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
Document Type
Article (peer-reviewed)
Publication Date
3-15-2023
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.
Recommended Citation
Steytler, John, Charles Craig, Elna van der Ryst, Ben Van Baelen, Jeremy Nuttall, Neliëtte van Niekerk, John Mellors, Urvi Parikh, Carole Wallis, for the Ring Study and the DREAM Trial Study Teams. 2023. "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," Clinical Infectious Diseases 76(6): 996–1002.
DOI
10.1093/cid/ciac875
Language
English
Project
International Partnership for Microbicides (IPM)
https://doi.org/10.1093/cid/ciac875