Significant advancements in topical microbicide development have occurred since the prevention strategy was first described as a means to inhibit the sexual transmission of HIV-1. The lack of clinical efficacy of the first generation microbicide products has focused development attention on specific antiretroviral agents, and these agents have proven partially successful in human clinical trials. With greater understanding of vaginal and rectal virus infection, replication, and dissemination, better microbicide products and delivery strategies should result in products with enhanced potency. However, a variety of development gaps exist which relate to product dosing, formulation and delivery, and pharmacokinetics and pharmacodynamics which must be better understood in order to prioritize microbicide products for clinical development. In vitro, ex vivo, and in vivo models must be optimized with regard to these development gaps in order to put the right product at the right place, at the right time, and at the right concentration for effective inhibition of virus transmission. As the microbicide field continues to evolve, we must harness the knowledge gained from unsuccessful and successful clinical trials and development programs to continuously enhance our preclinical development algorithms. 1. Introduction Significant progress has been made in the development of topical anti-HIV microbicides since their initial description and development nearly 20 years ago. The first products developed for microbicide use were nonspecific agents which prevented HIV-1 from entering target cells by disrupting the viral membrane, including nonoxynol-9 (N-9), SAVVY (C31G), and Ushercell (cellulose sulphate) [1–3]. Clinical results with N-9 demonstrated enhanced rates of infection in the treated groups, suggesting the surfactant caused vaginal damage which allowed greater rates of infection [3]. SAVVY was prematurely discontinued due to the HIV incidence being half of the expected rate (one of the characteristics rendering the trial uninformative) [1]; however, it could not be conclusively determined that SAVVY promoted HIV infection as in the case of N-9. Ushercell was also discontinued due to a higher rate of infection compared to the placebo group [2]. Following the failure of the nonspecific surfactants, microbicide development has focused on the identification and development of specific antiretroviral (ARV) agents targeted at preventing early steps in virus replication such as virus attachment and entry and reverse transcription. Most recently, microbicide
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