HIV‐1 drug resistance among individuals who seroconverted in the ASPIRE dapivirine ring trial

Abstract

IntroductionA potential concern with the use of dapivirine (DPV) for HIV prevention is the selection of a drug‐resistant virus that could spread and reduce the effectiveness of non‐nucleoside reverse transcriptase (NNRTI)‐based first‐line antiretroviral therapy. We evaluated HIV‐1 seroconversions in MTN‐020/ASPIRE for selection of drug resistance and evaluated the genetic basis for observed reductions in susceptibility to DPV.MethodsMTN‐020/ASPIRE was a placebo‐controlled, Phase III safety and effectiveness study of DPV ring for HIV‐1 prevention conducted at 15 sites in South Africa, Zimbabwe, Malawi and Uganda between 2012 and 2015. Plasma from individuals who seroconverted in ASPIRE was analysed for HIV‐1 drug resistance using both population Sanger sequencing and next‐generation sequencing (NGS) with unique molecular identifiers to report mutations at ≥1% frequency. DPV susceptibility of plasma‐derived recombinant HIV‐1 containing bulk‐cloned full‐length reverse transcriptase sequences from MTN‐020/ASPIRE seroconversions was determined in TZM‐bl cells. Statistical significance was calculated using the Fisher's exact test.ResultsPlasma from all 168 HIV seroconversions were successfully tested by Sanger sequencing; 57 of 71 DPV arm and 82 of 97 placebo (PLB) arm participants had NGS results at 1% sensitivity. Overall, 18/168 (11%) had NNRTI mutations including K101E, K103N/S, V106M, V108I, E138A/G, V179D/I/T and H221Y. Five samples from both arms had low‐frequency NNRTI mutations that were not detected by Sanger sequencing. The frequency of NNRTI mutations from the DPV arm (11%) was not different from the PLB arm (10%; p = 0.80). The E138A mutation was detected in both the DPV (3 of 71 [4.2%]) and PLB arm (5 of 97 [5.2%]) and conferred modest reductions in DPV susceptibility in some reverse transcriptase backgrounds but not others.ConclusionsHIV‐1 drug resistance including NNRTI resistance did not differ between the DPV and placebo arms of the MTN‐020/ASPIRE study, indicating that drug resistance was not preferentially acquired or selected by the DPV ring and that the preventive benefit of DPV ring outweighs resistance risk.

Brief Report: HIV Drug Resistance Assessment Among Women Who Seroconverted During the MTN-025/HOPE Open-Label Extension Dapivirine Vaginal Ring Trial

“…We undertook a comprehensive assessment of the 38 seroconversions in the HOPE open-label study of DPV ring and found infrequent NNRTI resistance. However, the overall rate of resistance observed among participants becoming HIV seropositive (20%) was higher than that observed in the DPV ring arm of the Phase III ASPIRE trial (10.4%), 12,24 but 20% is consistent with the contemporaneous national NNRTI pretreatment drug resistance rates of 10%–30% in Uganda, South Africa, and Zimbabwe as reported in the 2019 World Health Organization HIV Drug Resistance Report. 27 That the frequency of NNRTI resistance in HOPE participants who became HIV seropositive is similar to that of circulating NNRTI resistance in the community argues for transmitted drug resistance in HOPE participants and against selection of resistance by DPV.…”

How could HIV-1 drug resistance impact preexposure prophylaxis for HIV prevention?

“…An exhaustive phenotypic evaluation of plasma-derived bulk-cloned HIV-1 with E138A and systematic reversion to 138E (wild-type) showed a modest reduction in susceptibility to DPV (median 4.7-fold) in some genotypic backgrounds but not others. Alterations in DPV susceptibility of viruses with E138A were independent of the study arm in ASPIRE [75 ▪▪ ].…”

“…In the two Phase III DPV ring studies, a high but equivalent rate of NNRTI resistance was observed among seroconversions from both the active and placebo ring arms, indicating that resistance was likely transmitted and not selected by DPV ring use. In ASPIRE, 8 of 71 (11.3%) and 10 of 97 (10.3%) participants who seroconverted had one or more NNRTI mutations detected by Sanger sequencing [75 ▪▪ ]. Similarly, 13 of 82 (15.9%) in the DVR arm had NNRTI resistance compared to 8 of 57 (14.0%) in the placebo arm from the Phase III Ring study [76].…”

Casting a Wide Net: HIV Drug Resistance Monitoring in Pre-Exposure Prophylaxis Seroconverters in the Global Evaluation of Microbicide Sensitivity Project

“…As new PrEP drugs and delivery methods, such as the monthly dapivirine vaginal ring and the cabotegravir long-acting injectable, become available on the global market and as countries transition to alternative first-line ART regimens in the same drug classes as PrEP agents, more research and surveillance will be needed to monitor and limit the risk of HIVDR. 46,47 Systems developed to monitor for HIVDR with PrEP use must be adaptable to these new PrEP agents as drug resistance risk and profiles may change.…”