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

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).

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