Adherence and Acceptability to and Blood Levels of Tenofovir Gel and Tablets in HIV Uninfected Women

Phase 2 Adherence and Pharmacokinetics Study of Oral and Vaginal Preparations of Tenofovir

A new approach to HIV prevention currently being studied includes the use of microbicides, substances that kill microbes. Tenofovir disoproxil fumarate (TDF) is an oral, FDA-approved, anti-HIV drug, and tenofovir gel is an experimental microbicide. The purpose of this study is to determine the adherence and acceptability to and blood levels of three daily regimens of tenofovir in both oral and gel form.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Tenofovir disoproxil fumarate; Drug: Tenofovir gel

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 an anti-HIV drug (TDF), this study will measure the adherence and acceptability to and blood levels of the two interventions in three separate regimens given to HIV-uninfected women.

The expected duration of participation for each participant is 21 weeks. Study participants will be randomly assigned into one of six study groups, each with a different regimen sequence. Each sequence will consist of three study periods and three wash-out periods. Each study period lasts 6 weeks, followed by a 1 week wash-out period. The regimen assigned for a given study period will include either oral TDF, tenofovir vaginal gel, or both. All participants will be prescribed all three regimens in the order designated by their randomized assignment.

Study visits will occur at Weeks 1, 3, 6, 7, 10, 13, 14, 17, 20, and 21. Medical history, a physical exam, behavioral assessment, and urine, blood, pelvic sample collection, and counseling will occur at all visits. At some study sites rectal swabs may be performed. Counseling will include information regarding contraception, protocol adherence, HIV, HIV/Sexually Transmitted Infection risk reduction, and male condom use. Pharmacokinetic (PK) studies, to be determined by the study site, will occur during all three study periods. These studies may involve additional procedures.

• Study Type: Interventional
• Enrollment (Actual): 168
• Phase: Phase 2

Contacts and Locations

Study Locations

• South Africa
  • KwaZulu-Natal
    • Durban, KwaZulu-Natal, South Africa
      • Botha's Hill CRS
    • Durban, KwaZulu-Natal, South Africa
      • Umkomaas CRS
• Uganda
  • Kampala, Uganda
    • Makerere University- JHU Research Collaboration {MUJHU CARE LTD} CRS
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Alabama Microbicide CRS
  • New York
    • Bronx, New York, United States
      • Bronx- Lebanon Hospital Center Clinical Research Site (BLHC CRS)
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Case CRS
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213-2582
      • Pitt CRS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• General good health
• HIV-uninfected
• Normal menstrual cycle. More information can be found in the protocol.
• Creatinine clearance greater than 70 ml/min
• Sexually active. More information can be found in the protocol.
• Normal Pap smear result within 12 months prior to study entry
• Agrees to not participate in other investigational studies
• Willing to use effective forms of contraception. More information can be found in the protocol.

Exclusion Criteria:

• Adverse reaction to either of the study products
• Adverse reaction to latex
• Currently sexually active with a partner with history of adverse reaction to latex
• More than three sexual partners in the month prior to screening
• Pathologic bone fracture not related to trauma
• Last pregnancy outcome within 90 days or less prior to enrollment
• Gynecologic or genital procedure within 90 days of study entry
• Enrollment in other investigational study within 30 days of study entry
• Nontherapeutic injection drug use within 12 months of screening
• Any social or medical condition that, in the opinion of the investigator, would interfere with the study
• Abnormal laboratory values
• Grade 2 or higher genital lesions, erythema, and/or edema or has any other abnormal physical or pelvic exam finding that, in the opinion of the investigator, would interfere with the study
• Kidney, reproductive, or urinary tract infection requiring treatment. More information on this criterion can be found in the protocol.
• Pregnant, breastfeeding, or intend to become pregnant
• Unwilling to comply with study participation requirements, including attendance at all scheduled study visits
• Per participant report, use of the following at enrollment, and/or anticipated use during the period of study participation - use of a diaphragm, vaginal ring, and/or spermicide for contraception, acyclovir or valacyclovir, post-exposure prophylaxis for HIV exposure, TDF/emtricitabine, non-study vaginal products

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; Oral tenofovir disoproxil fumarate (TDF) for Weeks 1 through 6, vaginal tenofovir gel application for Weeks 8 through 13, and oral TDF and vaginal tenofovir gel application for Weeks 15 through 20	Drug: Tenofovir disoproxil fumarate; 300 mg tablet daily; Other Names: TDF; Drug: Tenofovir gel; 1 gm/100 ml of 1% gel vaginally daily; Other Names: TFV; 9-[2-(Phosphonomethoxy)propyl]adenine
Experimental: 2; Vaginal tenofovir gel application for Weeks 1 through 6, oral TDF for Weeks 8 through 13, and oral TDF and vaginal tenofovir gel application for Weeks 15 through 20	Drug: Tenofovir disoproxil fumarate; 300 mg tablet daily; Other Names: TDF; Drug: Tenofovir gel; 1 gm/100 ml of 1% gel vaginally daily; Other Names: TFV; 9-[2-(Phosphonomethoxy)propyl]adenine
Experimental: 3; Oral TDF and vaginal tenofovir gel application for Weeks 1 through 6, oral TDF for Weeks 8 through 13, and vaginal tenofovir gel application for Weeks 15 through 20	Drug: Tenofovir disoproxil fumarate; 300 mg tablet daily; Other Names: TDF; Drug: Tenofovir gel; 1 gm/100 ml of 1% gel vaginally daily; Other Names: TFV; 9-[2-(Phosphonomethoxy)propyl]adenine
Experimental: 4; Oral TDF and vaginal tenofovir gel application for Weeks 1 through 6, vaginal tenofovir gel application for Weeks 8 through 13, and oral TDF for Weeks 15 through 20	Drug: Tenofovir disoproxil fumarate; 300 mg tablet daily; Other Names: TDF; Drug: Tenofovir gel; 1 gm/100 ml of 1% gel vaginally daily; Other Names: TFV; 9-[2-(Phosphonomethoxy)propyl]adenine
Experimental: 5; Oral TDF for Weeks 1 through 6, oral TDF and vaginal tenofovir gel application for Weeks 8 through 13, and vaginal tenofovir gel application for Weeks 15 through 20	Drug: Tenofovir disoproxil fumarate; 300 mg tablet daily; Other Names: TDF; Drug: Tenofovir gel; 1 gm/100 ml of 1% gel vaginally daily; Other Names: TFV; 9-[2-(Phosphonomethoxy)propyl]adenine
Experimental: 6; Vaginal tenofovir gel application for Weeks 1 through 6, oral TDF and vaginal tenofovir gel application for Weeks 8 through 13, and oral TDF for Weeks 15 through 20	Drug: Tenofovir disoproxil fumarate; 300 mg tablet daily; Other Names: TDF; Drug: Tenofovir gel; 1 gm/100 ml of 1% gel vaginally daily; Other Names: TFV; 9-[2-(Phosphonomethoxy)propyl]adenine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Self-reported Adherence to Each Regimen	Participant self-reported product use. For each woman, adherence to each regimen was computed by dividing the number of daily doses she reported having taken by the number of doses expect if she were fully adherent.	Measured through Week 21
Proportion of Participants Who Indicate They Would be "Unlikely" Use Study Product in the Future		Measured through Week 21
Systemic and Local PK Among Three Regimens of Tenofovir (Oral, Vaignal, and Dual Use)	PK measures, including maximum concentrations (Cmax) in serum, tissue, and cervicovaginal lavage.	Measured through Week 21

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of Product Use	This number represents how often participant used study product during the preceding 3 weeks and is measured twice during each 6 week product period.	Measured through Week 21
Number of Days Product Missed	This represents the longest number of days in a row during the past 3 weeks that a participant missed using the study product.	Measured through Week 21
Proportion of Women Who Report Taking at Least 90% of Expected Daily Doses		Measured through Week 21
Frequency of Sexual Activity	This represents the rate during the past 3 weeks at which participants engaged in vaginal sex.	Measured through Week 21
Frequency of Male Condom Use		Measured through Week 21
Tablet Usage Before Sex	These summaries represent counts and percentages of participants using tablet before last instance of vaginal sex.	Measured through Week 21
Length of Time Vaginal Sexual Intercourse Took Place After Using Tablet.	Median and inter-quartile range of the time between product usage and instance of vaginal intercourse (given tablet was used before the encounter).	Measured through Week 21
Tablet Usage After Sex	These summaries represent counts and percentages of participants using tablet after last instance of vaginal sex.	Measured through Week 21
Length of Time Vaginal Sexual Intercourse Took Place Before Using Tablet.	Median and inter-quartile range of the time between product usage and instance of vaginal intercourse (given tablet was used after the encounter).	Measured through Week 21
Gel Usage Before Sex	These summaries represent counts and percentages of participants using gel before last instance of vaginal sex.	Measured through Week 21
Length of Time Vaginal Sexual Intercourse Took Place After Using Gel.	Median and inter-quartile range of the time between product usage and instance of vaginal intercourse (given gel was used before the encounter).	Measured through Week 21
Gel Usage After Sex	These summaries represent counts and percentages of participants using gel after last instance of vaginal sex.	Measured through Week 21
Length of Time Vaginal Sexual Intercourse Took Place Before Using Gel.	Median and inter-quartile range of the time between product usage and instance of vaginal intercourse (given gel was used after the encounter).	Measured through Week 21
Reported Sharing of Product	Number and percentage of participants who had a product sharing event during the 6-week product use period, where a sharing event includes 1) being asked for the study product, or 2) selling, trading, or giving away study product, or 3) having someone take the study product from the participant.	Measured through Week 21
Grade 3 or Higher Toxicity for Systemic and Local Effects as Defined by the Protocol		Measured through Week 21

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Microbicide Trials Network
• Investigators: Study Chair: Craig W. Hendrix, MD, Johns Hopkins University

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.
• Bateman C. Tenofovir gel--the new HIV prevention 'banker'? S Afr Med J. 2007 Jul;97(7):496, 498. No abstract available.
• Hendrix CW, Chen BA, Guddera V, Hoesley C, Justman J, Nakabiito C, Salata R, Soto-Torres L, Patterson K, Minnis AM, Gandham S, Gomez K, Richardson BA, Bumpus NN. MTN-001: randomized pharmacokinetic cross-over study comparing tenofovir vaginal gel and oral tablets in vaginal tissue and other compartments. PLoS One. 2013;8(1):e55013. doi: 10.1371/journal.pone.0055013. Epub 2013 Jan 30.
• Minnis AM, van der Straten A, Salee P, Hendrix CW. Pre-exposure Prophylaxis Adherence Measured by Plasma Drug Level in MTN-001: Comparison Between Vaginal Gel and Oral Tablets in Two Geographic Regions. AIDS Behav. 2016 Jul;20(7):1541-8. doi: 10.1007/s10461-015-1081-3.
• Minnis AM, Gandham S, Richardson BA, Guddera V, Chen BA, Salata R, Nakabiito C, Hoesley C, Justman J, Soto-Torres L, Patterson K, Gomez K, Hendrix CW. Adherence and acceptability in MTN 001: a randomized cross-over trial of daily oral and topical tenofovir for HIV prevention in women. AIDS Behav. 2013 Feb;17(2):737-47. doi: 10.1007/s10461-012-0333-8.

Helpful Links

• Click here for the Microbicide Trials Network Web site

Study record dates

Study Major Dates

• Study Start: June 1, 2008
• Primary Completion (Actual): July 1, 2010
• Study Completion (Actual): July 1, 2010

Study Registration Dates

• First Submitted: December 31, 2007
• First Submitted That Met QC Criteria: December 31, 2007
• First Posted (Estimate): January 11, 2008

Study Record Updates

• Last Update Posted (Actual): October 19, 2021
• Last Update Submitted That Met QC Criteria: October 15, 2021
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: HIV Seronegativity; Microbicide
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; 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
• Other Study ID Numbers: MTN-001; 10617 (Registry Identifier: DAIDS ES); 1U01AI068633-01 (U.S. NIH Grant/Contract)