Fixed-dose combination dolutegravir, abacavir, and lamivudine versus ritonavir-boosted atazanavir plus tenofovir disoproxil fumarate and emtricitabine in previously untreated women with HIV-1 infection (ARIA): week 48 results from a randomised, open-label, non-inferiority, phase 3b study

Summary

Background

Dolutegravir is a once-daily integrase strand transfer inhibitor with no need for pharmacokinetic boosting that is approved for the treatment of HIV-1 infection. Because women are often under-represented in HIV clinical trials, we addressed the safety and efficacy of dolutegravir in women with HIV-1.

Methods

The ARIA study is a randomised, open-label, multicentre, active-controlled, parallel-group, non-inferiority phase 3b study done in 86 hospital and university infectious disease clinics, local health clinics, and private infectious disease clinics in 12 countries and one US territory, in North America, South America, Europe, Africa, and Asia. Eligible participants were women aged 18 years or older who had HIV-1 RNA viral loads of 500 copies per mL or greater, had received 10 days or less of previous antiretroviral therapy, and had tested negative for the HLA-B*5701 allele. Pregnant women were excluded. Eligible women were randomly assigned (1:1) to receive either a single-tablet regimen of dolutegravir plus abacavir and lamivudine once a day (dolutegravir group) or a three-tablet combination of ritonavir-boosted atazanavir plus coformulated tenofovir disoproxil fumarate and emtricitabine once a day (atazanavir group). Random treatment group assignment was stratified by plasma HIV-1 RNA viral loads and CD4 cell count at baseline. The primary endpoint was the proportion of participants with HIV-1 RNA viral loads of less than 50 copies per mL at week 48 in all participants who received at least one dose of study medication (intention-to-treat exposed population). We used a non-inferiority margin of −12%. Investigators monitored adverse events to assess safety. This study is registered with ClinicalTrials.gov, number NCT01910402.

Findings

Between Aug 22, 2013, and Sept 22, 2015, of 705 women assessed, 499 were randomly assigned to either the dolutegravir group (n=250) or the atazanavir group (n=249); two participants from each group were randomised to treatment but did not receive study medication. At week 48, 203 (82%) of 248 participants in the dolutegravir group compared with 176 (71%) of 247 in the atazanavir group had HIV-1 RNA viral loads of less than 50 copies per mL (mean difference 10·5%, 95% CI 3·1–17·8, p=0·005). One participant in the atazanavir group had nucleoside reverse transcriptase inhibitor–associated resistance that led to reduced emtricitabine susceptibility. Adverse events were similar between the dolutegravir and atazanavir groups; the most common were nausea (46 [19%] of 248 in the dolutegravir group vs 49 [20%] of 247 in the atazanavir group) and headache (28 [11%] vs 32 [13%]). Fewer participants in the dolutegravir group than the atazanavir group reported drug-related adverse events (83 [33%] vs 121 [49%]) or adverse events that led to discontinuation (ten [4%] vs 17 [7%]). One death was reported in each treatment group, but neither was considered related to the study medications.

Interpretation

The non-inferior efficacy and similar safety profile of the dolutegravir combined regimen compared with the atazanavir regimen support the use of dolutegravir for HIV-1 infection in treatment-naive women.

Funding

ViiV Healthcare.

Introduction

Dolutegravir is an integrase strand transfer inhibitor (INSTI) with pharmacological properties that allow for once-daily dosing, has a low potential for drug interactions, and does not require pharmacokinetic boosting.1, 2 A series of phase 3 clinical trials have established the safety and efficacy of dolutegravir,3, 4, 5, 6, 7 leading to approval for the treatment of HIV-1 infection in multiple countries worldwide.⁸ In previously untreated participants, dolutegravir taken with investigator-selected background regimens was superior to ritonavir-boosted darunavir (FLAMINGO)³ and non-inferior to raltegravir (SPRING-2).9, 10 In another phase 3 trial,⁵ the regimen of dolutegravir, abacavir, and lamivudine was associated with rapid and sustained suppression of HIV-1 RNA and met criteria for superiority compared with a regimen of efavirenz, tenofovir disoproxil fumarate, and emtricitabine. These trials in previously untreated patients also showed that dolutegravir has a safety profile similar or favourable to other drugs, with no known instances of treatment-emergent INSTI resistance.3, 4, 5, 9, 11 In studies that enrolled previously treated men and women with HIV-1 infection,⁴ dolutegravir given with investigator-selected background regimens met criteria for superior virological efficacy compared with raltegravir (SAILING)⁴ and was effective in inducing virological responses in participants with HIV-1 resistant to raltegravir and elvitegravir (VIKING-3).⁷ Treatment guidelines now recommend dolutegravir as initial HIV therapy in previously untreated patients, and dolutegravir is the core drug in an approved single-tablet regimen containing dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg.¹²

Research in context

Evidence before this study

Dolutegravir is a novel integrase strand transfer inhibitor (INSTI) approved for the treatment of HIV-1 infection based on evidence of virological efficacy and safety from a series of phase 3 trials. Few data exist to support the benefits of dolutegravir-based antiretroviral regimens for women because most study participants in previous trials are men. To establish the background evidence for the present study, we searched PubMed for phase 3 clinical trials on dolutegravir, clinical trials and reviews of antiretroviral drugs focusing on women, and studies on the pharmacological and virological properties of dolutegravir and other INSTIs. We searched for articles in English on PubMed from Aug 11, 2016, to March 23, 2017, using combinations and derivatives of search terms including “dolutegravir”, “HIV-1”, “antiretroviral”, “integrase strand transfer inhibitor”, and “women”.

Added value of this study

To the best of our knowledge, the ARIA study is the first phase 3 randomised controlled trial to assess the virological efficacy and safety of dolutegravir in a study population fully composed of women who have not received previous antiretroviral therapy. The results support the continued use of dolutegravir to treat women with HIV, and the ARIA study also provides a specific and comprehensive safety profile for this population.

Implications of all available evidence

Dolutegravir is associated with robust virological efficacy and favourable safety and tolerability properties in women who are antiretroviral treatment naive. This study provides robust virological evidence supporting the real world use of dolutegravir in women and provides new insight into the distinct adverse events that could occur in this population.

Most participants in phase 3 dolutegravir trials were men: 32% of patients in the SAILING trial were women,⁴ and between 14% and 23% were women in other dolutegravir trials.3, 5, 7, 9 Subgroup analyses of the virological efficacy of dolutegravir regimens in women in the SINGLE,³ SPRING-2,⁵ and FLAMINGO trials9, 10 suggested that dolutegravir was preferable, but findings were not significant as a result of insufficient statistical power.⁶ Women have been under-represented in clinical trials of antiretroviral therapies (ARTs) for the treatment of HIV-1 infection;¹³ however, more than half of the new HIV infections in adults worldwide are in women.¹⁴ To date, only one fully powered study (WAVES)¹⁵ has enrolled a population composed entirely of women with HIV-1 infection.

Women often leave clinical studies prematurely for reasons other than virological activity or tolerability. Although treatment guidelines for the use of combination ART do not differ for men and women, there are important differences in pharmacokinetics, predisposition to toxic effects, use of contraceptive drugs, and concerns of safety for issues related to sexual or reproductive health that should be considered in treatment decisions involving women.⁶ Thus, more data on the safety and efficacy of combination ART, including dolutegravir-based regimens, are needed to ensure the best care for women with HIV. To address this shortage of data, we did the ARIA study to assess safety and efficacy of a fixed-dose combination of dolutegravir plus abacavir and lamivudine in previously untreated women with HIV-1 compared with atazanavir with ritonavir plus a fixed-dose combination of tenofovir disoproxil fumarate and emtricitabine.