Abstract
Background
The Ring Study, a 2:1 randomized, double-blind, placebo-controlled Phase III trial, demonstrated 35.1% HIV-1 infection risk reduction among participants using the Dapivirine Vaginal Ring-004 (DVR). An open-label extension trial, DREAM, approximated a 62% risk reduction. The analysis of NNRTI resistance-associated mutations (RAMs) and effects on viral susceptibility observed in these trials are described.
Methods
Population-based genotyping was performed on plasma samples collected longitudinally, and Next Generation Sequencing (NGS) and phenotypic susceptibility testing was done on plasma collected at seroconversion. Retrospective HIV-1 RNA testing was used to establish more accurately the time of infection.
Results
In The Ring Study, NNRTI RAMs were not observed in most viruses at seroconversion (population-based genotyping: DVR: 71/84, 84.5%; placebo: 50/58, 86.2%). However, more E138A was found in the DVR group (E138A: DVR: 9/84, 10.7%; placebo: 2/58, 3.4%,
P = 0.2, Fisher's exact test). NGS detected one 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 [FC], 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, 2/63 viruses had emergent G190G/A or K103K/N with V106V/M at final study visit. Resistance profiles from DREAM were consistent with The Ring Study.
Conclusion
DVR used for HIV-1 prevention showed little potential for selection of NNRTI resistant variants.
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