• Combined incidence of HIV-1 and HIV-2 infection as determined by detection of HIV antibodies using HIV rapid tests [ Time Frame: 29 months per site ] [ Designated as safety issue: Yes ]
  
• Incidence of confirmed Grade 2 or higher serum creatinine toxicity, and Grade 3 or higher AST, ALT, or phosphorus toxicity during and 4 weeks after study product administration [ Time Frame: 41 months per site ] [ Designated as safety issue: Yes ]
  
• Frequency and nature of adverse events (AEs) during and within 4 weeks after study product administration [ Time Frame: 41 months per site ] [ Designated as safety issue: Yes ]
  

• Viral load and CD4+ T cell counts at the time of HIV diagnosis and at 4, 8, 12, 16, 24, 36 and 52 weeks later [ Time Frame: 37-41 months per site ] [ Designated as safety issue: Yes ]
  
• FTC and/or tenofovir resistance at the time of HIV diagnosis and 4 weeks later. If resistance is present, testing will be repeated at weeks 12, 24, 36 and 52 as necessary (resistance testing will stop if no resistance is detected) [ Time Frame: 37-41 months per site ] [ Designated as safety issue: Yes ]
  
• Bone mineral density by dual-energy x-ray absorptiometry (DEXA) in a subset of participants (N=200) at 24 and 52 weeks during study product administration [ Time Frame: 35 months per site ] [ Designated as safety issue: Yes ]
  
• Incidence of pregnancy loss, prematurity, low birth weight, and congenital abnormalities [ Time Frame: 37-50 months per site ] [ Designated as safety issue: Yes ]
  
• Pill counts and participant report of adherence to once-daily pill taking [ Time Frame: 29 months per site ] [ Designated as safety issue: No ]
  
• Participant report of the number of sexual partners and frequency of unprotected sexual acts over time [ Time Frame: 29 months per site ] [ Designated as safety issue: No ]
  
• Participant report of sexual behaviors and sex partner characteristics by participants who seroconvert and matched HIV negative participants [ Time Frame: 37-40 months per site ] [ Designated as safety issue: No ]
  

This Phase III, double-blind, randomized, placebo-controlled trial will enroll an estimated 3900 HIV-negative women from 7 sites in 5 countries (Kenya, Malawi, Tanzania,South Africa and Zambia). The study's purpose is to investigate the safety and effectiveness of a once-daily Truvada® pill (compared with placebo) in preventing HIV among HIV-uninfected women at risk of becoming infected through sexual intercourse.

The study population includes HIV-antibody-negative women between the ages of 18-35 who are at risk of HIV acquisition through sexual intercourse. Each participant will be randomized to take either a daily single oral tablet of Truvada®, which is a fixed-dose combination of emtricitabine (FTC; 200 mg) and tenofovir disoproxil fumarate (TDF; 300 mg), or an identical placebo. All participants will receive risk reduction counseling and condoms. Women must be using a study-approved effective non-barrier contraceptive method at the time of enrollment and will be asked to do so for the whole period they are on study drug. They will receive contraceptive counseling throughout the study. Any diagnosed, treatable sexually transmitted infection will be treated free of charge.

Study duration is approximately 37-40 months at each site; participant screening and enrollment is anticipated to take approximately 12-16 months. After enrollment, each participant will be followed every four weeks for 52 weeks on study drug. All participants will be followed for an additional four weeks after study drug has been stopped. Participants at risk for Hepatitis B Virus (HBV) flare will be followed every four weeks for at least 12 weeks after stopping study product. Participants who acquire HIV infection during the study will stop taking the study drug at the time of HIV diagnosis, and will be followed for 52 weeks post diagnosis and will be referred for care and treatment. Participants who become pregnant will stop taking the study drug but will continue follow-up visits. After the study, incidence rates of HIV infection will be compared between the two groups (active drug and placebo) using the intent-to-treat principle.