Safety and Effectiveness of Tenofovir Gel in the Prevention of Human Immunodeficiency Virus (HIV-1) Infection in Women and the Effects of Tenofovir Gel on the Incidence of Herpes Simplex Virus (HSV-2) Infection

This is a phase III, multicenter trial to assess the safety and effectiveness of 1% tenofovir gel, administered vaginally by approximately 2900 sexually active women at high risk for sexually transmitted HIV. Approximately 2600 women aged 18-30 years old will be enrolled to achieve the required number of endpoints to show an effect on HIV-1 infection, while up to 300 additional women aged 31-40 years old will be enrolled to collect more safety information in this age group.

This is an event driven study that plans to randomize seronegative women. Participants will be randomized to a 1:1 ratio to receive 1% tenofovir gel or placebo gel. Each will be asked to insert a dose of the assigned study product within 12 hours prior to a coital event and another dose as soon as possible within 12 hours after a coital event. Participants will be advised to use only two doses of gel in a 24 hour period.

All women will be evaluated for the rates of adverse events and the rate of HIV seroconversion. In addition, the study will evaluate several secondary endpoints that bear directly on potential risks and benefits of vaginal tenofovir gel use.

Inclusion criteria

• Confirmed age 18-40 years (inclusive)
• Able and willing to provide written informed consent
• Able and willing to provide adequate locator information for study retention and safety purposes
• Sexually active, defined as having had vaginal intercourse at least twice in the past 30 days prior to screening
• HIV negative on two rapid tests performed by study staff within 30 days of enrolment (see algorithm in Appendix 3).
• No evidence of glycosuria
• No evidence of proteinuria greater than trace*
• No history of pathological bone fractures
• Have a negative pregnancy test
• Women currently breastfeeding may be enrolled in the study
• Agree to use a study-approved effective non-barrier form of contraception
• Agree to adhere to study visits and procedures
• Willing to use study gel as advised
• Not using or taking any of the following groups of medications:

• Nephrotoxic agents
• Drugs that slow renal excretion
• Immune system modulators
• Other antiretrovirals

Exclusion criteria

• History of adverse reaction to latex.
• Plans any of the following during the study period

• To travel away from the study site for more than 30 consecutive days.
• To relocate away from the study site.
• To become pregnant.
• To enrol in any other study of an investigational product or behaviour modification related to HIV prevention.
• If in the opinion of the examining clinician, is not sexually active
• Inadequate renal function (serum creatinine greater than 1.5mg/dl and creatinine clearance less than 50ml/min, as estimated using the method of Cockcroft and Gault96 )
• Grade 3 and above ALT and AST at screening or any clinical sign of liver disease ( e.g. ascites, hepatomegaly, jaundice)
• Abnormal serum phosphate levels (Grade 3 and above)
• Has a clinically apparent finding on speculum pelvic examination (observed by study staff) involving deep epithelial disruption. Otherwise eligible participants with speculum pelvic examination findings involving deep epithelial disruption may proceed with enrolment after the findings have resolved and the inclusion/exclusion are met.
• Received previously or receiving an experimental HIV vaccine
• Currently participating in another HIV prevention intervention study or participation in any other clinical trial with a biomedical intervention in the last six months
• Has current STI symptoms and/or other reproductive tract infection requiring treatment, as assessed by study staff. Otherwise eligible participants diagnosed during screening with infection(s) requiring treatment may be enrolled provided that treatment has been completed.
• Any clinical evidence of untreated cervical abnormalities
• Has any other condition that, based on the opinion of the Investigator or designee, would preclude provision of informed consent, make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives.