Topical Metronidazole and Miconazole Co-formulated Vaginal Suppositories for Preventing Vaginal Infections in HIV-seronegative Women

• Bacterial Vaginosis (BV) determined by applying standard microscopic scoring criteria (Nugent's criteria) to vaginal Gram stained slides. BV is diagnosed when the score is greater than or equal to 7. [ Time Frame: Enrollment, Months 2, 4, 6, 8, 10, and 12. ] [ Designated as safety issue: No ]
  
• Vulvovaginal candidiasis (VVC) based on the presence of fungal elements (pseudohyphae, blastoconidia, or both) on vaginal saline wet mount plus a positive culture showing yeast on Sabouraud's agar. [ Time Frame: Enrollment, Months 2, 4, 6, 8, 10, and 12. ] [ Designated as safety issue: No ]
  

• Efficacy of the periodic presumptive treatment (PPT) regimen versus placebo on the overall rate of any vaginal infection (a combined endpoint including BV, VVC, and T. vaginalis infection). [ Time Frame: Enrollment, Months 2, 4, 6, 8, 10, and 12. ] [ Designated as safety issue: No ]
  
• Diagnosis of BV by clinical criteria (Amsel's criteria). [ Time Frame: Enrollment, Months 2, 4, 6, 8, 10, and 12. ] [ Designated as safety issue: No ]
  

Vaginal infections including bacterial vaginosis (BV), vulvovaginal candidiasis (VVC), and Trichomonas (T.) vaginalis are common and have been associated with increased risk of HIV and other sexually transmitted infections (STIs) in multiple prospective studies. Effective interventions for prevention of vaginal infections could substantially reduce the risk of HIV and other STIs in women. A recently completed trial has demonstrated that monthly periodic presumptive treatment (PPT) can reduce vaginal infections and promote Lactobacillus colonization. However, the oral regimen of metronidazole 2 grams plus fluconazole 150 mg was not sufficiently effective to warrant moving to Phase III HIV/STI prevention trials using this intervention. The identification of more efficacious regimens for reducing vaginal infections is a crucial step towards the development of inexpensive, female-controlled, non-coitally dependent HIV/STI risk reduction interventions for women. There is growing evidence that higher doses and longer courses may be more effective for treatment of vaginal infections than single-dose therapy. The overall goal of this protocol is to conduct a randomized, double-blind, placebo-controlled trial to test the efficacy of monthly PPT with topical metronidazole 750 mg plus miconazole 200 mg (co-formulated suppositories) versus matching placebo suppositories nightly for five nights each month for reducing the rates of BV and VVC among HIV-seronegative women. This regimen could produce sufficient reductions in vaginal infections to support its use in Phase III HIV and STI prevention trials. The study participants will include 234 women who are sexually active (greater than or equal to 4 episodes of heterosexual intercourse during the past month), HIV-seronegative, 18 to 45 years old, with BV and/or VVC and/or T. vaginalis detected by laboratory testing at a screening visit. There will be two study arms. The treatment arm (117 subjects) will receive PPT with intravaginal metronidazole 750 mg plus miconazole 200 mg (co-formulated suppositories) for five consecutive nights each month. The placebo arm (117 subjects) will receive PPT with identical placebo intravaginal suppositories for five consecutive nights each month. Individual participants will be in the study for one year.