Safety and Effectiveness of TFV 1% Gel, TDF Tablets, and FTC/TDF Tablets in Preventing HIV in Women

Phase 2

Completed

• Conditions: HIV Infections
• Interventions: Drug: Emtricitabine/tenofovir disoproxil fumarate placebo; Drug: Emtricitabine/tenofovir disoproxil fumarate; Drug: Tenofovir placebo; Drug: Tenofovir 1% vaginal gel; Drug: Tenofovir disoproxil fumarate placebo; Drug: Tenofovir disoproxil fumarate

• Registration Number: NCT00705679
• Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary

A new approach to HIV prevention currently being studied includes the use of microbicides, substances that kill microbes. Tenofovir disoproxil fumarate (TDF) and emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) are oral, FDA-approved, anti-HIV drugs, and tenofovir gel is an experimental microbicide. The purpose of this study is to determine the safety and effectiveness of daily tenofovir 1% gel compared to a vaginal placebo gel, and the safety and effectiveness of oral TDF and oral FTC/TDF compared to an oral placebo in preventing HIV infection among women at risk for sexually transmitted infections.

Detailed Description

It is necessary to monitor both the adherence and blood levels of microbicides in order to gauge its efficacy in a study population. Utilizing an experimental microbicide (tenofovir gel) and anti-HIV drugs (TDF, FTC/TDF), this study will measure the effectiveness and safety to and blood levels of the three interventions in three regimens given to HIV uninfected women.

The expected duration of participation for each participant ranges from a minimum of 12 months to a maximum of 38 months. Study participants will be randomly assigned into one of five study groups, each with a different regimen. Group 1 participants will take one TDF tablet daily and one FTC/TDF placebo tablet daily. Group 2 participants will take one TDF placebo tablet daily and one FTC/TDF tablet daily. Group 3 participants will take one TDF placebo tablet daily and one FTC/TDF placebo tablet daily. Group 4 participants will apply tenofovir 1% gel vaginally once daily. Group 5 participants will apply tenofovir 1% placebo gel vaginally once daily.

Study visits will occur every 28 days after enrollment. Medical history, a physical exam, behavioral and adherence assessment, urine and blood collection, and counseling will occur at all visits. Blood will also be collected and archived for future research at select visits. Pharmacokinetic studies will occur at some visits. A pap smear will occur at select visits. Some participants may have hair samples collected on an optional basis at study visits every 2 months.

Study Timeline

• Study First Submitted: 2008-06-24
• Study First Submitted QC: 2008-06-24
• Study First Posted: 2008-06-26
• Study Start: 2009-08
• Primary Completion: 2012-08
• Study Completion: 2012-08
• Disposition First Submitted: 2015-05-28
• Disposition First Submitted QC: 2015-07-02
• Disposition First Posted: 2015-07-24
• Results First Submitted: 2016-01-12
• Results First Submitted QC: 2016-01-12
• Status Verified: 2016-02
• Results First Posted: 2016-02-10
• Last Update Submitted: 2021-10-15
• Last Update Posted: 2021-10-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 5029

Inclusion Criteria

• Willing to provide adequate locator information
• Sexually active, defined as having vaginal intercourse at least once in the 3 months prior to screening
• Agree to not participate in other research studies involving drugs, medical devices, or vaginal products for duration of study.
• Agree to use effective method of contraception. More information on this criterion can be found in the protocol.

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Exclusion Criteria

• HIV infected
• Known adverse reaction to any of the study products
• Known adverse reaction to latex
• Pathologic bone fracture not related to trauma
• Non-therapeutic injection drug use in the 12 months prior to screening
• Post-exposure prophylaxis for HIV exposure within 6 months prior to enrollment
• Last pregnancy outcome 42 days or less prior to enrollment
• Gynecologic or genital procedure 42 days or less prior to enrollment
• Participation in any other research study involving drugs, medical devices, or vaginal products 30 days or less prior to enrollment
• Currently using spermicide, interferon or interleukin therapy, or certain medications. More information on this criterion can be found in the protocol.
• Any significant uncontrolled active or chronic disease. More information on this criterion can be found in the protocol.
• Certain abnormal laboratory values. More information on this criterion can be found in the protocol.
• Intends to become pregnant in the 24 months after enrollment
• Plans to relocate or travel away from the study site for more than 8 consecutive weeks in the 24 months after enrollment
• Urinary tract infection
• Pelvic inflammatory disease, an STI, or reproductive tract infection requiring treatment
• Grade 2 or higher pelvic exam finding
• Any condition that, in the opinion of the investigator, would interfere with the study
• Pregnant or breastfeeding

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
1	Emtricitabine/tenofovir disoproxil fumarate placebo	TDF 300 mg tablet taken orally once daily and one FTC/TDF placebo tablet taken orally once daily for 12 to 36 months
2	Emtricitabine/tenofovir disoproxil fumarate	TDF placebo tablet taken orally once daily and one FTC 200 mg/TDF 300 mg tablet taken orally once daily for 12 to 36 months
2	Tenofovir disoproxil fumarate placebo	TDF placebo tablet taken orally once daily and one FTC 200 mg/TDF 300 mg tablet taken orally once daily for 12 to 36 months
5	Tenofovir placebo	Application of tenofovir placebo gel once daily
3	Emtricitabine/tenofovir disoproxil fumarate placebo	TDF placebo tablet taken orally once daily and one FTC/TDF placebo tablet taken orally once daily for 12 to 36 months
3	Tenofovir disoproxil fumarate placebo	TDF placebo tablet taken orally once daily and one FTC/TDF placebo tablet taken orally once daily for 12 to 36 months
4	Tenofovir 1% vaginal gel	Application of tenofovir 1% vaginal gel once daily
1	Tenofovir disoproxil fumarate	TDF 300 mg tablet taken orally once daily and one FTC/TDF placebo tablet taken orally once daily for 12 to 36 months

Primary Outcome Measures

Name	Time	Method
Person-years of Follow-up of Tenofovir 1% Gel and Vaginal Placebo Gel Arms	For up to 30 months of follow-up	Participants were followed for up to 30 months. Person-years measures the amount of time for each participant, in years, from the date of enrollment to the date of the first HIV-positive test result if HIV-infected during follow-up or to the date of the last HIV-negative test result on follow-up if not HIV-infected during follow-up.
Number of HIV-1 Infections of Tenofovir 1% Gel and Vaginal Placebo Gel Arms	For up to 30 months of follow-up	Participants were followed for up to 30 months. Participants were tested monthly for HIV-1 and positive rapid test results were confirmed by means of an enzyme-linked immunosorbent assay (EIA) and subsequent Western blotting (WB).
Incidence Rate of HIV-1 Infections of Tenofovir 1% Gel and Vaginal Placebo Gel Arms	For up to 30 months of follow-up	This is the number of HIV-1 infections divided by the amount of person-years of follow-up time to HIV-1 infection status, multiplied by 100 (per 100 person-years).
Person-years of Follow-up of Oral TDF and Oral Placebo Arms	For up to 30 months of follow-up	Participants were followed for up to 30 months. Person-years measures the amount of time for each participant, in years, from the date of enrollment to the date of the first HIV-positive test result if HIV-infected during follow-up or to the date of the last HIV-negative test result on follow-up if not HIV-infected during follow-up. Note that the data for both of these arms were censored on the date when sites were asked to discontinue treatment in the oral TDF group.
Incidence Rate of HIV-1 Infections of Oral TDF-FTC and Oral Placebo Arms	For up to 30 months of follow-up	This is the number of HIV-1 infections divided by the amount of person-years of follow-up time to HIV-1 infection status, multiplied by 100 (per 100 person-years).
Extended Safety of Daily Tenofovir 1% Gel, Oral TDF, and Oral FTC/TDF in Women at Risk for Sexually Transmitted HIV Infection Based on Occurrence of Grade 2, 3, and 4 Adverse Events	Throughout study, up to 2.5 years	This measure describes the number of participants with elevated serum creatinine levels, the only safety outcome of concern where a significant difference was detected between an active arm and the corresponding placebo arm.
Number of HIV-1 Infections of Oral TDF and Oral Placebo Arms	For up to 30 months of follow-up	Participants were followed for up to 30 months. Participants were tested monthly for HIV-1 and positive rapid test results were confirmed by means of an enzyme-linked immunosorbent assay (EIA) and subsequent Western blotting (WB).
Incidence Rate of HIV-1 Infections of Oral TDF and Oral Placebo Arms	For up to 30 months of follow-up	This is the number of HIV-1 infections divided by the amount of person-years of follow-up time to HIV-1 infection status, multiplied by 100 (per 100 person-years).
Person-years of Follow-up of Oral TDF-FTC and Oral Placebo Arms	For up to 30 months of follow-up	Participants were followed for up to 30 months. Person-years measures the amount of time for each participant, in years, from the date of enrollment to the date of the first HIV-positive test result if HIV-infected during follow-up or to the date of the last HIV-negative test result on follow-up if not HIV-infected during follow-up.
Number of HIV-1 Infections of Oral TDF-FTC and Oral Placebo Arms	For up to 30 months of follow-up	Participants were followed for up to 30 months. Participants were tested monthly for HIV-1 and positive rapid test results were confirmed by means of an enzyme-linked immunosorbent assay (EIA) and subsequent Western blotting (WB).

Secondary Outcome Measures

Name	Time	Method
Frequency of HIV-1 Drug Resistance in Women Who Acquire HIV-1 Infection While Using Study Product	Throughout study, up to 2.5 years	The primary resistance mutations for the study were pre-defined as K65R and K70E (which confer resistance to TDF), and M184I and M184V (which confer resistance to FTC), for their potential to cause a decrease in susceptibility to the study drug. K65R, K70E, and M184I were not detected in HIV-1 from any HIV-1 seroconverters while on study product. The number of HIV-1 seroconverters while on study with the M184V resistance mutation are reported for this outcome measure.

Trial Locations

Locations (15)

Seke South CRS; 🇿🇼 Chitungwiza, Zimbabwe

CAPRISA Aurum CRS; 🇿🇦 Klerksdorp, South Africa

MU-JHU Research Collaboration CRS; 🇺🇬 Kampala, Uganda

Tongaat CRS; 🇿🇦 Tongaat, KwaZulu-Natal, South Africa

Isipingo CRS; 🇿🇦 Westville, KwaZulu-Natal, South Africa

eThekwini CRS; 🇿🇦 Durban, KwaZulu-Natal, South Africa

Chatsworth CRS; 🇿🇦 Chatsworth, KwaZulu-Natal, South Africa

Umkomaas CRS; 🇿🇦 Umkomaas, KwaZulu-Natal, South Africa

Botha's Hill CRS; 🇿🇦 Westville, KwaZulu-Natal, South Africa

Overport CRS; 🇿🇦 Asherville, KwaZulu-Natal, South Africa

Verulam CRS; 🇿🇦 Verulam, KwaZulu-Natal, South Africa

Wits Reproductive Health and HIV Institute CRS (WRHI CRS); 🇿🇦 Johannesburg, Gauteng, South Africa

Soweto MTN CRS; 🇿🇦 Johannesburg, Gauteng, South Africa

Spilhaus CRS; 🇿🇼 Harare, Zimbabwe

Zengeza CRS; 🇿🇼 Chitungwiza, Zimbabwe