ssessment of the in vitro phenotypic drug susceptibility of HIV-1 subtype C drug-resistant variants to Islatravir

Abstract

Nucleoside reverse transcriptase inhibitors (NRTIs) are the cornerstones of antiretroviral therapy as they are included in all treatment regimens. However, the frequent emergence of NRTI drug-resistance mutations calls for new NRTIs with novel modes of action. Islatravir (ISL) is a first-in-class NRT-translocation-inhibitor (NRTtI) with a high genetic barrier to resistance. Although some data on ISL drug resistance are available for HIV-1 subtype B, limited data are available for the prevalent circulating subtype (i.e., subtype C) in South Africa. Here, we investigated the in vitro phenotypic drug susceptibility of wild-type and NRTI- resistant HIV-1 subtype C variants to ISL. In vitro testing showed no significant inter- and intra-subtype differences in the potency of ISL between subtypes B and C. In addition, dual- drug synergy assays showed an additive inhibition of a wild-type subtype C variant with ISL+doravirine, while ISL+tenofovir disoproxil fumarate (TDF) showed a significant synergistic inhibition. High-level ISL resistance was not observed with any of the prevalent single NRTI mutations (e.g. K65R, M184V). However, high-level ISL resistance was observed with combinations of two or more Type-2 thymidine analogue mutations (TAMs), as well as the A114S+M184V combination. Our data suggest that ISL will be effective in the treatment of patients failing a TDF- or lamivudine-containing regimen, but less likely for those failing a zidovudine- or abacavir-containing regimen due to the selection of Type-2 TAMs. Since the latter two drugs are typically included in a PI-based second-line regimen, genotypic drug resistance testing would likely be required after treatment failure and prior to the inclusion of ISL in their regimens.