Evaluating the Safety and Pharmacokinetics of Raltegravir in Infants
Evaluating the Safety and Pharmacokinetics of Raltegravir in Infants
The purpose of this study was to determine the washout pharmacokinetics (PK) and safety of in
 utero/intrapartum exposure to maternal raltegravir (RAL) in infants born to pregnant women
 with HIV infection who received RAL 400 mg twice daily. The study also provided data for the
 development of an infant RAL starting dosing regimen for IMPAACT P1110 (NCT01780831).
Study participants were enrolled in two cohorts.

 -  Cohort 1 enrolled mother-infant pairs in which the infant was expected to be ≥2000 grams
 at birth (i.e. full term) at time of enrollment and the mother was living with HIV and
 received RAL 400 mg twice daily for at least 2 weeks prior to delivery and continued to
 receive antiretroviral (ARV) drugs during labor.

 -  Cohort 2 enrolled mother-infant pairs in which the infant was expected to be ≤2500 grams
 at birth [i.e. low birth weight (LBW)] at time of enrollment and the mother was living
 with HIV and received at least one dose of RAL 400 mg within 2 to 24 hours prior to
 delivery.

 Cohorts 1 and 2 provided pharmacokinetics and safety data of in utero and intrapartum
 exposure to maternal RAL in full-term and LBW infants, respectively. Also, the study data
 were pooled with data from IMPAACT P1066 (NCT00485264) (Cohorts IV and V) and P1026s
 (NCT00042289) to determine the starting RAL dosing regimen for full-term and LBW infants in
 IMPAACT P1110 (NCT01780831).

 The study initially opened accrual to Cohort 1 under protocol Version 1.0. Upon completion of
 accrual and follow-up of Cohort 1, the protocol was amended and accrual to and follow-up of
 Cohort 2 was under protocol Version 2.0.

 No study-specific treatment was given to the participants during this study. The women
 (mothers) received RAL for clinical indications outside of the study. Infants received
 standard of care ARV therapy for prophylaxis of perinatal transmission of HIV as prescribed
 by their primary care physicians.

 Cohort 1 mother-infant pairs were enrolled prior to delivery. The women were followed-up
 until discharge from the labor/delivery unit. Infants were followed from birth through 20
 weeks after birth. If infant was eligible for PK sampling (see "Eligibility" section), blood
 samples were collected at 1-5, 8-14, 18-24, and 30-36 hours after birth. Protocol defined
 infant safety evaluations were at birth, and at 8-14 hours, 30-36 hours, 1 week and 20 weeks
 after birth.

 Cohort 2 mother-infant pairs were enrolled prior to delivery or within 48 hours after
 delivery. The women were followed-up until discharge from the labor/delivery unit. Infants
 were followed from birth/entry through 6 weeks after birth. If infant was eligible for PK
 sampling, blood samples were collected at 1-6, 12-24, 36-48, 72-84, and 108-132 hours and
 7-14 days after birth. Protocol defined infant safety evaluations were at entry/birth, and at
 36-48 hours, 72-84 hours, 1 week and 6 weeks after birth.

 For both cohorts, all infants regardless of whether they were eligible for PK sampling were
 included in the safety analyses. Infant safety data included adverse birth outcomes,
 signs/symptoms, diagnoses and chemistry/hematology test results. Protocol required chemistry
 tests were AST, ALT, serum creatinine, total bilirubin and direct bilirubin. Protocol
 required hematology tests were CBC with differential and platelet count. Also included in the
 safety data were additional laboratory events done outside of the study but considered by the
 site as relevant information.

 For both cohorts, maternal blood and cord blood for RAL concentration testing were collected
 at delivery when specimen collection was possible. The optional genotypic testing (i.e.
 testing was done only if the mother consented) was limited to infants who were eligible for
 PK sampling. Information obtained about the effect of UGT1A1 polymorphisms on the PK of RAL
 was thought to provide a better understanding of the effect of genetics on the metabolism of
 RAL in neonates.
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