HIV drug resistance assessment among seroconverters from the MTN-025/HOPE Open-Label Dapivirine Vaginal Ring Study


BACKGROUND: A concern about dapivirine(DPV) for HIV prevention is potential selection of resistant virus with breakthrough infection that could contribute to spread of NNRTI resistance and reduced effectiveness of 1st-line-NNRTI-based ART. The frequency of NNRTI resistance in seroconverters from the placebo-controlled MTN-020/ASPIRE Phase-III trial of DPV vaginal ring was high(11%) but did not differ by arm, suggesting that resistance profiles detected were likely transmitted and not selected by DPV ring use. To further evaluate resistance risk, we tested samples from seroconverters in the MTN-025/HOPE open-label-extension of DPV ring for HIV drug resistance.
METHODS: In MTN-025, HIV-1-uninfected women from MTN-020 were offered 12 months of access to DPV ring for HIV prevention at 14 sites in Malawi, South Africa, Uganda, and Zimbabwe between July 2016 and August 2018. Plasma from the 35 women who seroconverted during the study was tested by population genotyping and next generation sequencing with unique molecular identifiers (NGS-UMI) targeting HIV-1 RT aa81-149 and 152-212. Drug resistance mutations (DRM) were defined by 2019-IAS-USA and reported if their frequency was '¥1% of the virus population. Bulk-cloned plasma-derived recombinant HIV-1 from samples with NNRTI mutations and a matched number without NNRTI mutations was phenotyped for susceptibility to DPV.
RESULTS: Seven of 35(20%) samples had NNRTI-DRM detected by both population genotyping and NGS-UMI including A98G,K103N,V106M,E138A and V179D. Only 1 sample had a low frequency DRM detected (2.8%Y188H) that was missed by standard genotyping. Major NNRTI mutations previously selected by DPV in vitro including L100I,E138K,V179F or Y181C/I were not detected, even at low frequency. Samples with K103N had varying susceptibility to DPV, ranging from fully susceptible(1.4-FC) to moderate reduction in susceptibility(17-FC)(Table).

CONCLUSIONS: NNRTI resistant-HIV-1 in HOPE seroconverters was common but selection of DPV specific mutations was not observed. Ongoing monitoring of NNRTI resistance is important to further understand the potential risk of resistance in the community.