Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings

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  • Campbell, T.B.
    • Other Affiliation: University of Colorado School of Medicine
  • Smeaton, L.M.
    • Other Affiliation: Harvard School of Public Health
  • Kumarasamy, N.
    • Other Affiliation: YRG Centre for AIDS Research and Education
  • Flanigan, T.
    • Other Affiliation: Brown Medical School
  • Klingman, K.L.
    • Other Affiliation: National Institutes of Health
  • Firnhaber, C.
    • Other Affiliation: University of the Witwatersrand
  • Grinsztejn, B.
    • Other Affiliation: Evandro Chagas Clinical Research Institute
  • Hosseinipour, M.C.
    • Other Affiliation: Kamuzu Central Hospital
  • Kumwenda, J.
    • Other Affiliation: College of Medicine
  • Lalloo, U.
    • Other Affiliation: Nelson R. Mandela School of Medicine
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    • Other Affiliation: Institut Nacional de laboratoire et de Recherches
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    • Other Affiliation: Asociacion Civil Impacta Salud y Educacion
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    • Other Affiliation: Hospital Nossa Senhora da Conceicao-GHC
  • Supparatpinyo, K.
    • Other Affiliation: Chiang Mai University
  • Tripathy, S.
    • Other Affiliation: National AIDS Research Institute
  • Martinez, A.I.
    • Other Affiliation: National Institutes of Health
  • Nair, A.
    • Other Affiliation: Frontier Science and Technology Research Foundation
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    • Other Affiliation: Frontier Science and Technology Research Foundation
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    • Other Affiliation: Social and Scientific Systems, Inc
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    • Other Affiliation: Bristol-Myers Squibb Company
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    • Other Affiliation: University of California San Diego
  • de Gruttola, V.
    • Other Affiliation: Harvard School of Public Health
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    • Other Affiliation: University of Zimbabwe College of Health Sciences
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    • Other Affiliation: NIH
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    • Other Affiliation: UCLA CARE Center
  • Eshleman, S.
    • Other Affiliation: Johns Hopkins University
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    • Other Affiliation: Harvard Medical School
  • Fiscus, S.A.
    • Other Affiliation: Department of Microbiology and Immunology
  • Andrade, A.
    • Other Affiliation: John Hopkins University
  • Haas, D.W.
    • Other Affiliation: Vanderbilt University
  • Amod, F.
    • Other Affiliation: Nelson R Mandela School of Medicine
  • Berthaud, V.
    • Other Affiliation: Vanderbilt University Medical Centre
  • Bollinger, R.C.
    • Other Affiliation: John Hopkins University
  • Bryson, Y.
    • Other Affiliation: UCLA School of Medicine
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    • Other Affiliation: Johns Hopkins School of Hygiene and Public Health
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  • Cohen, M.
    • Affiliation: University of North Carolina at Chapel Hill
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    • Other Affiliation: University of Washington
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    • Other Affiliation: University of California, Los Angeles
  • Cu-Uvin, S.
    • Other Affiliation: The Miriam Hospital, Brown University
  • Eron, J.
    • Affiliation: School of Medicine, Division of Infectious Diseases
  • Flexner, C.
    • Other Affiliation: Johns Hopkins University Hospital
  • Gallant, J.E.
    • Other Affiliation: Johns Hopkins University School of Medicine
  • Gulick, R.M.
    • Other Affiliation: The Cornell Clinical Trials Unit
  • Hammer, S.M.
    • Other Affiliation: Columbia Presbyterian Medical Centre
  • Hoffman, I.
    • Affiliation: University of North Carolina at Chapel Hill
  • Kazembe, P.
    • Other Affiliation: Baylor College of Medicine-Abbott Fund Childrens Clinical Centre of Excellence
  • Kumwenda, N.
    • Other Affiliation: Johns Hopkins Project, Malawi
  • Lama, J.R.
    • Other Affiliation: Investigaciones Medicas en Salud (INMENSA)
  • Lawrence, J.
    • Other Affiliation: University of California, San Francisco
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    • Other Affiliation: Medical University of Zimbabwe
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  • Mayer, K.
    • Other Affiliation: Brown University School of Medicine
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    • Other Affiliation: UCLA School of Medicine
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    • Other Affiliation: Brown University Medical School
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    • Other Affiliation: University of Witwatersrand
  • Severe, P.
    • Other Affiliation: Institute de Laboratories et de Recherches
  • Sirisanthana, T.
    • Other Affiliation: Chiang Mai University
  • Solomon, S.
    • Other Affiliation: YRG Centre for AIDS Research and Education
  • Tabet, S.
    • Other Affiliation: University of Washington, Harborview Medical Centre
  • Taha, T.
    • Other Affiliation: Johns Hopkins University, School of Hygiene and Public Health
  • van der Horst, C.
    • Affiliation: School of Medicine, Department of Medicine
  • Wanke, C.
    • Other Affiliation: Tufts University School of Medicine
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    • Other Affiliation: The Miriam Hospital, Immunology Centre
  • Marcus, C.J.
    • Affiliation: University of North Carolina at Chapel Hill
  • Putnam, B.
    • Other Affiliation: University of Colorado Health Sciences
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  • Loeliger, E.
    • Other Affiliation: Clinical Development and Medical Affairs
  • Pappa, K.A.
    • Other Affiliation: GlaxoSmithKline
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    • Other Affiliation: University of Colorado Health Sciences
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    • Other Affiliation: Stanford University Medical Center
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    • Other Affiliation: Gilead Sciences
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  • Cheng, A.
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    • Other Affiliation: YRG Centre for AIDS Research and Education
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    • Other Affiliation: YRG Centre for AIDS Research and Education
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    • Other Affiliation: Instituto de Pesquisa Clinica Evandro Chagas-Fiocruz
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    • Other Affiliation: Instituto de Pesquisa Clinica Evandro Chagas-Fiocruz
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    • Other Affiliation: College of Medicine, Blantyre, Malawi
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  • Mngqibisa, R.
    • Other Affiliation: Nelson Mandela School of Medicine
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    • Other Affiliation: Kamuzu Central Hospital
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    • Other Affiliation: Kamuzu Central Hospital
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    • Other Affiliation: University of Zimbabwe College of Health Sciences
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    • Other Affiliation: Hospital Conceicao
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    • Other Affiliation: Hospital Conceicao
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    • Other Affiliation: National AIDS Research Institute
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    • Other Affiliation: Asociacion Civil Impacta Salud y Educacion - Miraflores
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    • Other Affiliation: Investigaciones Medicas en Salud - INMENSA
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    • Other Affiliation: UT Southwestern Medical Center at Dallas
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    • Other Affiliation: NARI Clinic at Gadikhana Dr. Kotnis Municipal Dispensary
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  • Ray, M.G.
    • Other Affiliation: University of Colorado Hospital
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    • Other Affiliation: The Ohio State University
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    • Other Affiliation: The Ohio State University
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    • Other Affiliation: Northwestern University
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    • Other Affiliation: Northwestern University
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    • Other Affiliation: University of Minnesota, Minneapolis
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    • Other Affiliation: University of Minnesota, Minneapolis
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    • Other Affiliation: Washington University
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    • Other Affiliation: Duke University Medical Center
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    • Other Affiliation: Duke University Medical Center
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    • Other Affiliation: Beth Israel Medical Center
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    • Other Affiliation: Beth Israel Medical Center
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    • Other Affiliation: The Miriam Hospital
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    • Other Affiliation: University of Southern California
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    • Other Affiliation: Harbor-UCLA
  • Lopez, R.
    • Other Affiliation: Harbor-UCLA
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    • Affiliation: University of North Carolina at Chapel Hill
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    • Affiliation: University of North Carolina at Chapel Hill
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    • Other Affiliation: Vanderbilt University
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    • Other Affiliation: Hospital of the University of Pennsylvania
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    • Other Affiliation: Columbia University
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    • Other Affiliation: Hospital of the University of Pennsylvania
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    • Other Affiliation: Columbia University
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    • Other Affiliation: Columbia University
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    • Other Affiliation: Rush University Medical Center
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    • Other Affiliation: Rush University Medical Center
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    • Other Affiliation: New York University/NYC HHC at Bellevue Hospital Center
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    • Other Affiliation: New York University/NYC HHC at Bellevue Hospital Center
  • OBrien, W.A.
    • Other Affiliation: The University of Texas Medical Branch
  • Mogridge, C.
    • Other Affiliation: The University of Texas Medical Branch
  • Hurley, C.
    • Other Affiliation: Georgetown University
  • Corales, R.
    • Other Affiliation: Georgetown University
  • Palmer, M.
    • Other Affiliation: UCLA CARE Center
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    • Other Affiliation: University of Rochester
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    • Other Affiliation: University of Rochester
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    • Other Affiliation: Cornell University
  • Stroberg, T.
    • Other Affiliation: Cornell University
Abstract
  • Background:Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world.Methods and Findings:1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure.An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72-1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54-0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39-0.64 for women; HR 0.79, CI 0.62-1.00 for men; p = 0.01). Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12-2.04; p = 0.007).Conclusion: EFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are advantageous for use of this regimen for initial treatment of HIV-1 infection in resource-limited countries. ATV+DDI+FTC had inferior efficacy and is not recommended as an initial antiretroviral regimen.Trial Registration:http://www.ClinicalTrials.gov NCT00084136.
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  • Article
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  • In Copyright
Journal title
  • PLoS Medicine
Journal volume
  • 9
Journal issue
  • 8
Language
  • English
ISSN
  • 1549-1277
Publisher
  • Public Library of Science

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