A Phase I Open Label Trial of the Safety and Pharmacokinetics of Tenofovir Disoproxil Fumarate in HIV-1 Infected Pregnant Women and Their Infants

Rates of MTCT of HIV have dramatically decreased in resource-rich countries since the introduction of antiretroviral (ARV) prophylaxis; increased prenatal care, HIV testing, and counseling; elective cesarean delivery; and avoidance of breastfeeding. In resource-limited countries, however, MTCT of HIV continues to be a widespread problem. In these parts of the world, ARV prophylaxis is too expensive and too difficult to adequately administer; mothers often do not receive proper prenatal care; cesarean delivery may pose risks to the mother and and her infant; and due to the lack of safe, affordable, and socially acceptable alternatives, HIV infected mothers breastfeed their infants. The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics (PK) of TDF in HIV infected pregnant women and their infants.

Participants in this study will be enrolled through 12 months after delivery. During the last trimester of pregnancy, HIV infected women will be screened for eligibility. Women will be enrolled into the study upon presentation at the study site for delivery. Standard of care with ARVs for prevention of MTCT will be offered to all women and their infants both inside and outside of the study; however, such ARVs will not be provided by this study.

There will be four cohorts in this study:

• Cohort 1 women will receive a single dose of TDF (SD TDF) during active labor. Cohort 1 women will be hospitalized at the delivery facility through Day 3 postpartum.
• Cohort 2 women will not receive any TDF. Cohort 2 women will be hospitalized at the delivery facility through Day 7 postpartum. Their infants will receive TDF at birth and on Days 3 and 5 after birth.
• Cohort 3 will not begin enrolling women until data safety evaluations of Cohorts 1 and 2 are completed. Cohort 3 women will be hospitalized at the delivery facility through Day 7 postpartum. Women in Cohort 3 will receive SD TDF during active labor, and their infants will receive TDF at birth and on Days 3 and 5 after birth.
• Cohort 4, which was added to the study based on a review of data from the other cohorts, will be similar to Cohort 3, except that infants will receive daily TDF for the 7 days after birth. Researchers believe this higher and more frequent dosing of TDF in infants will help them meet the target TDF concentration specified in the protocol.

There will be seven study visits for women at study entry (Day 0), Day 2, between Days 5 and 7, at Weeks 6 and 12, and at Months 6 and 12 postpartum. Medical history, a short physical exam, and blood collection will occur at all visits. In Cohorts 1, 3, and 4, blood collection for PK studies will occur prior to receiving TDF and seven times post-dose.