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The following questions were addressed: would the introduction of vaginal microbicides substantially reduce the risk of female sex workers (FSWs) acquiring HIV? Which factor would it be most important to maximize, microbicide efficacy or microbicide use? What level of microbicide efficacy and use would be necessary to counterbalance a possible reduction in condom use?Mathematical modeling, with parameter estimations from available literature.Risk equations were developed and Monte Carlo simulations were performed to model a FSW's daily risk of HIV acquisition currently, and after, microbicide introduction. Uncertainty and sensitivity analyses were used as well as tornado plots for two ranges of microbicide efficacy (30–50%) and (50–80%). Risk was estimated for FSWs whose clients sometimes (10–50%) use condoms, and those whose clients never use condoms. An analytical threshold for which reducing condom use increases risk was estimated.For both groups of FSWs, daily risk would decrease by approximately 17% or approximately 28% using 30–50% or 50–80% effective microbicides, respectively. Increasing microbicide use would have greater impact on reducing risk than increasing microbicide efficacy. The microbicide efficacy and usage required to ensure that ‘condom replacement’ does not increase a FSW's risk of acquiring HIV was calculated.Microbicides could substantially reduce FSWs’ risk of acquiring HIV; absolute decrease in risk would be greatest in high-prevalence regions. The public health impact of microbicides will depend upon usage and efficacy. Even if the microbicides that become available are only low-to-moderately effective, the probability that risk in FSWs will increase (due to replacing condoms with microbicides) is low.