Using Nevirapine to Prevent Mother-to-Child HIV Transmission During Breastfeeding

A Phase III Trial to Determine the Efficacy and Safety of an Extended Regimen of Nevirapine in Infants Born to HIV-Infected Women to Prevent Vertical HIV Transmission During Breastfeeding

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute on Drug Abuse (NIDA), National Institute of Mental Health (NIMH)

The many benefits of breastfeeding are well documented. However, because of the risk of mother-to-child transmission (MTCT) of HIV from an HIV infected mother to her infant, there is considerable concern over the practice, especially in developing countries. The purpose of this study is to determine the safety and effectiveness of the anti-HIV drug nevirapine (NVP) in preventing MTCT of HIV in breastfeeding infants born to HIV infected women in South Africa, Tanzania, Uganda, and Zimbabwe.

Breastfeeding provides general health, growth, and development benefits to an infant and significantly decreases the risk of certain acute and chronic diseases. Breastfeeding also decreases financial burden on the mother by decreasing the need for infant formula and health care for the infant. However, clinical evidence has shown that HIV can be readily transmitted through breast milk, although the risk of HIV MTCT over time while breastfeeding has been difficult to determine. Given the many advantages of breastfeeding and the significant obstacles to substituting formula for breast milk in developing countries, there is an urgent need to make breastfeeding by HIV infected women safe. This study will evaluate the safety and efficacy of an extended NVP regimen for prevention of MTCT of HIV through breastfeeding. This study will last approximately 3.5 years. Mother/infant pairs will be enrolled over a period of 18 to 24 months. During the third trimester of pregnancy, HIV infected participants will receive HIV counseling and the intrapartum/neonatal two-dose NVP prophylaxis regimen to prevent MTCT. Mothers will also be given infant feeding options counseling and information on administering the study drug to the infant. Infants who were randomly assigned to receive a placebo and older than 6 weeks of age as of 08/10/07 OR to receive NVP will continue their treatment assignment. Infants who were randomly assigned to receive a placebo and are 6 weeks of age or less as of 08/10/07 will receive open-label NVP through Day 42 of life. For all other participants, all randomized infants will receive extended NVP through 6 weeks (Day 42) of life. All eligible infants will be randomly assigned to one of two groups at Week 6 following birth. The first group will receive extended NVP treatment; the second group will receive nevirapine placebo. Randomized infants will receive the extended NVP or NVP placebo through the first 6 months of life or until cessation of breastfeeding, whichever occurs earlier. Mothers will be instructed to begin giving their infants their assigned intervention starting at Day 3 to Day 7 postpartum. All mothers and infants outside of the study will be offered the local standard of care antiretroviral (ARV) regimen for the prevention of MTCT, but these ARVs will not be provided by the study. Follow-up evaluations will be conducted at Weeks 2 and 6 and Months 3, 6, 12, and 18 for mothers, and at Weeks 2, 5, 6, and 8 and Months 3, 4, 5, 6, 9, 12, and 18 for infants. Study visits will include physical examinations, blood tests (including HIV tests), and medical histories. Study participants will be followed for up to 3.5 years.

10 mg/ml oral suspension taken once daily up to 6 months of age. Dosage will increase throughout study.

HIV Infection in Infants Determined to be HIV Uninfected at 6 Weeks Enrolled in Each Arm of the Study

For those infants who were randomized at 6 weeks and who initiated study drug we looked at the frequency and severity of adverse reactions through 18 months of study. The severity of all AEs was graded according to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. The term severity is described as the intensity grade or level for specific event (i.e. mild, moderate, severe, or life-threatening). Severity is not the same as seriousness.

Note: As of 08/10/07, the arm assignments for current and new participants have changed. Please see the above description for this trial for more information. Inclusion Criteria for Mothers: 18 years of age or older HIV infected In third trimester of pregnancy, or at most 3 days post-delivery If baby is not yet born, planning to deliver at a facility where the study is being conducted Plan to breastfeed Exclusion Criteria for Mothers: Complications with this pregnancy Serious medical condition that would interfere with the study (e.g., that would prevent breastfeeding or adherence to the follow-up schedule), as judged by the on-site clinician Inclusion Criteria for Infants: Born to an HIV infected mother who is eligible for the study Weighed at least 2000 grams (4.4 lbs) at birth Blood sample obtained from the infant for HIV-1 DNA PCR, CBC with differential, and ALT Infants in a multiple birth are eligible only if both/all infants are eligible for the study and assigned to the same study group Able to breastfeed (e.g., mother and infant alive with no condition apparent that would prevent breastfeeding) Exclusion Criteria for Infants: HIV DNA PCR positive at birth ALT of Grade 2 or higher at birth Hemoglobin, absolute neutrophil count, or platelet count of Grade 3 or higher at birth Skin rash of Grade 2B (urticaria), Grade 3, or above Confirmed or suspected clinical hepatitis Serious illness or condition that would interfere with compliance with study procedures

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