Evaluating the Safety and Pharmacokinetics of Raltegravir in Infants

Participants were enrolled in two cohorts.

Cohort 1 enrolled Mother-Infant (M-I) pairs prior to delivery. Infants expected to be full term (i.e. ≥2000 grams at birth) born to women with HIV-1 infection who received RAL 400 mg twice daily for at least two weeks prior to delivery and continued to receive ARVs during labor, and their mothers, were enrolled to Cohort 1.

Cohort 2 enrolled M-I pairs prior to delivery or within 48 hours after delivery. Infants expected to be LBW (i.e. ≤2500 grams at birth) born to women with HIV-1 infection who received at least one dose of RAL 400 mg within 2 to 24 hours prior to delivery, and their mothers, were enrolled to Cohort 2.

Participant study inclusions and exclusion criteria are listed below.

Cohort 1 M-I pairs were enrolled prior to delivery so that only maternal study inclusion and exclusion criteria were assessed at enrollment.

Cohort 1: Maternal Study Inclusion Criteria

• Documentation of HIV-1 infection.
• Viable singleton pregnancy with gestational age of at least 35 weeks based on clinical or other obstetrical measurements with normal fetal anatomy
• Currently receiving RAL 400 mg twice daily for at least 2 weeks prior to enrollment in combination with other ARV agents for clinical care
• Plan to continue taking RAL in combination with other ARV agents through labor prior to delivery
• Willing and intends to deliver at the study-affiliated clinic or hospital
• Willing and able to sign informed consent for participation of herself and her infant. Participant must be of an age to provide legal informed consent as defined by the country in which she resides. If not, informed consent must be signed by a legal guardian.

Cohort 1: Maternal Study Exclusion Criteria

- Receipt of disallowed medications (phenobarbital, phenytoin, rifampin) within 4 weeks prior to enrollment

Cohort 1 Infants were enrolled prior to delivery so there were no infant study inclusion/exclusion criteria. However, only infants who met the following criteria were eligible for PK blood sampling. Infants ineligible for PK sampling remained in the study and were followed-up for safety.

Cohort 1: Infant PK Sampling Inclusion Criteria

• Infant born to women who received at least 2 weeks of RAL prior to delivery and continue to receive RAL during labor prior to delivery in addition to their other ARV drugs
• Infant birth weight of at least 2 kg
• Infant at least 37 weeks gestation at delivery
• Infant not receiving disallowed medications (phenobarbital, phenytoin, rifampin). If these medications are required for the infant's care, the infant will be ineligible for further PK sampling. PK samples will be obtained up to the time of the introduction of the disallowed medication.

Cohort 1: Infant PK Sampling Exclusion Criteria

- Infant has a severe congenital malformation or other medical condition not compatible with life or that would interfere with study participation or interpretation, as judged by the examining clinician

Cohort 2 enrolled M-I pairs at two time points: prior to delivery and within 48 hours after delivery.

• For M-I pairs enrolled prior to delivery, the maternal study eligibility criteria were assessed at enrollment. There were no infant study eligibility criteria. However, only infants who met the PK sampling eligibility criteria had PK blood sampling. Infants ineligible for PK sampling remained in the study and were followed-up for safety.
• For M-I pairs enrolled within 48 hours delivery, the maternal and infant study eligibility criteria were assessed at enrollment. A M-I pair was enrolled only if both the mother and the infant were eligible for the study. For multiple births, only infants who met the study eligibility criteria were enrolled.

Cohort 2: Maternal Study Inclusion Criteria: M-I pairs enrolled prior to delivery

• Documentation of HIV-1 infection.
• Viable singleton or multiple birth pregnancy based on clinical or other obstetrical measurements with infant birth weight anticipated to be less than or equal to 2,500 grams
• RAL is currently used as part of maternal ARV regimen and planned to continue through labor and delivery
• Willing and intends to deliver at the study-affiliated clinic or hospital
• Willing and able to sign informed consent for participation of herself and her infant. Participant must be of an age to provide legal informed consent as defined by the country in which she resides. If not, informed consent must be signed by a legal guardian.

Cohort 2: Maternal Study Exclusion Criteria: M-I pairs enrolled prior to delivery

- Receipt of disallowed medications (phenobarbital, phenytoin, rifampin) within 4 weeks prior to enrollment or intent to be on any of the disallowed medications prior to delivery.

Cohort 2: Infant PK Blood Sampling Eligibility Criteria: M-I pairs enrolled prior to delivery

Infants were enrolled prior to delivery so there were no infant study eligibility criteria. Only infants who met the following criteria were eligible for PK blood sampling:

• Infant born to woman who received at least one dose of RAL within 2 to 24 hours prior to delivery. Dose administered to mother must have been at least 2 hours prior to delivery to allow time for adequate absorption and distribution.
• Infant birth weight less than or equal to 2,500 grams
• Infant not receiving disallowed medications (phenobarbital, phenytoin, rifampin) as described in the protocol. If these medications are required for the infant's care, the infant will be ineligible for further PK sampling. PK data will be obtained up to the time of the introduction of the disallowed medication.
• Infant less than or equal to 48 hours of age
• Infant does not have any severe congenital malformation or other medical condition not compatible with life or that would interfere with study participation or interpretation, as judged by the examining clinician

Cohort 2: Maternal Study Inclusion Criteria: M-I pairs enrolled after delivery

• Documentation of HIV-1 infection.
• Received at least one dose of RAL within 2 to 24 hours prior to delivery
• Willing and able to sign informed consent for participation of herself and her infant. Participant must be of an age to provide legal informed consent as defined by the country in which she resides. If not, informed consent must be signed by a legal guardian.

Cohort 2: Maternal Study Exclusion Criteria: M-I pairs enrolled after delivery

- Receipt of disallowed medications (phenobarbital, phenytoin, rifampin) within 4 weeks prior to delivery

Cohort 2: Infant Study Inclusion Criteria: M-I pairs enrolled after delivery

• Infant birth weight less than or equal to 2,500 grams
• Infant less than or equal to 48 hours of age

Cohort 2: Infant Study Exclusion Criteria: M-I pairs enrolled after delivery

• Received disallowed medications (phenobarbital, phenytoin, rifampin)
• Infant has a severe congenital malformation or other medical condition not compatible with life or that would interfere with study participation or interpretation, as judged by the examining clinician