Abstract Body

The reverse transcriptase (RT) polymorphism E138A occurs naturally in 5% of treatment-naïve HIV-1-subtype C-infected individuals, but is also selected by the diarylpyrimidine (DAPY) class of NNRTIs causing 3-fold resistance to etravirine and rilpivirine. E138A could reduce the protective efficacy of the vaginal ring candidate dapivirine (DPV) in preventing HIV-1 infection. DPV resistance was investigated among recombinant subtype C viruses with E138A derived from seroconverters in ASPIRE.

ASPIRE was a safety and effectiveness study of a DPV vaginal ring for HIV-1 prevention conducted at 15 sites in South Africa, Zimbabwe, Malawi and Uganda. Population sequencing of protease and RT (amino acids 1-560) was performed on plasma samples from 164 seroconverters with HIV-1 RNA levels ≥200 copies/ml using an in-house assay. Drug resistance mutations (DRM) were identified using the Stanford HIVdb program v7.0. DPV susceptibility of plasma-derived recombinant HIV-1 containing bulk-cloned full-length RT sequences from ASPIRE seroconverters with E138A was determined in TZM-bl cells. Fold-change (FC) values were calculated using a mean IC[sub]50[/sub] from a matched number of seroconverters without E138A from each arm. Statistical significance was calculated using Fisher’s Exact and Likelihood Ratio tests.

The frequency of E138A was not significantly different (p=1.0) between seroconverters in the DPV arm (3 of 68; 4.4%) vs. placebo arm (5 of 96; 5.2%) of ASPIRE. Of participants with E138A, 2 of 3 from the DPV arm (2.2-FC and 5.9-FC) and 2 of 5 from the placebo arm (3.4-FC and 4.1-FC) had significantly (p<0.05) higher IC50 compared to participants with wild type virus (Table). Mean IC50 values for E138A-containing HIV-1 from the DPV arm (2.1 nM) was not different from the placebo arm (2.7 nM; p=0.70).

E138A is a naturally occurring polymorphism in HIV subtype C that is associated with modest reductions in DPV susceptibility in some RT backgrounds but not others. The frequency and extent of reduced susceptibility associated with E138A as the major variant was independent of the ASPIRE study arm. Although the low frequency of E138A limited the sample size, these phenotypic data provide reassurance that the E138A mutation was not selected by the DPV vaginal ring and is unlikely to reduce efficacy of the DPV vaginal ring for HIV-1 prevention.