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

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.

Figure 1. Flow diagram for participant outcomes.

The outcomes of all participants randomized to the three arms are provided. The most common prior antiretroviral exposure was for prevention of mother-to-child transmission of HIV-1 with either ZDV monotherapy (19 women; median duration 32 d; intraquartile range 30–60 d) or a single dose of nevirapine in the peripartum period (16 women). Continuous variable values are the median for the treatment arm. Creatinine clearance was calculated by Crockoft-Gault equation. Follow-up visits were conducted for 1,571 participants. ATV plus FTC and DDI follow-up was terminated on 22 May 2008 in response to the DSMB recommendation and comparison of ATV plus FTC and DDI to EFV plus 3TC-ZDV used data available up to the time of the ATV arm closure (red box); median follow-up 81 wk. Comparison of EFV plus FTC-TDF to EFV plus 3TC-ZDV used all follow-up data for participants in these arms through 31 May 2010 (green box); median follow-up 184 wk.

Figure 2. Efficacy and safety of randomized study treatment over time.

(A–H) black circles, EFV plus 3TC-ZDV; red triangles, ATV plus DDI-EC and FTC; green squares, EFV plus FTC-TDF. (A–B) Estimated cumulative probability of antiretroviral regimen failure defined by the protocol-specified primary efficacy endpoint: comparison of EFV plus 3TC-ZDV to ATV plus FTC and DDI (A) and EFV plus FTC-TDF (B). (C–D) Proportion of participants with plasma HIV-1 RNA less than 400 copies/ml for comparison of EFV plus 3TC-ZDV to ATV plus FTC and DDI (C) and EFV plus FTC-TDF (D). These comparisons included all randomized study participants according to assigned study treatment. The analysis that counted missing values as greater than 400 copies/ml (open symbols) is truncated at the maximum potential duration of study follow-up for participants who entered the study at the end of the enrollment period (144 wk). (E–F) Median change in CD4+ lymphocyte count from screening value over time for comparison of EFV plus 3TC-ZDV to ATV plus FTC and DDI (E) and EFV plus FTC-TDF (F). (G–H) Estimated cumulative probability a safety endpoint over time for comparison of EFV plus 3TC-ZDV to ATV plus FTC and DDI (G) and EFV plus FTC-TDF (H). For (A–D, G and H), bars represent the 95% CI for the estimate. For (E–F), bars represent the interquartile range. (A–H) The number of evaluable participants at each time point is provided for each randomized treatment assignment.

Figure 3. Subgroup analysis for primary efficacy and safety endpoints by randomly assigned antiretroviral treatment.

Subgroup analyses were conducted for the baseline covariates self-reported sex and race/ethnicity and the countries in which the participating research sites were located. The relative risk and 95% CIs are provided for all participants (overall) and for each subgroup. p-Value represents interaction test between baseline covariate and randomized treatment group. Comparisons between ATV plus DDI and FTC and EFV plus 3TC-ZDV are in red. Comparisons between EFV plus FTC-TDF and EFV plus 3TC-ZDV are in green. (A) Treatment failure (efficacy) composite endpoint. (B) Safety events composite endpoint.