Safety and Pharmacokinetics of Raltegravir in HIV-1-Exposed Newborn Infants at Risk of Acquiring HIV-1 Infection

This study will evaluate the safety and PKs of RAL given to HIV-1-exposed newborn infants at
risk of acquiring HIV-1 infection. The study also seeks to determine the appropriate dosing
regimen of RAL that can be safely given to infants in the first 6 weeks of life.

The study will enroll 50 mother-infant pairs. Mothers will be followed until discharge from
the labor and delivery unit, and infants will be followed for 24 weeks after birth. Infants
will be assigned non-randomly to 1 of 2 cohorts. Each cohort will include two groups of
infants: a RAL-naïve group including infants born to mothers who did not receive RAL before
delivery, and a RAL-exposed group including infants born to mothers who received at least one
dose of RAL within 2 to 24 hours before delivery.

A minimum of 12 infants will be enrolled into Cohort 1. All infants in Cohort 1 will receive
RAL as oral granules for suspension as a single dose within 48 hours of birth, in addition to
standard of care ARV drugs for PMTCT, and a second dose of RAL at 7 to 10 days of life.

A minimum of 20 infants will be enrolled into Cohort 2. Within Cohort 2, RAL will be started
within 48 hours of birth in the RAL-naïve infants and between 12 and 60 hours of birth in the
RAL-exposed infants. Both the RAL-naïve and the RAL-exposed infants in Cohort 2 will receive
RAL for 6 weeks, in addition to standard of care ARV for PMTCT. Dosing will be determined
based on analyses of data generated from Cohort 1 and from other studies.

Study visits for infants in Cohorts 1 and 2 will occur at study entry through Week 24 and
include a medical history, physical exam, blood draw, and, at select study visits, PK
samplings.

Note: As of January 2017, enrollment and follow-up to Cohort 1 (RAL-exposed and RAL-naïve
groups) and enrollment to Cohort 2 (RAL-naïve group) are complete.

Maternal Inclusion Criteria:

- Mother is either i) known to be HIV-1 infected prior to labor (testing obtained and
designated per local SOC in the medical record and either on or recently started CART
prior to delivery) or ii) identified as HIV-1 infected at the time of labor or in the
immediate postpartum period. More information on this criterion can be found in the
protocol.

- For Cohort 1 and Cohort 2 (RAL-naive): Mother is at high risk of transmitting HIV to
infant as evidenced by any of the following: Mother has not received any ARV therapy
during the current pregnancy prior to the onset of labor and delivery; HIV RNA level
greater than 1000 copies/mL within 4 weeks (28 days) prior to delivery; receipt of ARV
for less than 4 weeks (28 days) before delivery; on ARVs for 4 weeks or longer but has
not taken any ARV for more than 7 days prior to delivery; mother has documented drug
resistant virus to at least one class of ARV drugs. Note: Mothers may have received
prenatal and/or intrapartum ARVs. Note: For Cohort 2 RAL-exposed, there is no
requirement that the mother be determined 'high-risk' of transmitting HIV to her
infant.

- Maternal written informed consent for study participation

Maternal Exclusion Criteria:

- Known maternal-fetal blood group incompatibility as evidenced by the presence of an
unexpected clinically significant maternal red cell antibody that is known to be
capable of causing hemolytic disease of the fetus/newborn

- Mother receiving RAL as part of her combination antiretroviral (cART) regimen after
delivery and intending to breastfeed her infant

- For Cohort 1 (up to 6 mothers only) and Cohort 2 RAL-naïve: Mother who received RAL
prior to and through delivery

Infant Inclusion Criteria:

- For Cohort 1 and Cohort 2 (RAL-naive): Full-term infants exposed to HIV aged 48 hours
or less. Infant may have received up to 48 hours of standard of care ARV prophylaxis
before enrollment. For Cohort 2 (RAL-exposed): Full-term infants exposed to HIV aged
60 hours or less. Infant may have received standard of care ARV prophylaxis/treatment
before enrollment.

- Infant gestational age at birth at least 37 weeks

- No known 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

- Birth weight at least 2 kg

- Able to take oral medications

- Parent or legal guardian able and willing to provide signed informed consent

- For Cohort 2 RAL-exposed Group: Infants born to a mother who received at least one
dose of RAL within 2 to 24 hours of delivery. Note: Based on mother's self-report and
confirmed by medical records if available. Note: For Cohort 1 RAL-exposed Group
infants were born to mothers receiving RAL as part of their ARV regimen.

Infant Exclusion Criteria:

- Infant with bilirubin exceeding the American Academy of Pediatrics guidelines for
phototherapy, using the infant's gestational age and risk factors as described in the
protocol

- Clinical evidence of renal disease, such as edema, ascites, or encephalopathy

- For Cohort 2 RAL naïve, and Cohort 1 (RAL-naive and RAL-exposed): Receipt of
disallowed medications (phenytoin, phenobarbital, or rifampin)