Contraception and Menstrual Cycle Effect on Pharmacokinetics, Pharmacodynamics and Safety in Tenofovir Vaginal Gel Use

Each woman will be seen in 6 visits and will be contacted by two scheduled follow-up
telephone calls/visits. Volunteers will be consented at Visit 1 and undergo procedures to
assess whether they are eligible to continue in the study. At Visit 2 (cycle days 20-25),
after it has been confirmed that the participant meets all of the inclusion criteria and
none of the exclusion criteria, genital samples will be taken and she will be given 2
applicators of tenofovir 1% gel to insert two hours apart. She will be instructed to return
for Visit 3, approximately 3 or 11 hours after insertion of the second gel, as determined by
randomization. The participant will retain this sampling assignment throughout the study.

At Visit 3 (cycle days 20-25), blood and genital samples will be collected. The participant
will again be given 2 applicators of tenofovir 1% gel to insert two hours apart. She will
be instructed to return approximately 3 or 11 hours after insertion of the second gel for
Visit 4 (cycle days 5-10) and blood and genital samples will be taken. The participant will
then start the contraceptive method that she has chosen from the two methods being evaluated
in the study.

Each participant will be contacted about 4-5 weeks after Visit 4 to confirm the next visit
date (Visit 5).

Visit 5 will take place about 6 weeks after starting contraception and will not have an
associated gel use. Follow-up genital samples will be collected at Visit 5. The participant
will be given 2 applicators of tenofovir 1% gel to insert two hours apart prior to Visit 6.

Visit 6 will take place about 10 weeks after starting contraception. Follow-up blood and
genital samples will be collected approximately 3 or 11 hours after insertion of the second
gel.

Each participant also will have a follow-up call or visit approximately 1-2 weeks after
Visit 6 to confirm that there have been no adverse experiences. If necessary, she may be
seen in an unscheduled visit for follow-up. She will then be exited from the study.

Inclusion Criteria:

- Willing and able to use OCs or DMPA

- General good health (by volunteer history and investigator assessment) without any
clinically significant systemic disease

- Currently having regular menstrual cycles of 25 to 35 days by volunteer report

- History of Pap smears and follow-up consistent with American Congress of
Obstetricians and Gynecologists (ACOG) practice bulletin #99 or #109 or willing to
undergo a Pap smear at Visit 1

- Willing to follow protocol requirements including abstinence, use of study condoms,
and prohibited use of intravaginal products

- Willing to follow post-biopsy restrictions for at least 5 days following genital
biopsies

- Meets one of the following criteria:

1. Sexually abstinent and planning to remain abstinent for the duration of the
study.

2. In a mutually monogamous relationship for at least the last 4 months with a male
partner who is at least 18 years of age, willing to use condoms, and has no
known HIV infection or risks for sexually transmitted infections (STIs)

3. In a mutually monogamous same-sex relationship for at least the last 4 months
with a partner who is at least 18 years of age and has no known HIV infection or
risks for STIs

- Vaginal and cervical anatomy that, in the opinion of the investigator, lends itself
to easy genital tract sample collection

- Negative urine pregnancy test

- Willing to give voluntary consent, sign an informed consent form and comply with
study procedures, as required by the protocol

Exclusion Criteria:

- History of hysterectomy

- Currently pregnant or within 2 calendar months from the last pregnancy outcome.
(Note: If recently pregnant must have had at least 2 spontaneous menses since
pregnancy outcome.)

- Use of any hormonal contraceptive method in the last 30 days (oral, transdermal,
transvaginal, implant, or hormonal intrauterine contraceptive device)

- Injection of DMPA in the last 6 months

- Protection from pregnancy by presence of a copper IUD

- Currently breastfeeding or having breastfed an infant in the last 2 months, or
planning to breastfeed during the course of the study

- History of sensitivity/allergy to any component of the study product, or topical
anesthetic, or allergy to both silver nitrate and Monsel's solution

- Diagnosed with or treated for any STI or pelvic inflammatory disease in the last 6
months. (Note: Women with a history of genital herpes or condylomata who have been
asymptomatic for at least 6 months may be considered for eligibility.)

- Positive test for Trichomonas vaginalis, Neisseria gonorrhoeae or Chlamydia
trachomatis

- Symptomatic vulvovaginal candidiasis, Nugent score greater than or equal to 7 at
screening or bacterial vaginosis (BV) at Visit 2, or urinary tract infection (UTI)

- Deep epithelial genital findings such as abrasions, ulcerations, or lacerations, or
vesicles suspicious for STIs

- Positive test for HIV

- Positive test for Hepatitis B surface antigen (HBsAg)

- Known bleeding disorder that could lead to prolonged or continuous bleeding with
biopsy

- Chronic or acute vulvar or vaginal symptoms (e.g., pain, irritation, or spotting)

- Contraindications to the chosen contraceptive method

- Known current drug or alcohol abuse which could impact study compliance

- Grade 1 or higher laboratory abnormality, per the August 2009 update of the DAIDS
Table for Grading the Severity of Adverse Events

- Participation in any other investigational trial (device, drug, or vaginal trial) in
the last 30 days or planned participation in any other investigational trial during
the study

- History of gynecological procedures (including genital piercing) on the external
genitalia, vagina or cervix in the last 14 days

- Abnormal finding on laboratory or physical examination or a social or medical
condition which, in the opinion of the investigator, would make participation in the
study unsafe or would complicate interpretation of data

- Systemic use in the last two weeks or anticipated use during the study of any of the
following: corticosteroids, antibiotics, antifungals, antivirals or antiretrovirals