Evaluating the Safety and Pharmacokinetics of Raltegravir in Infants

This study will enroll participants in two cohorts. Cohort 1 is now closed to enrollment.
Researchers are enrolling participants in Cohort 2.

Cohort 1 will include mother-infant pairs in which the HIV-infected pregnant mother will have
received RAL 400 mg twice daily for at least 2 weeks prior to delivery and will continue
antiretroviral (ARV) drugs during labor. Mother/infant pairs will be enrolled prior to
delivery, and women will be followed until discharge from the labor/delivery unit. At
delivery, cord blood will be drawn and a single blood sample will be collected from the
woman.

All infants will undergo a medical history, physical examination, and blood draw at the Week
1-2 visit and Week 20 visit. Infants who meet certain criteria defined in the protocol will
be eligible for PK sampling at the birth visit. These infants will have one blood sample
collected at 1 to 5, 8 to 14, 18 to 24, and 30 to 36 hours after birth. Infants not eligible
for PK sampling will undergo a blood draw at 8 to 14 hours and 30 to 36 hours after birth.

Optional genotyping for UGT1A1 polymorphisms will be done using dried blood spot on filter
paper. (UGT1A1 is the enzyme primarily responsible for RAL metabolism.) Only infants who have
PK sampling will have genotyping done.

No study-specific drugs will be given to women or infants during this study. Women will be
receiving RAL for clinical indications outside of the study. Infants will receive standard of
care ARV therapy for prevention of mother-to-child transmission (PMTCT) as prescribed by
their primary care physicians. Infants will be followed for 20 weeks after birth.

Cohort 2 will enroll mother-infant pairs in which the HIV-infected pregnant woman will have
received at least one dose of 400 mg of RAL within 2 to 24 hours prior to delivery, and their
infants will weigh less than or equal to 2,500 grams at birth. Participants will take part in
most of the same study procedures as participants in Cohort 1, except infants will only be
followed for 6 weeks after birth.

Enrollment into Cohort 1 is now closed.

Cohort 1: Maternal Inclusion Criteria

- Documentation of HIV-1 infection defined as positive results from two samples
collected at different time points. The same method may be used at both time points.
All samples tested must be whole blood, serum, or plasma. More information on this
criterion can be found in the protocol.

- 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 Exclusion Criteria

- Receipt of disallowed medications within 4 weeks prior to enrollment

Cohort 1: Infant Inclusion Criteria

Infants are enrolled prior to delivery so there are no infant inclusion criteria. Only
infants who meet the following criteria will be eligible for PK blood sampling:

- 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 described in protocol. If these
medications are required for the infant's care, the infant will be ineligible for
further PK sampling. Data will be obtained up to the time of the introduction of the
disallowed medication, but such infant will not be considered one of the evaluable 15
infants.

Cohort 1: Infant 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 will allow enrollment of mother-infant (M-I) pairs at two time points: prior to
and within 48 hours after delivery.

- For enrollment prior to delivery, the mother must meet all the eligibility criteria
(i.e., there are no infant eligibility criteria for prenatal enrollment). However,
only infants who meet all the eligibility criteria will have PK blood sampling
performed. Infants must be PK eligible and then meet the definition of evaluable to
contribute to the sample size of 15 evaluable infants. PK ineligible infants will
remain in the study and will be followed for safety.

- For enrollment within 48 hours after delivery, both mother and infant(s) must meet all
the eligibility criteria. For multiple births, only infants who meet all the
eligibility criteria will be enrolled.

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

- Documentation of HIV-1 infection defined as positive results from two samples
collected at different time points. All samples tested must be whole blood, serum, or
plasma. More information on this criterion can be found in the protocol.

- 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 definied by the
country in which she resides. If not, informed consent must be signed by a legal
guardian.

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

- Receipt of disallowed medications within 4 weeks prior to enrollment or intent to be
on any of the disallowed medications prior to delivery. Note: Infant(s) of a woman who
received any of the disallowed medications will be ineligible for PK sampling.

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

Infants are enrolled prior to delivery so there are no infant inclusion criteria. Only
infants who meet the following criteria will be 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 as described in the protocol. If these
medications are required for the infant's care, the infant will be ineligible for
further PK sampling. Data will be obtained up to the time of the introduction of the
disallowed medication, but such infant will not be considered one of the evaluable 15
infants if fewer than 3 PK samples from the first 5 time points are collected.

- 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 Inclusion Criteria: M-I pairs enrolled after delivery

- Documentation of HIV-1 infection as described in the protocol. Enrollment is allowed
if an initial HIV test is positive and a confirmatory test has been drawn and is
pending.

- 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 Exclusion Criteria: M-I pairs enrolled after delivery

- Receipt of disallowed medications within 4 weeks prior to delivery

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

- Received disallowed medications as described in the protocol

- 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