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

Overview

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. After enrollment, each participant was followed every four weeks. All participants were followed for an additional eight weeks after study drug was stopped. Incidence rates of HIV infection were compared between the two groups (active drug and placebo) using the intent-to-treat principle.

Full Title of Study: “Phase 3, Multi-center, Double-blind, Randomized, Placebo-controlled Effectiveness and Safety Study to Assess the Role of Truvada® in Preventing HIV Acquisition in Women”

Study Type

• Study Type: Interventional
• Study Design
  • Allocation: Randomized
  • Intervention Model: Parallel Assignment
  • Primary Purpose: Prevention
  • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Study Primary Completion Date: August 2012

Detailed Description

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.

Interventions

• Drug: Truvada
  • Daily single oral tablet of Truvada – a fixed-dose combination of emtricitabine (FTC; 200 mg) and tenofovir disoproxil fumarate (TDF; 300 mg).
• Other: Placebo
  • Daily single oral tablet of Placebo. Tablets are identical to Truvada tablets in taste and appearance; however, they contain no active ingredients.

Arms, Groups and Cohorts

• Experimental: Truvada Arm
  • Daily single oral tablet of Truvada (TDF/FTC), a fixed-dose combination of emtricitabine (FTC; 200 mg) and tenofovir disoproxil fumarate (TDF; 300 mg).
• Placebo Comparator: Placebo Arm
  • Daily single oral tablet of Placebo. Tablets are identical to Truvada tablets in taste and appearance; however, they contain no active ingredients.

Clinical Trial Outcome Measures

Primary Measures

• HIV Infection
  • Time Frame: Cumulative HIV infection between enrollment and 52 weeks
  • HIV Seroconversion, with time to infection refined based on PCR results obtained from stored specimens.
• Confirmed Grade 2 or Higher Serum Creatinine Toxicity
  • Time Frame: cumulative toxicity through 52 weeks of product use and 4 weeks post product
  • Repeat specimens were collected to confirm chemistry toxicities. Grade 2 or higher serum creatinine toxicity was defined as ≥1.4 times the upper limit of normal
• Frequency of Adverse Events (AEs) During and Within 4 Weeks After Study Product Administration
  • Time Frame: 10-26 months per site
  • The total number of adverse events in the placebo and Truvada arms during and within 4 weeks after study product administration.
• Confirmed Grade 3 or Higher Reduction in Phosphorus
  • Time Frame: Through 52 weeks on product and 4 weeks post-product
  • Repeat specimens were collected to confirm chemistry toxicities. Grade 3 phosphorus reduction was defined as ≤2.4mg/dL
• Confirmed Grade 3 or Higher ALT Elevation
  • Time Frame: Through 52 weeks on product and 4 weeks post-product
  • Grade 3 or higher ALT elevation was defined as ≥ 2.6 times the upper limit of normal
• Confirmed Grade 3 or Higher AST Elevation
  • Time Frame: Through 52 weeks on product and 4 weeks post-product
  • Grade 3 or higher AST elevation was defined as ≥ 2.6 times the upper limit of normal

Secondary Measures

• Plasma HIV RNA Level (HIV-1 Viral Load)
  • Time Frame: up to 16 weeks
  • Viral load at the time of HIV detection, HIV conversion and through 16 weeks
• CD4+ T-cell Count
  • Time Frame: Up to 16 weeks
  • CD4+ T-cell Count at the Time of HIV Seroconversion through 16 weeks
• FTC and/or Tenofovir Resistance
  • Time Frame: up to 52 weeks
  • Genotypic resistance to FTC and/or tenofovir at the time of HIV diagnosis and 4 weeks later. If resistance was present, testing was repeated at weeks 12, 24, 36 and 52 as necessary (resistance testing will stop if no resistance is detected). participants were classified as having resistance if they had one or more visits in which resistance was detected, even if the resistance became undetectable over time.
• Pregnancy Complications
  • Time Frame: up to 60 weeks
  • Reported complications during pregnancy, including spontaneous abortion, vaginal or uterine bleeding, emergency c-section and other complications
• Pill Counts and Participant Report of Adherence to Once-daily Pill Taking
  • Time Frame: Up to 52 weeks
  • Pill counts and participant report of adherence to once-daily pill taking reported as mean days study product could have been used according to pill counts
• Participant Report of Change in Number of Sexual Partners
  • Time Frame: Up to 52 weeks
  • Difference in mean number of reported sexual partners between final study visit and enrollment visit

Participating in This Clinical Trial

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 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)

Gender Eligibility: Female

Minimum Age: 18 Years

Maximum Age: 35 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

• Lead Sponsor
  • FHI 360
• Provider of Information About this Clinical Study
  • Sponsor
• Overall Official(s)
  • Lut Van Damme, MD, MS, PhD, Principal Investigator, FHI 360
  • Amy Corneli, PhD, MPH, Principal Investigator, FHI 360
  • Jennifer Deese, MPH, Study Director, FHI 360

Citations Reporting on Results

Van Damme L, Corneli A, Ahmed K, Agot K, Lombaard J, Kapiga S, Malahleha M, Owino F, Manongi R, Onyango J, Temu L, Monedi MC, Mak'Oketch P, Makanda M, Reblin I, Makatu SE, Saylor L, Kiernan H, Kirkendale S, Wong C, Grant R, Kashuba A, Nanda K, Mandala J, Fransen K, Deese J, Crucitti T, Mastro TD, Taylor D; FEM-PrEP Study Group. Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012 Aug 2;367(5):411-22. doi: 10.1056/NEJMoa1202614. Epub 2012 Jul 11.