Influence of Reproductive Cycle and Menopause on HIV-1 Infection and TFV Gel Activity

Study Overview
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Brief Summary
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Purpose of the study is to assess tenofovir (TFV) PK and PD endpoints, cervicovaginal safety parameters, susceptibility to HIV-1 infection, and objective measures of vaginal applicator use in premenopausal and postmenopausal women.

Detailed Description
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Premenopausal women: Baseline blood and genital samples will be taken in the follicular and luteal phase (visits 2 and 3). The participant will be given TFV gel and instructed to insert two doses, separated by 2 hours, and return to the clinic 3 hours after the second insertion for blood and genital samples (visits 4/4a and 5/5a). Postmenopausal women: Premenopausal women: Baseline blood and genital samples will be taken (visit 2). The participant will be given TFV gel and instructed to insert two doses, separated by 2 hours, and return to the clinic 3 hours after the second insertion for blood and genital samples (visit 3/3a). Estradiol cream will be distributed at visit 4. Post estradiol blood and genital samples will be taken at Visit 5. The participant will given TFV gel and instructed to insert 2 doses as before, while continuing to use the estradiol cream. Post TFV gel and estradiol cream blood and genital samples will be taken (visit 6/6a).

Official Title
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Influence of Female Reproductive Cycle and Menopause on Cervicovaginal Tissue Susceptibility to HIV-1 Infections and Tenofovir 1% Gel Activity

Conditions
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HIV Prevention

Intervention / Treatment
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* Drug: TFV 1% gel
* Drug: Estradiol vaginal cream


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All volunteers In good healthsignificant systemic disease Not at risk of an STI, meaning: In a monogamous heterosexual or same sex relationship for at least the last four months with a partner who is not known to be HIV positive and has no known risks for STIs OR sexually abstinent Willing and able to comply with study procedures Normal Pap smear (by written report) in the past year. Inclusion Criteria: Premenopausal volunteers 21-to-45 years of age Not at risk for pregnancy, meaning: Regular menstrual cycles (every 24 - 35 days) Luteal phase P level of greater than or equal to 3 ng/ml Inclusion Criteria: Postmenopausal volunteers 46-89 years of age OR both ovaries removed at least 30 days prior to Visit 1 No menstrual periods/vaginal bleeding in the past 12 months OR both ovaries removed at least 30 days prior to Visit 1 FSH level of greater than or equal to 20 MIU/ml Exclusion Criteria: All volunteers Clinically significant history of an abnormal Pap smear in the past year Surgery or biopsy of the vagina or cervix within 30 days Current STI or lower genital tract infection Current use of chronic immunosuppressants Current presence of vulvar, anal and/or vaginal genital warts Current tobacco use of any amount History of sensitivity/allergy to any component of the study product, topical anesthetic, or allergy to silver nitrate and/or Monsel's solution Known bleeding disorder that could lead to prolonged or continuous bleeding Grade 1 or higher laboratory abnormality, per the August 2009 update of the DAIDS Table for Grading the Severity of Adverse Events Systemic use in the last two weeks or anticipated use during the study of any of the following: corticosteroids, antibiotics, anticoagulants or other drugs known to prolong bleeding and/or clotting, antifungals, antivirals or antiretrovirals. Investigator discretion Current participation in any other drug or device study Exclusion Criteria: Premenopausal women Use of DMPA in last six months Use of any other hormonal contraceptive method without 2 subsequent, normal menses since stopping hormonal contraceptives Current use of copper IUD Currently pregnant or pregnancy within the past 3 months Currently breastfeeding/having breastfed an infant in the last 2 months Exclusion Criteria: Postmenopausal women Use of any hormonal medications in the past 30 days Contraindications to vaginal estrogen cream

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 89 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Baseline<br>Premenopausal women will undergo baseline sampling in each the follicular and luteal phase. Postmenopausal women will undergo baseline sampling one time. | |
| Experimental: TFV 1% Gel<br>Participants will vaginally insert 1 applicator of TFV gel followed by a 2nd applicator 2 hours later. Each applicator contains 4.4 gm of TFV 1% gel. Premenopausal women will undergo sampling after TFV gel use in each the follicular and luteal phase. Postmenopausal women will undergo sampling after TFV gel use one time. | Drug: TFV 1% gel<br> <br> |
| Experimental: Estradiol Vaginal Cream<br>Post menopausal women only: Participants will insert 2 grams of estradiol cream into the vagina every night for 14 days and then one gram of estradiol cream into the vagina every other night | Drug: Estradiol vaginal cream<br> <br> |
| Experimental: TFV 1% gel and estradiol cream<br>Postmenopausal women only: Participants will vaginally insert 1 applicator of TFV gel followed by a 2nd applicator 2 hours later. Each applicator contains 4.4 gm of TFV 1% gel. In addition, participants will one gram of estradiol cream into the vagina every other night. | Drug: TFV 1% gel<br> <br> Drug: Estradiol vaginal cream<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentrations of tenofovir in plasma, vaginal aspirate, and genital tissue |  | 3 hours after dosing | 
| Concentrations of TFV-DP in genital tissue |  | 3 hours after dosing |