Human Immunodeficiency Virus Type 1 Resistance or Cross-Resistance to Nonnucleoside Reverse Transcriptase Inhibitors Currently under Development as Microbicides

摘要: Microbicides based on nonnucleoside reverse transcriptase inhibitors (NNRTIs) are currently being developed to protect women from HIV acquisition through sexual contact. However, the large-scale introduction of these products raises two major concerns. First, when microbicides used by undiagnosed HIV-positive women, they could potentially select for viral resistance, which may compromise subsequent therapeutic options. Second, NNRTI-based that inactive against NNRTI-resistant strains might promote selective transmission viruses. In order address concerns, drug resistance was selected in vitro serial passage three isolates subtypes B and C CRF02_AG (a circulating recombinant form) activated peripheral blood mononuclear cells (PBMCs) under conditions increasing concentrations NNRTIs (i.e., TMC120, UC781, MIV-160) as candidate microbicides. TMC120 MIV-160 displayed a high genetic barrier development, whereas UC781 emerged rapidly, similarly efavirenz nevirapine. Phenotypically, viruses appeared be highly cross-resistant current first-line delavirdine, nevirapine, efavirenz), although retained some susceptibility more recently lersivirine etravirine. The ability inhibit vitro-selected also limited, residual activity observed microbicide NNRTI MIV-170. Interestingly, only four p2/p7/p1/p6/PR/RT/INT TMC120-resistant VI829, EFV-resistant MIV-160-resistant MP568) showed impairments replicative fitness. Overall, analyses demonstrate due potential cross-resistance, single-NNRTI-based should considered with caution.