Efficacy and safety of three antiretroviral regimens for initial treatment of HIV-1: a randomized clinical trial in diverse multinational settings.

TitleEfficacy and safety of three antiretroviral regimens for initial treatment of HIV-1: a randomized clinical trial in diverse multinational settings.
Publication TypeJournal Article
Year of Publication2012
AuthorsCampbell TB, Smeaton LM, Kumarasamy N, Flanigan T, Klingman KL, Firnhaber C, Grinsztejn B, Hosseinipour MC, Kumwenda J, Lalloo U, Riviere C, Sanchez J, Melo M, Supparatpinyo K, Tripathy S, Martinez AI, Nair A, Walawander A, Moran L, Chen Y, Snowden W, Rooney JF, Uy J, Schooley RT, De Gruttola V, Hakim JGita
Corporate AuthorsPEARLS study team of the ACTG
JournalPLoS Med
Volume9
Issue8
Paginatione1001290
Date Published2012
ISSN1549-1676
KeywordsAnti-HIV Agents, Antiretroviral Therapy, Highly Active, Coinfection, Drug Therapy, Combination, Female, Follow-Up Studies, HIV Infections, HIV-1, Humans, Internationality, Male, Mycobacterium tuberculosis, Pregnancy, Time Factors, Treatment Outcome, Withholding Treatment
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: www.ClinicalTrials.gov NCT00084136. Please see later in the article for the Editors' Summary.

DOI10.1371/journal.pmed.1001290
Alternate JournalPLoS Med.
PubMed ID22936892
PubMed Central IDPMC3419182
Grant ListA1069424 / / PHS HHS / United States
A1069432 / / PHS HHS / United States
A1069467 / / PHS HHS / United States
A1069472 / / PHS HHS / United States
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