walensky RP, Losina E, Pitt J, Freedberg KA, et al. (2009) HIV type-1 line antiretroviral therapy after single-dose nevirapine exposure in South Africa: clade C resistance genotypes in treatment-naive patients and after firstvirological failure in a large community antiretroviral therapy programme.
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PLoS Medicine June 2012 Volume 9 Issue 6 e1001236 LPV/r- Versus NVP-Based ART among Women in Africa Background. About 34 million people (mostly living in low- During the initial assigned treatment, similar proportions of or middle-income countries) are currently infected with HIV, women in both treatment arms developed serious drug- the virus that causes AIDS. HIV destroys CD4 lymphocytes related signs and symptoms and laboratory abnormalities.
and other immune cells, leaving infected individuals suscep- However, whereas 14% of the women in the NVP arm tible to other infections. Early in the AIDS epidemic, most discontinued treatment because of adverse effects, none of HIV-infected people died within 10 years of infection. Then, the women in the LPV/r arm discontinued treatment. Finally, in 1996, antiretroviral therapy (ART)—cocktails of drugs that nearly half of the women tested in the NVP arm but only 15% attack different parts of HIV—became available. For people of the women tested in the LVP/r arm had developed any living in affluent countries, HIV/AIDS became a chronic drug resistance at the time of virologic failure.
condition. But, because ART was expensive, for people livingin developing countries, HIV/AIDS remained a fatal illness. In What Do These Findings Mean? These findings indicate 2006, the international community set a target of achieving that, among HIV-infected, treatment-naı¨ve African women, universal access to ART by 2010 and, although this target has initial NVP-based ART is as effective as LPV/r-based ART in not been reached, by the end of 2010, 6.6 million of the terms of virologic failure and death although more women in estimated 15 million people in need of ART in developing the NVP arm discontinued treatment or developed new drug countries were receiving one of the ART regimens recom- resistance than in the LPV/r arm. Several limitations of this mended by the World Health Organization (WHO) in its 2010 study may affect the accuracy of these findings. In particular, some of the study participants may have been exposed tosingle-dose NVP during childbirth to prevent mother-to-child Why Was This Study Done? A widely used combination transmission of HIV; in a parallel randomized trial, the for the initial treatment of HIV-infected people (particularly researchers found that LPV/r-based ART was superior to NVP- women) in resource-limited settings is tenofovir and based ART among women with prior exposure to single- emtricitabine (both nucleotide reverse transcriptase inhibi- dose NVP. Moreover, the duration of the current study tors; reverse transcriptase is essential for HIV replication) and means the long-term effects of the two treatments cannot nevirapine (NVP, a non-nucleoside reverse transcriptase be compared. Nevertheless, these findings support the WHO inhibitor). However, little is known about the efficacy of this recommendation of NVP-based ART with careful early NVP-based ART combination. Moreover, its efficacy and toxicity monitoring as an initial affordable and effective HIV toxicity has not been compared with regimens containing treatment regiment in resource-limited settings, until access lopinavir/ritonavir (LPV/r). LPV/r, which inhibits the viral to better-tolerated and more potent regimens is possible.
protease that is essential for HIV replication, is available inresource-limited settings but is usually reserved for second- Additional Information. Please access these Web sites via line treatment. LPV/r-based ART is more expensive than NVP- the online version of this summary at
based ART but if it were more effective or better tolerated than NVP-based ART, then first-line treatment with LPV/r-based ART might be cost-effective in resource-limited N Information is available from the US National Institute of settings. Conversely, evidence of the clinical equivalence of Allergy and Infectious Diseases on all aspects of HIV NVP-based and LPV/r-based ART would provide support for infection and AIDS NVP-based ART as an initial therapy. In this randomized N NAM/aidsmap provides basic information about HIV/AIDS, equivalence trial, the researchers compare the efficacy and and summaries of recent research findings on HIV care and toxicity of NVP-based and LVP/r-based initial therapy for HIV treatment (in several languages) infection among antiretroviral-naı¨ve African women. In a N Information is available from Avert, an international AIDS randomized trial, patients are assigned different treatments charity on many aspects of HIV/AIDS, including detailed by the play of chance and followed to compare the effects of information on HIV treatment and care (in English and these treatments; an equivalence trial asks whether the effects of two treatments are statistically equivalent.
N WHO provides information about universal access to AIDS treatment (in English, French and Spanish); its 2010 ART What Did the Researchers Do and Find? The researchers guidelines can be downloaded followed 500 antiretroviral-naı¨ve HIV-infected women with alow CD4 cell count living in seven African countries, half of N More information about this trial, the OCTANE trial, is whom received NVP-based ART and half of whom received LPV/r-based ART, for an average of 118 weeks and recorded N MedlinePlus provides detailed information about the time to virologic failure (the presence of virus in the nevirapine and lopinavir/ritinovir (in English and Spanish) blood above pre-specified levels) or death among the N Patient stories about living with HIV/AIDS are available participants. Forty-two women in the NVP arm reached this through Avert; the nonprofit website Healthtalkonline also primary endpoint (37 virologic failures and five deaths) provides personal stories about living with HIV, including compared to 50 women in the LPV/r arm (43 virologic stories about taking anti-HIV drugs and the challenges of failures and seven deaths), a result that indicates equivalent virologic efficacy according to preset statistical criteria.
PLoS Medicine June 2012 Volume 9 Issue 6 e1001236


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ROYAUME DU MAROC Université Mohammed V -Agdal Faculté des Sciences Juridiques, Economiques et Sociales CAHIER DES PRESCRIPTIONS SPECIALES (CPS) Appel d'offres ouvert sur offres de prix N° 03/2013 (lot unique) (Séance publique) OBJET: Achat et Installation de Matériel Informatique et de Logiciels Destinataire: Faculté des Sciences Juridiques, Economiques et Sociales Rabat-Agdal

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