Week 48 resistance analysis of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF versus Atazanavir + Ritonavir + Emtricitabine/Tenofovir DF in HIV-1 infected women (WAVES study GS-US-236-0128)

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Background—Women and those with non-B subtype HIV-1 are typically underrepresented in clinical trials. WAVES (GS-US-236-0128) was a double-blind phase 3b study among treatmentnaïve HIV-1-infected women that demonstrated that elvitegravir/cobicistat/emtricitabine/tenofovir DF (EVG/COBI/FTC/TDF; N=289) was superior to atazanavir+ritonavir+FTC/TDF (ATV+RTV +FTC/TDF; N=286) for HIV-1 RNA <50 copies/mL by FDA snapshot analysis at Week 48. Here, we describe resistance development through Week 48 in women with virologic failure and determine the impact of pre-existing mutations and HIV-1 subtype on viral suppression. Methods—Genotypic analyses (population and deep sequencing) and phenotypic analyses of HIV-1 protease, reverse transcriptase (RT), and integrase (IN) were performed. The resistance analysis population (participants with HIV-1 RNA ≥400 copies/mL at confirmed virologic failure, at discontinuation ≥Week 8, or at Week 48) had genotypic and phenotypic analyses at failure and baseline. Results—The proportion of women qualifying for resistance analyses was similar between treatment groups (6.2% EVG/COBI/FTC/TDF; 7.3% ATV+RTV+FTC/TDF). Emergent resistance was rare (0% EVG/COBI/FTC/TDF; 1% ATV+RTV+FTC/TDF—3 with M184V/I in RT). Deep sequencing of HIV-1 did not detect additional resistance development. Pre-existing mutations did not lead to virologic failure; most with the polymorphic primary IN substitution T97A, or with substitutions in RT (i.e. A62V, V90I, K103N, or E138) demonstrated virologic suppression at Week 48, with no resistance development. Most participants (74%) had non-B HIV-1, and subtype did not affect outcome. Conclusions—Emergent resistance to study drugs was rare in this global study of women, and no resistance was observed among EVG/COBI/FTC/TDF-treated participants, despite a high proportion of participants with natural or transmitted viral mutations and non-B HIV-1 subtypes.