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The objective of this study was to explore how a microbicide’s HIV impact is affected by behavioral and epidemiologic factors in 2 African settings: Cotonou, Benin, and Hillbrow, South Africa.A mathematical model, fit to epidemiologic data from each setting, was used to estimate the HIV impact of introducing a microbicide with different HIV/sexually transmitted infection (STI) efficacies. Simulations were compared to explore how impact is affected by context.Widespread microbicide use results in a greater relative reduction in HIV incidence in Cotonou, where HIV/STIs are less prevalent. Most infections averted are from commercial sex in Cotonou but noncommercial sex in Hillbrow. The microbicide’s STI efficacy is important in determining its HIV impact in both settings, but especially in Cotonou where the microbicide’s HIV impact was mainly the result of its STI efficacy.It is important to develop and evaluate microbicides that are efficacious against STIs. However, even with the same patterns of use, a microbicide’s impact and the importance of its STI efficacy will vary considerably between settings.