Safety and Blood Levels of Tenofovir Disoproxil Fumarate in HIV Infected Pregnant Women and Their Babies

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

To prevent mother-to-child transmission (MTCT) of HIV in resource-limited countries, a simple yet effective treatment plan is needed. Tenofovir disoproxil fumarate (TDF) is an anti-HIV drug approved for use in the United States for the treatment of HIV infected adults. The purpose of this study is to determine the safety, tolerability, and blood levels of TDF in HIV infected pregnant women and their babies. The study will be conducted at sites in Malawi and Brazil.

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.

There will be eight study visits for infants, which will occur within 24 hours of birth; on Day 3; between Days 5 and 7; at Weeks 6 and 12; and at Months 6, 9, and 12. Medical history, a physical exam, and blood collection will occur at all visits. Infants will have x-rays to assess bone health at Day 3 and Month 3, except in Cohort 4, which will not include x-rays of infants. Infants of Cohort 1 will have blood collection for PK studies at birth and four times after birth. Infants of Cohorts 2 and 3 will undergo blood collections for PK studies at birth, Day 3, and Day 5. Blood collection at these visits will occur before receiving TDF and 2 and 10 hours after receiving TDF. At birth, an additional collection will occur 18 to 24 hours after receiving TDF, and on Day 5, two additional collections will occur--at 18 to 24 hours and at 36 to 48 hours after receiving TDF. Infants of Cohort 4 will have blood collection for PK studies at birth and after their fourth and seventh doses of TDF.

Inclusion Criteria for HIV Infected Pregnant Women:

• HIV-1 infected
• Intend to deliver at the study site
• Willing to be contacted or visited at home
• Willing to be admitted to and remain in the delivery facility through Day 3 postpartum (Cohort 1) or Day 7 postpartum (Cohorts 2 and 3)

Exclusion Criteria for HIV Infected Pregnant Women:

• Prior treatment with TDF
• Active opportunistic infection
• Serious bacterial infection
• Chronic malabsorption or diarrhea during the current pregnancy
• Clinically significant disease or condition that, in the opinion of the study clinician, would interfere with the study
• Known multiple gestation (twins, etc.) prior to study entry
• Participation in any other therapeutic or vaccine trial during the current pregnancy
• Use of certain medications
• Any other condition or situation that, in the opinion of the investigator, would interfere with the study
• For Cohort 4, use of atazanavir or lopinavir/ritonavir (Kaletra) within 2 weeks of anticipated delivery

Exclusion Criteria for Infants Born to HIV Infected Pregnant Women:

• Birth weight of less than 2 kg (4.4 lbs)
• Severe congenital malformation or other medical condition that may affect survival and, in the opinion of the clinician, participation in this study
• Grade 2 or higher serum creatinine level or any other Grade 3 or higher toxicity
• Part of a multiple birth (twins, etc.)