Evaluation of the Cellular Pharmacology of Tenofovir and Emtricitabine According to HIV Infection Status

Tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) are both nucleoside reverse
transcriptase inhibitors (NRTIs), a class of medications used for the treatment and
prevention of HIV/AIDS. Analyzing how the body interacts with these medications at the
cellular level may lead to more effective dosing strategies for both HIV prevention and
treatment. This study will examine the pharmacokinetics of TDF and FTC at the cellular level
in HIV-infected people (N=20) and HIV-uninfected people (N=20). HIV-infected participants
will be allowed to take part in this study only if their doctor already plans to prescribe
TDF, FTC, and efavirenz (EFV) for their HIV care, regardless of their participation in this
study. HIV-infected participants will receive Truvada (TDF/FTC) and EFV for the first 30
days. After Day 30, participants will continue to receive TDF, FTC, and EFV through Day 60,
under the direction of their physician. HIV-infected participants will remain on their
therapy throughout the study as part of their HIV care. HIV-uninfected volunteers will
receive 30 days of Truvada (TDF/FTC).

The study duration is 60 days. Study visits will occur at baseline and on Days 1, 3, 7, 20,
30, and 60. At most study visits, participants will undergo blood and urine collection for
pharmacology studies, a medication history review, and an adverse effects questionnaire.
HIV-uninfected participants will also attend two additional study visits at Days 35 and 45 -
while off study medication - for blood and urine collection, adverse effects questionnaires,
and a medication history review. At varying study visits during the first 30 days, all
participants will undergo one rectal biopsy, female participants will undergo one cervical
cell and fluid sampling procedure, and male participants will provide one semen sample. In
addition to the collections from enrolled participants, study researchers will also analyze
previously collected and stored blood samples from participants in the "Chemoprophylaxis for
HIV Prevention in Men (iPrEx)" study, which examined the use of TDF and FTC for the
prevention of HIV in men who have sex with men (MSM).

Inclusion Criteria for HIV-Uninfected Participants:

- Ability to provide informed consent

- Ability to comply with the study procedures

Exclusion Criteria for HIV-Uninfected Participants:

- Positive screening test for HIV infection

- Positive screening test for hepatitis B (HBV) infection

- Pregnant or planning to become pregnant in the 3 months after study entry

- Breastfeeding

- If sexually active and fertile (no tubal ligation or hysterectomy), refusal to use
two forms of birth control (e.g., condom and hormonal birth control) during the
60-day study

- Estimated glomerular filtration rate (GFR) less than 60 mL/min/1.73 m^2 by the
Modification of Diet in Renal Disease (MDRD) method

- Albuminuria (greater than 30 mg urine albumin per g of urine creatinine)

- Blood donation within 56 days of the screening visit

- Any grade I or higher abnormality in hemoglobin, platelets, serum phosphorous, and
lipase on the screening visit; grade I abnormalities in other labs will be evaluated
on a case by case basis (using DAIDS criteria)

- Any greater than grade I abnormality in screening laboratory tests (using DAIDS
grading criteria)

- Medical history of chronic uncontrolled high blood pressure equal to or above 140/90
mm Hg

- Use of any investigational medication in the 30 days before study entry

- Daily anticoagulant therapy (daily aspirin or non-steroidal anti-inflammatory drugs
[NSAIDs] will be allowed if discontinued for 1 week prior to the rectal biopsy)

- Any nephrotoxic concomitant medication (e.g., aminoglycosides, cyclosporine,
cidofovir, foscarnet, amphotericin B)

- Active recreational drug or alcohol abuse

- Any concomitant medication (or herbal product) that, in the opinion of the
investigators, would interfere with the study outcomes (acceptable medications
include acetaminophen, occasional ibuprofen/NSAID, vitamins, and birth control pills)

- History of pathologic bone fractures

- Any chronic or acute medical condition that, in the opinion of the investigator,
would interfere with study conditions, such as cancer, heart disease, or diabetes

- Body weight under 110 pounds

Inclusion Criteria for HIV-Infected Participants:

- HIV-infected adults (HIV documented in medical record or by the primary clinician)

- Clinician/participant plan to initiate TDF/FTC/EFV therapy and agree to separate
TDF/FTC and EFV prescriptions for the initial 30 days of the study

- Ability to provide informed consent

- Ability to comply with the study procedures

Exclusion Criteria for HIV-Infected Participants:

- Antiretroviral therapy in the preceding 6 months

- Pregnant or planning to become pregnant in the 3 months after study entry

- Breastfeeding

- If sexually active and fertile (no tubal ligation or hysterectomy), refusal to use
two forms of birth control (e.g., condom and hormonal birth control) during the
60-day study

- Estimated GFR less than 60 mL/min/1.73 m^2 by the MDRD method

- Albuminuria (greater than 30 mg urine albumin per g of urine creatinine)

- Greater than a grade II abnormality in hemoglobin or platelets. Greater than a grade
II abnormality in other clinical chemistry or hematology tests that, in the opinion
of the investigators (principal investigator, study coordinator, and study physician)
and primary clinician, would preclude participation in the study. DAIDS grading
criteria will be used.

- Use of any investigational medication in the 30 days before study entry

- Daily anticoagulant therapy (daily aspirin or NSAIDs will be allowed if discontinued
for 1 week prior to the rectal biopsy)

- Any nephrotoxic concomitant medication (e.g., aminoglycosides, cyclosporine,
cidofovir, foscarnet, amphotericin B)

- Any concomitant medication (or herbal product) that, in the opinion of the
investigators, would interfere with the study outcomes (acceptable medications
include acetaminophen, occasional ibuprofen/NSAID, vitamins, and birth control pills)

- Any chronic or acute medical condition that, in the opinion of the investigator,
could lead to emergent health complications, or could interfere with the
participant's ability to follow study procedures

- Body weight under 110 pounds