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

Phase 2B Safety and Effectiveness Study of Tenofovir 1% Gel, Tenofovir Disproxil Fumarate Tablet and Emtricitabine/Tenofovir Disoproxil Fumarate Tablet for the Prevention of HIV Infection in Women

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.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Emtricitabine/tenofovir disoproxil fumarate placebo; Drug: Tenofovir disoproxil fumarate; Drug: Emtricitabine/tenofovir disoproxil fumarate; Drug: Tenofovir disoproxil fumarate placebo; Drug: Tenofovir 1% vaginal gel; Drug: Tenofovir placebo

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 Type: Interventional
• Enrollment (Actual): 5029
• Phase: Phase 2

Contacts and Locations

Study Locations

• South Africa
  • Klerksdorp, South Africa, 2571
    • CAPRISA Aurum CRS
  • Gauteng
    • Johannesburg, Gauteng, South Africa, 2001
      • Wits Reproductive Health and HIV Institute CRS (WRHI CRS)
    • Johannesburg, Gauteng, South Africa
      • Soweto MTN CRS
  • KwaZulu-Natal
    • Asherville, KwaZulu-Natal, South Africa, 4091
      • Overport CRS
    • Chatsworth, KwaZulu-Natal, South Africa, 4030
      • Chatsworth CRS
    • Durban, KwaZulu-Natal, South Africa, 4001
      • eThekwini CRS
    • Tongaat, KwaZulu-Natal, South Africa, 4400
      • Tongaat CRS
    • Umkomaas, KwaZulu-Natal, South Africa, 4170
      • Umkomaas CRS
    • Verulam, KwaZulu-Natal, South Africa, 4340
      • Verulam CRS
    • Westville, KwaZulu-Natal, South Africa, 3630
      • Botha's Hill CRS
    • Westville, KwaZulu-Natal, South Africa, 3630
      • Isipingo CRS
• Uganda
  • Kampala, Uganda
    • MU-JHU Research Collaboration CRS
• Zimbabwe
  • Chitungwiza, Zimbabwe
    • Seke South CRS
  • Chitungwiza, Zimbabwe
    • Zengeza CRS
  • Harare, Zimbabwe
    • Spilhaus CRS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; TDF 300 mg tablet taken orally once daily and one FTC/TDF placebo tablet taken orally once daily for 12 to 36 months	Drug: Emtricitabine/tenofovir disoproxil fumarate placebo; placebo tablet; Other Names: FTC/TDF placebo; Truvada placebo; Drug: Tenofovir disoproxil fumarate; 300 mg tablet; Other Names: TDF
Experimental: 2; 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	Drug: Emtricitabine/tenofovir disoproxil fumarate; 200 mg/300 mg tablet; Other Names: Truvada; FTC/TDF; Drug: Tenofovir disoproxil fumarate placebo; placebo tablet; Other Names: TDF placebo
Experimental: 3; TDF placebo tablet taken orally once daily and one FTC/TDF placebo tablet taken orally once daily for 12 to 36 months	Drug: Emtricitabine/tenofovir disoproxil fumarate placebo; placebo tablet; Other Names: FTC/TDF placebo; Truvada placebo; Drug: Tenofovir disoproxil fumarate placebo; placebo tablet; Other Names: TDF placebo
Experimental: 4; Application of tenofovir 1% vaginal gel once daily	Drug: Tenofovir 1% vaginal gel; 1 gm/100 ml of 1% gel; Other Names: TFV; 9-[2-(Phosphonomethoxy)propyl]adenine
Experimental: 5; Application of tenofovir placebo gel once daily	Drug: Tenofovir placebo; placebo gel; Other Names: TFV placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Person-years of Follow-up of Tenofovir 1% Gel and Vaginal Placebo Gel Arms	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.	For up to 30 months of follow-up
Number of HIV-1 Infections of Tenofovir 1% Gel and Vaginal Placebo Gel Arms	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).	For up to 30 months of follow-up
Incidence Rate of HIV-1 Infections of Tenofovir 1% Gel and Vaginal Placebo Gel Arms	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).	For up to 30 months of follow-up
Person-years of Follow-up of Oral TDF and Oral Placebo Arms	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.	For up to 30 months of follow-up
Number of HIV-1 Infections of Oral TDF and Oral Placebo Arms	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).	For up to 30 months of follow-up
Incidence Rate of HIV-1 Infections of Oral TDF and Oral Placebo Arms	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).	For up to 30 months of follow-up
Person-years of Follow-up of Oral TDF-FTC and Oral Placebo Arms	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.	For up to 30 months of follow-up
Number of HIV-1 Infections of Oral TDF-FTC and Oral Placebo Arms	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).	For up to 30 months of follow-up
Incidence Rate of HIV-1 Infections of Oral TDF-FTC and Oral Placebo Arms	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).	For up to 30 months of follow-up
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	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.	Throughout study, up to 2.5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of HIV-1 Drug Resistance in Women Who Acquire HIV-1 Infection While Using Study Product	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.	Throughout study, up to 2.5 years

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Microbicide Trials Network
• Investigators: Study Chair: Zvavahera M. Chirenje, MD, FRCOG, UZ-UCSF Collaborative Research Programme; Study Chair: Jeanne Marrazzo, MD, MPH, University of Washington, Division of Allergy and Infectious Disease

Publications and helpful links

General Publications

• Mayer KH, Maslankowski LA, Gai F, El-Sadr WM, Justman J, Kwiecien A, Masse B, Eshleman SH, Hendrix C, Morrow K, Rooney JF, Soto-Torres L; HPTN 050 Protocol Team. Safety and tolerability of tenofovir vaginal gel in abstinent and sexually active HIV-infected and uninfected women. AIDS. 2006 Feb 28;20(4):543-51. doi: 10.1097/01.aids.0000210608.70762.c3.
• Rosen RK, Morrow KM, Carballo-Dieguez A, Mantell JE, Hoffman S, Gai F, Maslankowski L, El-Sadr WM, Mayer KH. Acceptability of tenofovir gel as a vaginal microbicide among women in a phase I trial: a mixed-methods study. J Womens Health (Larchmt). 2008 Apr;17(3):383-92. doi: 10.1089/jwh.2006.0325.
• Chirenje ZM, Gundacker HM, Richardson B, Rabe L, Gaffoor Z, Nair GL, Mirembe BG, Piper JM, Hillier S, Marrazzo J. Risk Factors for Incidence of Sexually Transmitted Infections Among Women in a Human Immunodeficiency Virus Chemoprevention Trial: VOICE (MTN-003). Sex Transm Dis. 2017 Mar;44(3):135-140. doi: 10.1097/OLQ.0000000000000568.
• Moodley J, Naidoo S, Moodley J, Ramjee G. Sharing of Investigational Drug Among Participants in the Voice Trial. AIDS Behav. 2016 Nov;20(11):2709-2714. doi: 10.1007/s10461-016-1414-x. Erratum In: AIDS Behav. 2016 Nov;20(11):2715-2716.
• van der Straten A, Brown ER, Marrazzo JM, Chirenje MZ, Liu K, Gomez K, Marzinke MA, Piper JM, Hendrix CW; MTN-003 VOICE Protocol Team for Microbicide Trials Network. Divergent adherence estimates with pharmacokinetic and behavioural measures in the MTN-003 (VOICE) study. J Int AIDS Soc. 2016 Feb 4;19(1):20642. doi: 10.7448/IAS.19.1.20642. eCollection 2016.
• Noguchi LM, Richardson BA, Baeten JM, Hillier SL, Balkus JE, Chirenje ZM, Bunge K, Ramjee G, Nair G, Palanee-Phillips T, Selepe P, van der Straten A, Parikh UM, Gomez K, Piper JM, Watts DH, Marrazzo JM; VOICE Study Team. Risk of HIV-1 acquisition among women who use diff erent types of injectable progestin contraception in South Africa: a prospective cohort study. Lancet HIV. 2015 Jul;2(7):e279-87. doi: 10.1016/S2352-3018(15)00058-2.
• Dai JY, Hendrix CW, Richardson BA, Kelly C, Marzinke M, Chirenje ZM, Marrazzo JM, Brown ER. Pharmacological Measures of Treatment Adherence and Risk of HIV Infection in the VOICE Study. J Infect Dis. 2016 Feb 1;213(3):335-42. doi: 10.1093/infdis/jiv333. Epub 2015 Jun 29.
• Marrazzo JM, Ramjee G, Richardson BA, Gomez K, Mgodi N, Nair G, Palanee T, Nakabiito C, van der Straten A, Noguchi L, Hendrix CW, Dai JY, Ganesh S, Mkhize B, Taljaard M, Parikh UM, Piper J, Masse B, Grossman C, Rooney J, Schwartz JL, Watts H, Marzinke MA, Hillier SL, McGowan IM, Chirenje ZM; VOICE Study Team. Tenofovir-based preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2015 Feb 5;372(6):509-18. doi: 10.1056/NEJMoa1402269.

Helpful Links

• Click here for the Microbicide Trials Network Web site

Study record dates

Study Major Dates

• Study Start: August 1, 2009
• Primary Completion (Actual): August 1, 2012
• Study Completion (Actual): August 1, 2012

Study Registration Dates

• First Submitted: June 24, 2008
• First Submitted That Met QC Criteria: June 24, 2008
• First Posted (Estimate): June 26, 2008

Study Record Updates

• Last Update Posted (Actual): October 29, 2021
• Last Update Submitted That Met QC Criteria: October 15, 2021
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Keywords: HIV Seronegativity; Microbicide
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; HIV Infections; Infections; Acquired Immunodeficiency Syndrome; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Tenofovir; Emtricitabine; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
• Other Study ID Numbers: MTN-003 (VOICE); 10622 (DAIDS ES); MTN-003 (Other Identifier: Microbicide Trials Network); 5U01AI068633-05 (U.S. NIH Grant/Contract); VOICE (Other Identifier: Microbicide Trials Network)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No