The predominant route of human immunodeficiency virus type 1 (HIV-1) transmission is across the vaginal and rectal epithelia during sexual intercourse. Yet the development of safe and clinically effective vaginal and rectal antiretroviral microbicides remains an unmet challenge despite more than 25 years of accelerated product development. The clinical failure of seven microbicide candidates points to major unresolved challenges associated with target specificity, safety, potency as well as drug-delivery of validated candidates undergoing preclinical and clinical development as anogenital microbicides. Currently, additional antiretroviral agents are sought as anogenital microbicides to provide potential anti-HIV protection by directly inactivating HIV-1, preventing HIV-1 from attaching, entering or replicating in susceptible target cells, and/or by hindering the dissemination of HIV-1 to the host cells that line the vaginal/rectal walls along with targeting novel HIV-host dependency factors. Among the several types of anti-HIV microbicides currently in preclinical and clinical development, only one clinical trial of an HIV-1 reverse transcriptase inhibitor has shown clinical promise as a potential microbicide. This article reviews the preclinical/ clinical efficacy and safety profiles of current antiretroviral microbicide candidates (Tenofovir, Stampidine, UC-781, Dapivirine/TMC120, MIV-150, HI-443, CCR5 antagonists, neutralizing antibodies, targeted RNA interference, RNAbased aptamers, Aptamer-siRNA-chimeric RNA), as well as advances in multimodal microbicide delivery systems (nanocarriers - liposomes, dendrimers, polymeric, solid lipid and metal nanoparticles, nanospheres, nanocapsules, intravaginal rings and recombinant lactobacilli delivery strategies). The clinical failure of first-generation antiretroviral gels is spearheading efforts to evaluate new mechanism-based antiretrovirals with a rational design and engineering of long-acting and novel delivery systems more appropriate to curb anogenital HIV transmission.
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