期刊
AIDS
卷 25, 期 13, 页码 1585-1594出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/QAD.0b013e3283491f89
关键词
combination antiretrovirals; drug resistance; microbicides; preexposure prophylaxis; subtype diversity
资金
- International Partnership for Microbicides (IPM)
- Canadian Institutes for Health Research (CIHR)
- CIHR
Objective: To evaluate the candidate antiretroviral microbicide compounds, dapivirine (DAP) and tenofovir (TFV), alone and in combination against the transmission of wild-type and nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV-1 from different subtypes. Design and methods: We determined single-drug efficacy of the RTIs, DAP and TFV, against subtype B and non-B wild-type and NNRTI-resistant HIV-1 in vitro. To assess breadth of activity, compounds were tested alone and in combination against wild-type and NNRTI-resistant subtype C primary HIV-1 isolates and complimentary clonal HIV-1 from subtypes B, C and CRF02_AG to control for viral variation. Early infection was quantified by counting light units emitted from TZM-bl cells less than 48-h post-infection. Combination ratios were based on drug inhibitory concentrations (IC(50)s) and combined effects were determined by calculating combination indices. Results: Both candidate microbicide antiretrovirals demonstrated potent anti-NNRTI-resistant HIV-1 activity in vitro, albeit the combination protected better than the single-drug treatments. Of particular interest, the DAP with TFV combination exhibited synergy (50% combination index, CI50 = 0.567) against subtype C NNRTI-resistant HIV-1, whereas additivity (CI50 = 0.987) was observed against the wild-type counterpart from the same patient. The effect was not compounded by the presence of subdominant viral fractions, as experiments using complimentary clonal subtype C wild-type (CI50 = 0.968) and NNRTI-resistant (CI50 = 0.672) HIV-1, in lieu of the patient quasispecies, gave similar results. Conclusion: This study supports the notion that antiretroviral drug combinations may retain antiviral activity against some drug-resistant HIV-1 despite subtype classification and quasispecies diversity. (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
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