Characterization of Viruses in Phase 3 and Phase 3b Trials (the Ring Study and the Dapivirine Ring Extended Access and Monitoring Trial) of the Dapivirine Vaginal Ring for Human Immunodeficiency Virus Type 1 Infection Risk Reduction

Abstract

Background: The Ring Study demonstrated 35.1% human immunodeficiency virus type 1 (HIV-1) infection risk reduction among participants who used the Dapivirine vaginal ring-004 (DVR), whereas the Dapivirine Ring Extended Access and Monitoring (DREAM) trial, approximated a 62% risk reduction. The observed non-nucleoside reverse-transcriptase inhibitor (NNRTI) resistance-associated mutations (RAMs) and effects on viral susceptibility are described here.

Methods: Population-based genotyping on plasma samples collected longitudinally, and next-generation sequencing (NGS) and phenotypic susceptibility testing were done on plasma collected at seroconversion. Retrospective HIV-1 RNA testing was used to more accurately establish the time of infection.

Results: In the Ring Study, NNRTI RAMs were not observed in most viruses at seroconversion (population-based genotyping: DVR: 71 of 84, 84.5%; placebo: 50 of 58, 86.2%). However, more E138A was found in the DVR group (E138A DVR: 9 of 84, 10.7%; placebo: 2 of 58, 3.4%; P = .2, Fisher exact test). NGS detected 1 additional mutation in each group (DVR: G190A; placebo: G190A and G190E). Marginal dapivirine susceptibility reduction was found with NNRTI RAMs at seroconversion (geometric mean fold-change, range: DVR, 3.1, 1.3-5.1; placebo, 5.8, 0.9-120). NNRTI RAMs were not emergent between first detectable HIV-1 RNA and seroconversion when these visits differed (paired samples, mean ring use: DVR, n = 52, 35 days; placebo, n = 26, 31 days). After stopping DVR, 2 of 63 viruses had emergent G190G/A or K103K/N with V106V/M at final study visit. Resistance profiles from the DREAM trial were consistent with the Ring Study.

Conclusions: DVR showed little potential for selection of NNRTI-resistant variants.

Clinical trials registration: NCT01539226 and NCT02862171.

Keywords: Dapivirine vaginal ring-004; HIV-1; antiretroviral drug susceptibility; preexposure prophylaxis.

Figure 1.

Overview of randomization, outcomes, and virology data availability at the seroconversion time point for the Ring Study. ¹Participants were given the option to enter an open-label phase when the randomized part of the trial was ended. Participants and investigators remained blinded to the randomized treatment. ² All available samples at the seroconversion time point were submitted for this retrospective analysis. ³ Viruses with NNRTI resistance-associated mutations were all assessed retrospectively for dapivirine susceptibility; for other NNRTIs, susceptibility was assessed only for viruses encoding E138A. Abbreviations: DVR, Dapivirine vaginal ring; NNRTI, nonnucleoside reverse-transcriptase inhibitor.