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Topical microbicides are products that may be formulated as gels, sponges, films, or rings that can be applied to vaginal or rectal mucosa with the goal of preventing or significantly reducing the risk of acquiring STIs, including HIV (Stein 1990). One of the first products studied as a topical microbicide, the spermicidal agent Nonoxynol-9 (N-9), unfortunately was shown to be neither safe nor effective (Hillier et al. 2005; Van Damme et al. 2002). There currently are almost 80 candidate microbicides in development (McGowan 2006). However, most of these candidates have been studied either in test tubes or in animal studies, and relatively few human studies have been fully evaluated. The current group of microbicides act through several different mechanisms of action, including (1) vaginal defense enhancers that help maintain the acidic vaginal pH, which is protective against foreign microbes. This has been studied as both a gel that can be applied topically and through the development of efficient recolonizing bioengineered lactobacilli, because they produce the majority of the hydrogen peroxide that are ultimately responsible for the acidic vaginal environment. (2) detergents that disrupt microbial membranes. (3) entry or fusion inhibitors that target viral or cell receptors to prevent the sequence of viral binding, fusion, and entry; and (4) inhibitors of viral replication. Some topical microbicides that were evaluated in clinical trials, cellular sulfate and C31g (Savvyä), were shown to be ineffective in protecting against HIV transmission (Van Damme et al. 2002). However, the most recent large-scale efficacy trial comparing PRO2000, a microbicide to inhibit HIV entry, with an acidifying agent, Buffergel, suggested that those receiving PRO2000 had a 30 percent decreased risk of HIV transmission compared with a nongel comparison group and a placebo control group (Abdool-Karim et al. 2009). The women who were most adherent to using the PRO2000 gel, particularly those who engaged in unprotected intercourse, seemed to have even higher levels of protection. Because 30 percent efficacy is at a borderline level for public health significance, this first positive finding in a microbicide efficacy trial will not lead to immediate licensure of PRO2000. A second, larger study conducted by the Medical Research Council of the United Kingdom is underway in East Africa. If that study shows that PRO2000 is at least as effective as the levels of protection seen in the earlier study, HVTN 035, then it is very likely that PRO2000 could be the first licensed topical microbicide agent. 041b061a72