| Over the last 30 years, the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) melee has endured despite valiant efforts made by the research community. Although great strides in treatment efficacy have been made, an effective vaccine remains beyond our reach. Anti- HIV microbicides, (topically applied agents to prevent the transmission of HIV), offer an infection prevention strategy that may buy us time until an effective vaccine is discovered. Indeed, antiretroviral (ARV)-based microbicides have proven more effective than any vaccine clinical trial to date. Improved formulations, including combination ARV- based microbicides, may prove to be even more clinically efficacious in the future. However, the pre-clinical evaluation of candidate microbicide ARVs is prudent, lest a formulation proves inimitably toxic or useless during human trials. Of course, pre-clinical drug assessments have limitations; what we learn from in vitro tissue culture experiments does not necessarily translate seamlessly to in vivo efficacy. Pre-clinical assessment may, nevertheless, aid in advancing the best possible candidate ARVs, permitting each candidate microbicide ARV to be ranked in the context of better toxicity, efficacy, and drug resistance development profiles. The following thesis describes the pre-clinical assessment of the lead candidate microbicide ARVs, tenofovir (TFV) (a nucleotide reverse transcriptase inhibitor (NtRTI)), dapivirine (DAP) (a nonnucleoside reverse transcriptase inhibitor (NNRTI)), and BMS- 599793, an HIV-1 entry inhibitor. How these drugs perform as HIV-1 infection preventatives in the context of wild type (WT) and drug resistant (DR)HIV-1 transmission in vitro is focused upon. |
