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Human Immunodeficiency Virus type 1 resistance or cross-resistance to nonnucleoside reverse transcriptase inhibitors currently under development as microbicides
Journal Contribution - Journal Article
Microbicides based on non-nucleoside reverse transcriptase inhibitors (NNRTIs) are currently being developed to protect woman from HIV acquisition through sexual contact. However, the large-scale introduction of these products raises two major concerns. First, when these microbicides are used by undiagnosed HIV+ woman, they could potentially select for viral resistance which may compromise subsequent therapeutic options. Second, NNRTI-based microbicides which are inactive against NNRTI-resistant strains, might promote the selective transmission of these viruses. In order to address these concerns, drug resistance was selected in vitro by serial passage of three viral isolates from subtypes B, C, and CRF02_AG in activated peripheral blood mononuclear cells (PBMC) under increasing concentrations of three NNRTIs (i.e., TMC120, UC781, and MIV-160) which are currently being developed as candidate microbicides. TMC120 and MIV-160 displayed a high genetic barrier to resistance development whereas resistance to UC781 emerged rapidly, similar to efavirenz and nevirapine. Phenotypically, the selected viruses appeared highly cross-resistant to current first-line therapeutic NNRTIs (i.e., delavirdine, nevirapine, and efavirenz) although they retained some susceptibility to the more recently developed NNRTIs lersivirine and etravirine. The ability of UC781, TMC120 and MIV-160 to inhibit the in vitro selected NNRTI-resistant viruses was also limited, although residual activity could be observed for the candidate microbicide NNRTI MIV-170. Interestingly, only four p2/p7/p1/p6/PR/RT/INT-recombinant NNRTI-resistant viruses (i.e., TMC120-r VI829, EFV-r VI829, MIV-160-r VI829, and EFV-r MP568) showed impairment in replicative fitness. Overall, these in vitro analyses demonstrate that, due to potential cross-resistance, the large scale introduction of mono-RTI-based microbicides should be considered with caution.
Journal: Antimicrobial Agents and Chemotherapy
Number of pages: 11
Keywords:Viral diseases, HIV, AIDS, Prevention, Microbicides, Non-nucleoside, Reverse transcriptase inhibitors, Cross-resistance, Women, Disease transmission-sexual, Transmission interruption, In vitro, Strains, CRF02_AG, Subtype B, Subtype C, Peripheral blood mononuclear cell (PBMC), Virus replication, Laboratory techniques and procedures, B780-tropical-medicine