Integrase inhibitor versus protease inhibitor based regimen for HIV-1 infected women (WAVES): a randomised, controlled, double-blind, phase 3 study

Abstract

Background: Women are under-represented in HIV antiretroviral therapy (ART) studies. Guidelines for selection of ART as initial therapy in patients with HIV-1 infection do not contain sex-specific treatment. We aimed to assess the safety and efficacy of the single tablet integrase inhibitor regimen containing elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate compared with a boosted protease inhibitor regimen of ritonavir-boosted atazanavir with emtricitabine and tenofovir disoproxil fumarate.

Methods: In this international, randomised, controlled, double-blind, phase 3 study (Women AntiretroViral Efficacy and Safety study [WAVES]), we recruited treatment-naive HIV-infected women with an estimated creatinine clearance of 70 mL/min or higher from 80 centres in 11 countries. Women were randomly assigned (1:1) to receive elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (integrase inhibitor regimen) or ritonavir-boosted atazanavir with emtricitabine and tenofovir disoproxil fumarate (protease inhibitor based regimen); regimens were masked with matching placebos. Randomisation was done by a computer-generated allocation sequence (block size four) and was stratified by HIV-1 RNA viral load and race. Investigators, patients, study staff, and those assessing outcomes were masked to treatment group. All participants who received one dose of study drug were included in the primary efficacy and safety analyses. The main outcome was the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48 as defined by US Food and Drug Administration snapshot algorithm (prespecified non-inferiority margin of 12%). This study is registered with ClinicalTrials.gov, number NCT01705574.

Findings: Between Nov 28, 2012, and March 12, 2014, 575 women were enrolled. 289 were randomly assigned to receive the integrase inhibitor regimen and 286 to receive the protease inhibitor based regimen. 252 (87%) women in the integrase inhibitor group had plasma HIV-1 RNA less than 50 copies per mL at week 48 compared with 231 (81%) women in the protease inhibitor group (adjusted difference 6·5%; 95% CI 0·4-12·6). No participant had virological failure with resistance in the integrase inhibitor group compared with three participants ([1%]; all Met184Val/Ile) in the protease inhibitor group. 19 women in the protease inhibitor group discontinued because of adverse events compared with five in the integrase inhibitor group.

Interpretation: WAVES shows that clinical trials of ART regimens in global and diverse populations of treatment-naive women are possible. The findings support guidelines recommending integrase inhibitor based regimens in first-line antiretroviral therapy.

Funding: Gilead Sciences.

Copyright © 2016 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Trial profile

Study participants could have more than one reason for exclusion. Integrase inhibitor regimen was elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate and protease inhibitor based regimen was ritonavir-boosted atazanavir with emtricitabine and tenofovir disoproxil fumarate.

Figure 2. Efficacy data up to week 48

(A) Proportion of participants who were responders (HIV-1 RNA viral load of less than 50 copies per mL at week 48, according to the US Food and Drug Administration snapshot algorithm), had virological failure, or had no virological data. (B) Proportion of participants with HIV-1 RNA load of less than 50 copies per mL according to study visit through to week 48. (C) Difference in response rates in the subgroups from the intention-to-treat population; all comparisons are represented as adjusted differences in proportion (integrase inhibitor regimen minus the protease inhibitor based regimen); 95% CIs calculated after adjustment by baseline HIV-1 RNA and race strata. (D) shows the proportion of participants who are responders by regions by treatment group. *Data not calculable in subgroup CD4 count 350 cells per μL or greater due to imbalance in race and viral load distribution in the subgroup. †Statistical significance (p=0·0072).