FEM-PrEP (Truvada®): Study to Assess the Role of Truvada® in Preventing HIV Acquisition in Women

• Combined incidence of HIV-1 and HIV-2 infection [ Time Frame: 10-26 months per site ] [ Designated as safety issue: Yes ]
  as determined by infection (first detected via HIV rapid tests at the site); for participants who seroconvert, HIV RNA-PCR will be done on the previous visit(s) sample(s) to better determine the time of infection and to assess whether the participant was truly HIV-1 uninfected at her previous visit(s).
• 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: 10-26 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: 10-26 months per site ] [ Designated as safety issue: Yes ]

• Combined incidence of HIV-1 and HIV-2 infection as determined by detection of HIV antibodies using HIV rapid tests. [ Time Frame: 37 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: 37 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: 37 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: 10-38 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: 10-38 months per site ] [ Designated as safety issue: Yes ]
• Incidence of pregnancy loss, prematurity, low birth weight, and congenital abnormalities [ Time Frame: 10-35 months per site ] [ Designated as safety issue: Yes ]
• Pill counts and participant report of adherence to once-daily pill taking [ Time Frame: 10-24 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: 10-26 months per site ] [ Designated as safety issue: No ]
• • Participant report of sexual behaviors and sex partner characteristics by participants who seroconvert and HIV negative participants [ Time Frame: 10-26 months per site ] [ Designated as safety issue: No ]

• 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 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 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: 37 months per site ] [ Designated as safety issue: Yes ]
• Incidence of pregnancy loss, prematurity, low birth weight, and congenital abnormalities. [ Time Frame: 37 months per site ] [ Designated as safety issue: Yes ]
• Pill counts and participant report of adherence to once-daily pill taking. [ Time Frame: 37 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: 37 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 months per site ] [ Designated as safety issue: No ]

This Phase III, double-blind, randomized, placebo-controlled trial enrolled HIV-negative women from 4 sites in 3 countries (Kenya, Tanzania, South Africa). The study's purpose was 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 included HIV-antibody-negative women between the ages of 18-35 who were at risk of HIV acquisition through sexual intercourse. Each participant was 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 received risk reduction counseling and condoms. Women had to be using a study-approved effective non-barrier contraceptive method at the time of enrollment and were asked to do so for the whole period they were on study drug. They received contraceptive counseling throughout the study. Any diagnosed, treatable sexually transmitted infection was treated free of charge.

After enrollment, each participant was followed every four weeks. All participants were followed for an additional eight weeks after study drug was stopped. Participants at risk for Hepatitis B Virus (HBV) flare were followed every four weeks for 12 weeks after stopping study product. Participants who acquired HIV infection during the study stopped taking the study drug at the time of HIV diagnosis, and will be followed for 52 weeks post diagnosis and were referred for care and treatment. Participants who became pregnant stopped taking the study drug but continued follow-up visits. Incidence rates of HIV infection were compared between the two groups (active drug and placebo) using the intent-to-treat principle. In the final analysis, thirty-three infections occurred in the TDF/FTC group (IR, 4.7/100 person-years) and 35 in the placebo group (IR, 5.0/100 person-years), leading to an estimated hazard ratio of 0.94 (95% CI, 0.59 - 1.52; P=0.81 for a test of a non-zero effect of TDF/FTC).

This Phase III, double-blind, randomized, placebo-controlled trial enrolled HIV-negative women from 4 sites in 3 countries (Kenya, Tanzania, South Africa). The study's purpose was 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 included HIV-antibody-negative women between the ages of 18-35 who were at risk of HIV acquisition through sexual intercourse. Each participant was 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 received risk reduction counseling and condoms. Women had to be using a study-approved effective non-barrier contraceptive method at the time of enrollment and were asked to do so for the whole period they were on study drug. They received contraceptive counseling throughout the study. Any diagnosed, treatable sexually transmitted infection was treated free of charge.

After enrollment, each participant was followed every four weeks. All participants were followed for an additional eight weeks after study drug was stopped. Participants at risk for Hepatitis B Virus (HBV) flare were followed every four weeks for 12 weeks after stopping study product. Participants who acquired HIV infection during the study stopped taking the study drug at the time of HIV diagnosis, and will be followed for 52 weeks post diagnosis and were referred for care and treatment. Participants who became pregnant stopped taking the study drug but continued follow-up visits. Incidence rates of HIV infection were compared between the two groups (active drug and placebo) using the intent-to-treat principle. In the final analysis, thirty-three infections occurred in the TDF/FTC group (IR, 4.7/100 person-years) and 35 in the placebo group (IR, 5.0/100 person-years), leading to an estimated hazard ratio of 0.94 (95% CI, 0.59 - 1.52; P=0.81 for a test of a non-zero effect of TDF/FTC).

• Drug: Truvada®

  Truvada® is made by Gilead Sciences, Inc. Truvada® tablets are blue capsule-shaped film-coated tablets containing 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate. Each tablet contains the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch. Dosage for this study is one tablet per day, taken orally as close as possible to twenty-four hours apart.

  Participants in both study arms will receive risk reduction counseling and condoms.

  Other Name: TDF /FTC
• Drug: Placebo

  Placebo tablets are identical to Truvada tablets in taste and appearance; however, they contain no active ingredients. Placebo tablets contain the same inactive ingredients as Truvada (croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose and pregelatinized starch), plus denatonium benzoate to provide a bitter taste to match the active tablets.

  Participants in both study arms will receive risk reduction counseling and condoms.

• Experimental: 1

  Truvada®

  Participants in both study arms will receive risk reduction counseling and condoms.

  Intervention: Drug: Truvada®
• Placebo Comparator: 2

  Placebo tablets are identical to Truvada tablets in taste and appearance; however, they contain no active ingredients. Placebo tablets contain the same inactive ingredients as Truvada (croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose and pregelatinized starch), plus denatonium benzoate to provide a bitter taste to match the active tablets.

  Participants in both study arms will receive risk reduction counseling and condoms.

  Intervention: Drug: Placebo

Inclusion Criteria:

1. Willing and able (see criterion 2) to provide written informed consent to be screened for and to participate in the trial
2. Able to answer a percentage of informed consent screening (75%) and enrollment (100%) comprehension quiz questions correctly
3. Between 18-35 years old, inclusive
4. At higher risk of becoming HIV infected
5. Have a final negative result according to the site-specific screening HIV testing algorithm and a final negative result at enrollment according to the study HIV testing algorithm

6. Willing to participate in all aspects of the study and to comply with study procedures, for up to 60 weeks, including:

   • Be randomized
   • Use study product as directed
   • Adhere to follow-up schedule and willing to be contacted by site staff between study visits (by phone and/or in person)
   • Use a study-approved effective non-barrier method of contraception for the duration of the study
   • Take study product, as evidenced by swallowing a vitamin tablet that is similar in size to the study product at enrollment
   • Provide contact information and agrees to some form of contact method throughout the study
7. Not intending to relocate out of the area for the duration of the study participation and does not have a job or other obligations that may require long absences from the area ( > 1 month at a time)
8. In general good health and have no condition (social or medical) which, in the opinion of the Site Investigator, would make study participation unsafe or complicate data interpretation
9. Not pregnant or breastfeeding, and does not anticipate a desire for pregnancy during the 52 weeks of on-product participation

10. Medically eligible at screening including:

    • Adequate renal function (serum creatinine ≤ upper limit of normal [ULN] of local range and creatinine clearance ≥ 60ml/min estimated by the Cockcroft-Gault Creatinine Clearance Formula
    • Adequate hepatic function (hepatic transaminases ALT and AST < 2x upper limit of normal [ULN] [according to local normal ranges])
    • HBsAg negative
    • Serum phosphorus levels above the lower limit of the local normal range (according to local normal ranges - grade 3 & 4 hypophosphatemia will be excluded even if within normal local ranges)
11. Not received or receiving an experimental HIV vaccine, participating in another HIV prevention study or participating in any other clinical trial with a biomedical intervention
12. No clinical signs of liver disease (e.g., ascites, spider angiomata, hepatomegaly, jaundice)
13. No definite evidence of glycosuria or proteinuria (i.e., no repeated positive [ ≥ + 1 ] urine dipstick). If a urine dipstick is positive for either glucose and/or protein at the first test, a second urine sample will be tested.
14. No history of pathological bone fractures
15. No history of adverse reaction to latex
16. Not taking any of the following medications: nephrotoxic agents; aminoglycoside antibiotics (including gentamicin); intravenous (IV) amphotericin B; cidofovir; cisplatin; foscarnet; IV pentamidine; oral or IV vancomycin; oral or IV gancyclovir; other agents with significant nephrotoxic potential; drugs that slow renal excretion; probenecid; immune system modulators; systemic chemotherapeutic agents (i.e. cancer treatment medications); systemic corticosteroids; interleukin-2 (IL-2); immunomodulators; interferon (alpha, beta, or gamma); other antiretrovirals (including nucleoside analogs, non-nucleoside reverse transcriptase inhibitors, protease inhibitors or investigational antiretroviral agents)