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

doi:10.1016/S2352-3018(16)30016-9

The Lancet HIV

Volume 3, Issue 9, September 2016, Pages e410-e420

https://doi.org/10.1016/S2352-3018(16)30016-9 Get rights and content

Summary

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.

Introduction

Half of the cases of HIV worldwide are in women, and the number of women acquiring HIV infection continues to rise.¹ Research guidelines have long advocated for sex-based assessment of drug efficacy, toxicity, and tolerability profiles;2, 3 but women continue to be under-represented in clinical trials assessing efficacy and safety of antiretroviral treatment (ART) among HIV-1 infected people. One of the consequences of this restricted representation is the absence of definitive information about the specific efficacy and safety of ART in women.4, 5, 6, 7, 8, 9 The selection of ART should be evidence based and take into account several factors, including regimen potency, side-effects, level of adherence required for efficacy, and quality of life specific to the population of patients. Current guidelines for first-line treatment of HIV-1 infection include the use of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a third active drug from a different class.10, 11, 12 The integrase strand transfer inhibitor (elvitegravir, 150 mg) coformulated with cobicistat (150 mg), emtricitabine (200 mg), and tenofovir disoproxil fumarate (300 mg) in a single-tablet regimen is a preferred ART regimen in treatment-naive patients and atazanavir (300 mg) boosted by ritonavir (100 mg) plus a preferred two-NRTI backbone (emtricitabine plus tenofovir disoproxil fumarate) is well tolerated in HIV-infected women¹³ and remains a preferred regimen during pregnancy.10, 11, 14

We did the first antiretroviral trial to enrol only women and aimed to assess safety and efficacy of two approved HIV-1 regimens, the single-tablet integrase inhibitor regimen containing elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate compared with the protease inhibitor regimen of ritonavir-boosted atazanavir with emtricitabine and tenofovir disoproxil fumarate.

Research in context

Evidence before this study

We searched PubMed for reports of large randomised clinical trials assessing antiretroviral treatment in ART-naive women and found no studies. Search terms included “HIV, “naive” AND “women” or “female” AND “antiretroviral” AND “randomized trial” and searches were limited to articles published in English between Jan 1, 1997, and Dec 31, 2015. Women account for half of the global HIV epidemic yet remain under-represented in HIV clinical trials. Current HIV treatment guidelines are based on data obtained mainly from men and might promote sex bias and inaccuracies in the paradigm of evidence-based medicine. To our knowledge, there are no published data from randomised clinical studies that focus primarily on antiretroviral treatment in women.

Added value of this study

This first all-women, randomised, double-blind clinical trial compared two approved ART regimens: integrase based (elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate) and protease inhibitor based (ritonavir-boosted atazanavir with emtricitabine and tenofovir disoproxil fumarate). The integrase inhibitor group had superior efficacy to the protease inhibitor based, differing from previous clinical trials (with mostly male participants) in which the integrase inhibitor group was non-inferior in efficacy to the protease inhibitor group. Unanticipated regional differences in efficacy and tolerability were noted. The highest virological response was reported in Ugandan women and the lowest rate of viral suppression was seen in the USA, regardless of treatment group.

Interpretation

The WAVES study is the only completed randomised clinical trial to date done exclusively among women. The WAVES population was geographically and ethnically diverse, providing a better understanding of several factors that might affect clinical outcome. The randomised study groups were well matched and the outcome data indicate that in the setting of this clinical trial the integrase inhibitor group provided superior efficacy with increased tolerability, offering new insights and treatment information to clinicians caring for women with HIV infection.

Section snippets

Study design and participants

The Women AntiretroViral Efficacy and Safety study (WAVES) is an international, randomised, controlled, double-blind, phase 3 study done at 80 sites from Belgium, Dominican Republic, France, Italy, Mexico, Portugal, Puerto Rico, Russia, Thailand, Uganda, the UK, and the USA. Women aged 18 years or older were eligible if they were HIV-1 infected had not received previous ART, had plasma HIV-1 RNA viral load 500 copies per mL or greater, and an estimated glomerular filtration rate of at least 70

Results

Between Oct 24, 2012, and Jan 28, 2014, 810 women were screened for eligibility. Of the 227 who did not meet the study entry eligibility criteria (screened participants could have more than one inclusion or exclusion criterion), 129 (57%) women were from Uganda. The most common screen fail reasons for the Uganda site include: eGFR less than 70 mL/min (64%), HIV-1 RNA less than 500 copies per mL (14%), abnormal haematology profile (11%), positive serum pregnancy (4%), screening genotype with

Discussion

The integrase inhibitor regimen (elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate) had superior efficacy to the protease inhibitor based regimen (atazanavir, ritonavir, emtricitabine, and tenofovir disoproxil fumarate). High virological responses were noted in most regions and across different HIV subtypes. No emergent resistance was detected in the integrase inhibitor group but was present in three women in the protease inhibitor group.

The higher response rate in this

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Integrase strand-transfer inhibitor use and cardiovascular events in adults with HIV: an emulation of target trials in the HIV-CAUSAL Collaboration and the Antiretroviral Therapy Cohort Collaboration
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A recent observational study suggested that the risk of cardiovascular events could be higher among antiretroviral therapy (ART)-naive individuals with HIV who receive integrase strand-transfer inhibitor (INSTI)-based ART than among those who receive other ART regimens. We aimed to emulate target trials separately in ART-naive and ART-experienced individuals with HIV to examine the effect of using INSTI-based regimens versus other ART regimens on the 4-year risk of cardiovascular events.
We used routinely recorded clinical data from 12 cohorts that collected information on cardiovascular events, BMI, and blood pressure from two international consortia of cohorts of people with HIV from Europe and North America. For the target trial in individuals who had previously never used ART (ie, ART-naive), eligibility criteria were aged 18 years or older, a detectable HIV-RNA measurement while ART-naive (>50 copies per mL), and no history of a cardiovascular event or cancer. Eligibility criteria for the target trial in those with previous use of non-INSTI-based ART (ie, ART-experienced) were the same except that individuals had to have been on at least one non-INSTI-based ART regimen and be virally suppressed (≤50 copies per mL). We assessed eligibility for both trials for each person-month between January, 2013, and January, 2023, and assigned individuals to the treatment strategy that was compatible with their data. We estimated the standardised 4-year risks of cardiovascular events (myocardial infarction, stroke, or invasive cardiovascular procedure) via pooled logistic regression models adjusting for time and baseline covariates. In per-protocol analyses, we censored individuals if they deviated from their assigned treatment strategy for more than 2 months and weighted uncensored individuals by the inverse of their time-varying probability of remaining uncensored. The denominator of the weight was estimated via a pooled logistic model that included baseline and time-varying covariates.
The analysis in ART-naive individuals included 10 767 INSTI initiators and 8292 non-initiators of INSTI. There were 43 cardiovascular events in INSTI initiators (median follow-up of 29 months; IQR 15–45) and 52 in non-initiators (39 months; 18–47): standardised 4-year risks were 0·76% (95% CI 0·51 to 1·04) in INSTI initiators and 0·75% (0·54 to 0·98) in non-INSTI initiators; risk ratio 1·01 (0·57 to 1·57); risk difference 0·0089% (–0·43 to 0·36). The analysis in ART-experienced individuals included 7875 INSTI initiators and 373 965 non-initiators. There were 56 events in INSTI initiators (median follow-up 18 months; IQR 9–29) and 3103 events (808 unique) in non-INSTI initiators (26 months; 15–37) in non-initiators: standardised 4-year risks 1·41% (95% CI 0·88 to 2·03) in INSTI initiators and 1·48% (1·28 to 1·71) in non-initiators; risk ratio 0·95 (0·60 to 1·36); risk difference –0·068% (–0·60 to 0·52).
We estimated that INSTI use did not result in a clinically meaningful increase of cardiovascular events in ART-naive and ART-experienced individuals with HIV.
National Institute of Allergy and Infectious Diseases and National Institute on Alcohol Abuse and Alcoholism.
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The dynamics of HIV viral load following the initiation of antiretroviral therapy is not well-described by simple, single-phase exponential decay. Several mathematical models have been proposed to describe its more complex behavior, the most popular of which is two-phase exponential decay. The underlying assumption in two-phase exponential decay is that there are two classes of infected cells with different lifespans. However, with the exception of CD4 $^{+}$ T cells, there is not a consensus on all of the cell types that can become productively infected, and the fit of the two-phase exponential decay to observed data from SHIV.C.CH505 infected infant rhesus macaques was relatively poor. Therefore, we propose a new model for viral decay, inspired by the Gompertz model where the decay rate itself is a dynamic variable. We modify the Gompertz model to include a linear term that modulates the decay rate. We show that this simple model performs as well as the two-phase exponential decay model on HIV and SIV data sets, and outperforms it for the infant rhesus macaque SHIV.C.CH505 infection data set. We also show that by using a stochastic differential equation formulation, the modified Gompertz model can be interpreted as being driven by a population of infected cells with a continuous distribution of cell lifespans, and estimate this distribution for the SHIV.C.CH505-infected infant rhesus macaques. Thus, we find that the dynamics of viral decay in this model of infant HIV infection and treatment may be explained by a distribution of cell lifespans, rather than two distinct cell types.
Associations of modern initial antiretroviral drug regimens with all-cause mortality in adults with HIV in Europe and North America: a cohort study
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Citation Excerpt :
The introduction of integrase strand inhibitors (INSTIs) in 2007 was an important milestone in the history of ART.3 Most patients now start ART with an INSTI-based regimen following positive results from randomised trials.4–17 These trials showed superiority7,9,11,13–15 or non-inferiority6,8,10,12,16,17 of INSTI-based regimens for virological failure compared with other regimens, such as those containing efavirenz (a non-nucleoside reverse transcriptase inhibitor [NNRTI]) and atazanavir or darunavir (protease inhibitors).6–17
Over the past decade, antiretroviral therapy (ART) regimens that include integrase strand inhibitors (INSTIs) have become the most commonly used for people with HIV starting ART. Although trials and observational studies have compared virological failure on INSTI-based with other regimens, few data are available on mortality in people with HIV treated with INSTIs in routine care. Therefore, we compared all-cause mortality between different INSTI-based and non-INSTI-based regimens in adults with HIV starting ART from 2013 to 2018.
This cohort study used data on people with HIV in Europe and North America from the Antiretroviral Therapy Cohort Collaboration (ART-CC) and UK Collaborative HIV Cohort (UK CHIC). We studied the most common third antiretroviral drugs (additional to nucleoside reverse transcriptase inhibitor) used from 2013 to 2018: rilpivirine, darunavir, raltegravir, elvitegravir, dolutegravir, efavirenz, and others. Adjusted hazard ratios (aHRs; adjusted for clinical and demographic characteristics, comorbid conditions, and other drugs in the regimen) for mortality were estimated using Cox models stratified by ART start year and cohort, with multiple imputation of missing data.
62 500 ART-naive people with HIV starting ART (12 422 [19·9%] women; median age 38 [IQR 30–48]) were included in the study. 1243 (2·0%) died during 188 952 person-years of follow-up (median 3·0 years [IQR 1·6–4·4]). There was little evidence that mortality rates differed between regimens with dolutegravir, elvitegravir, rilpivirine, darunavir, or efavirenz as the third drug. However, mortality was higher for raltegravir compared with dolutegravir (aHR 1·49, 95% CI 1·15–1·94), elvitegravir (1·86, 1·43–2·42), rilpivirine (1·99, 1·49–2·66), darunavir (1·62, 1·33–1·98), and efavirenz (2·12, 1·60–2·81) regimens. Results were similar for analyses making different assumptions about missing data and consistent across the time periods 2013–15 and 2016–18. Rates of virological suppression were higher for dolutegravir than other third drugs.
This large study of patients starting ART since the introduction of INSTIs found little evidence that mortality rates differed between most first-line ART regimens; however, raltegravir-based regimens were associated with higher mortality. Although unmeasured confounding cannot be excluded as an explanation for our findings, virological benefits of first-line INSTIs-based ART might not translate to differences in mortality.
US National Institute on Alcohol Abuse and Alcoholism and UK Medical Research Council.
Design, synthesis, molecular docking and DFT computational insight on the structure of Piperazine sulfynol derivatives as a new antibacterial contender against superbugs MRSA
2022, Journal of Molecular Structure
Citation Excerpt :
Piperazine sulfonamides are the most widely used antibacterial agents [11] in the world, chiefly because of their low cost, low toxicity, and excellent activity against common bacterial disease. Piperazine core moieties are important pharmacophores that can be found in many marketed drugs, such as the HIV protease inhibitor Crixivan [12-14] and the other drugs under development. Diphenylpiperazine derivatives possess broad pharmacological action on the central nervous system (CNS), especially on dopaminergic neurotransmission [15-18].
In this investigation, a series of piperazine sulfynol derivatives 5(a-l) were synthesized and amply characterized by various spectral techniques viz, LC-MS, ¹H NMR, ¹³C NMR, and FT-IR. The energy and other quantum chemical computations of all the piperazine sulfynol derivatives were achieved using Density functional theory (DFT), Absorption, Distribution, Metabolism and Excretion (ADME), Blood Brain Barrier (BBB) and their Prediction of Activity Spectra of Computational Screening (PASS) for their possible approaches for biological applications were evaluated. The synthesized compounds were checked for the physicochemical properties such as clogP, clogS, drug-likeness, total surface area, polar surface area, H-acceptor, and H-donor parameters. The considerable change in the design with sulfonyl moiety on the piperazine core motivates to find out new antibacterial contender of the resultant molecules against superbugs-MRSA. All 5(a-l) moieties were tested for antibacterial potency against MRSA. The 5e moiety shows a MIC value of 35±0.41 µg/mL and 9.90±0.03 ZOI in mm compared to drug bacitracin 10 µg/disk (10.21±0.04) and streptomycin 10 µg/disk (14.10±0.06) ZOI in mm. The action of biocidal properties against MRSA was confirmed by an in silico docking study on the protein 1FZP and 3SRW of MRSA. The revealed data strongly recommended 5e having a good docking score, binding energy, and glide energy with high binding affinity. The antibacterial activity was validated by SEM, cellular leakage, potassium efflux and inhibitory effect on electron transport chain. The behavior of the 5e analog in haemostatic condition was well established and cytotoxicity was evaluated against L6 cell lines. The revealed data showed that 5e analog is a potential antibacterial contender against MRSA and it can be used as a futuristic drug in the eradication of MRSA infections.
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Comparisons between rilpivirine (RPV) and integrase strand transfer inhibitors (INSTIs) in antiretroviral therapy (ART)-naïve HIV-infected individuals are currently lacking. This study aimed to compare, in an observational cohort setting, the durability of treatment with RPV-based and INSTI-based first-line regimens.
Patients who started first-line ARTs based on RPV or INSTIs, with HIVRNA < 100 000 copies/mL and CD4 cell count > 200 cells/μL were included. The primary endpoint was the cumulative probability of treatment failure (TF = virological failure [confirmed HIV-RNA > 50 copies/mL] or discontinuation of the anchor drug in the regimen), as assessed by the Kaplan-Meier method. A multivariable Cox regression was used to control for potential confounding.
Of the 1991 included patients, 986 started ART with an RPV-based regimen and 1005 with an INSTIs-based regimen. The median (IQR) follow-up was 20 (10, 35) months. The cumulative 2-year probability of TF with RPV (9.1% [95% 7.2, 11.1]) was lower than that observed in the INSTIs group (16.6% [13.8, 19.4], P = 0.0002) but not when compared with dolutegravir (DTG) alone. Starting ART with an INSTIs-based regimen vs. RPV was associated with a higher risk of TF after controlling for potential confounding factors (adjusted hazard ratio, AHR [95% CI]: 1.64 [1.28, 2.10]; P < 0.001). The results were similar when restricting the analysis to single-tablet regimens, although the probability of virological success was higher for INSTIs and DTG.
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ArticlesIntegrase inhibitor versus protease inhibitor based regimen for HIV-1 infected women (WAVES): a randomised, controlled, double-blind, phase 3 study

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Lancet

Global report: UNAIDS report on the global AIDS epidemic 2013

Women in clinical trials: an FDA perspective

Science

Inclusion of women in clinical trials--policies for population subgroups

N Engl J Med

Meta-analysis of gender differences in efficacy outcomes for HIV-positive subjects in randomized controlled clinical trials of antiretroviral therapy (2000-2008)

AIDS Patient Care STDS

What do we know about antiretroviral treatment of HIV in women?

Antivir Ther

Effect of gender and race on the week 48 findings in treatment-naive, HIV-1-infected patients enrolled in the randomized, phase III trials ECHO and THRIVE

HIV Med

Sex differences in pharmacokinetics and toxicity of antiretroviral therapy

Expert Opin Drug Metab Toxicol

Sex-based outcomes of darunavir-ritonavir therapy: a single-group trial

Ann Intern Med

Better mind the gap: addressing the shortage of HIV-positive women in clinical trials

AIDS

European AIDS Clinical Society Guidelines

Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection

A systematic review of the use of atazanavir in women infected with HIV-1

Antivir Ther

Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States

Guidance for Industry: Human Immunodeficiency Virus-1 Infection: Developing Antiretroviral Drugs for Treatment

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