Assessment of the in vitro phenotypic drug susceptibility of HIV-1 subtype C drug-resistant variants to Doravirine (DOR)

Abstract

The high prevalence of antiretroviral drug resistance warrants approval of novel antiretroviral drugs that are effective against drug resistant-variants. Doravirine (DOR) is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) with an improved safety profile, requires only a single daily dose, and has shown activity against prevalent NNRTI drug resistance mutations. To understand the impact of NNRTI drug resistance mutations on DOR in South Africa, in which HIV-1 subtype C is prevalent, this study assessed the in vitro phenotypic drug susceptibility of DOR against prevalent HIV-1 subtype C drug-resistant variants. Replication-defective HIV-like pseudoviruses (PSV) containing the most prevalent NNRTI drug resistance mutation combinations (n=20), as well as the single mutations (n=15) they contain, were generated and screened in a single-cycle in vitro phenotypic assay for susceptibility to DOR. An initial screen of DOR against wild-type PSVs showed no significant differences in Islatravir (ISL) potency among subtypes B and C. Furthermore, the combination of DOR with ISL showed a significant synergistic inhibition of a wild-type HIV-1 subtype C PSV. High-level DOR resistance was observed with the V106M and Y188L single mutants, while the remaining single mutants remained susceptible or showed a low level of resistance to DOR. Combinations of mutations that included V106M, Y188L, and P225H showed a high level of resistance to DOR. Given the lower prevalence of the latter mutations in treatment-naïve and -experienced patients in South Africa, DOR would likely be an effective treatment option. However, genotypic drug resistance testing may be advised prior to initiation of DOR-containing regimens for NNRTI-experienced individuals.