Trial Outcomes & Findings for Safety and Pharmacokinetics of Raltegravir in HIV-1-Exposed Newborn Infants at Risk of Acquiring HIV-1 Infection (NCT NCT01780831)

Last Updated: 2021-11-05

Results Overview

Number of infants who died or had adverse events (AEs) of Grade 3 or 4 as defined in DAIDS AE Grading Table. Events with onset dates prior to first RAL dosing and congenital anomalies assessed as baseline by the study team were considered baseline events and not AEs.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

52 participants

Primary outcome timeframe

From first dosing of RAL through 6 weeks of life

Results posted on

2021-11-05

Participant Flow

Cohort 1 participants were from 2 sites in Brazil, 1 site in South Africa and 7 sites in the USA. Enrollment period was January 2014 - December 2015. Cohort 2 participants were from 3 sites in Brazil, 2 sites in South Africa,1 site in Thailand, and 4 sites in the USA. Enrollment period was September 2015 - November 2017.

Participant milestones

Participant milestones
Measure	Cohort 1 RAL-naive Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg or 2mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 1 RAL-exposed Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 2 RAL-naive Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL dosing through 6 weeks of life starting within 48 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Cohort 2 RAL-exposed Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL dosing through 6 weeks of life starting between 12 and 60 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.
Overall Study STARTED	10	6	26	10
Overall Study COMPLETED	10	6	22	9
Overall Study NOT COMPLETED	0	0	4	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Cohort 1 RAL-naive Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg or 2mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 1 RAL-exposed Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 2 RAL-naive Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL dosing through 6 weeks of life starting within 48 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Cohort 2 RAL-exposed Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL dosing through 6 weeks of life starting between 12 and 60 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.
Overall Study Withdrawal by Subject	0	0	4	0
Overall Study Lost to Follow-up	0	0	0	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort 1 RAL-naive n=10 Participants Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg or 2mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 1 RAL-exposed n=6 Participants Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 2 RAL-naive n=26 Participants Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Cohort 2 RAL-exposed n=10 Participants Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting between 12 and 60 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Total n=52 Participants Total of all reporting groups
Age, Categorical <=18 years	10 Participants n=93 Participants	6 Participants n=4 Participants	26 Participants n=27 Participants	10 Participants n=483 Participants	52 Participants n=36 Participants
Age, Categorical Between 18 and 65 years	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants
Age, Categorical >=65 years	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants
Age, Customized Gestational age at birth	39 weeks n=93 Participants	38 weeks n=4 Participants	38 weeks n=27 Participants	39 weeks n=483 Participants	39 weeks n=36 Participants
Sex: Female, Male Female	6 Participants n=93 Participants	2 Participants n=4 Participants	12 Participants n=27 Participants	4 Participants n=483 Participants	24 Participants n=36 Participants
Sex: Female, Male Male	4 Participants n=93 Participants	4 Participants n=4 Participants	14 Participants n=27 Participants	6 Participants n=483 Participants	28 Participants n=36 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=93 Participants	3 Participants n=4 Participants	19 Participants n=27 Participants	5 Participants n=483 Participants	30 Participants n=36 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	7 Participants n=93 Participants	2 Participants n=4 Participants	7 Participants n=27 Participants	4 Participants n=483 Participants	20 Participants n=36 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	1 Participants n=4 Participants	0 Participants n=27 Participants	1 Participants n=483 Participants	2 Participants n=36 Participants
Birth weight	3020 grams n=93 Participants	2948 grams n=4 Participants	2930 grams n=27 Participants	3085 grams n=483 Participants	3000 grams n=36 Participants
Apgar score at 1 minute	8 Scores on a scale n=93 Participants	9 Scores on a scale n=4 Participants	9 Scores on a scale n=27 Participants	9 Scores on a scale n=483 Participants	9 Scores on a scale n=36 Participants

PRIMARY outcome

Timeframe: From first dosing of RAL through 6 weeks of life

Population: All infants who received at least one dose of RAL. Excluded one Cohort 2 RAL-naive infant who received one dose of RAL at study entry but was off study right after study entry and thus had no post entry safety data.

Outcome measures

Outcome measures
Measure	Cohort 1 RAL-naive n=10 Participants Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg or 2mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 1 RAL-exposed n=6 Participants Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 1 Total n=16 Participants Full term Infants, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg, 2 mg/kg or 1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 2 RAL-naive n=25 Participants Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Cohort 2 RAL-exposed n=10 Participants Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting between 12 and 60 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Cohort 2 Total n=35 Participants Full term Infants, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth and between 12 to 60 hours of birth for in utero RAL-naive and RAL-exposed infants, respectively: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.
Number of Infants Who Died or Had Grade 3/4 Adverse Event Through 6 Weeks of Life	2 Participants	2 Participants	4 Participants	7 Participants	4 Participants	11 Participants

PRIMARY outcome

Timeframe: Cohort 1 RAL dose #1 (within 48 hours of birth) intensive PK sampling: within 30 min pre-dose; and 1-2, 4-8, 12 (±1), 24 (±1) hours post-dose.

Population: All Cohort 1 infants who received the first RAL dosing within 48 hours of birth and had AUC24 data for the dosing. AUC24 was missing for one Cohort 1 RAL-naive infant whose PK samples were possibly switched.

Area Under the Concentration-time Curve at 24-hour interval (AUC24) based on intensive PK sampling around Cohort 1 RAL dose #1 (within 48 hours of birth)

Outcome measures

Outcome measures
Measure	Cohort 1 RAL-naive n=6 Participants Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg or 2mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 1 RAL-exposed n=3 Participants Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 1 Total n=6 Participants Full term Infants, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg, 2 mg/kg or 1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 2 RAL-naive Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Cohort 2 RAL-exposed Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting between 12 and 60 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Cohort 2 Total Full term Infants, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth and between 12 to 60 hours of birth for in utero RAL-naive and RAL-exposed infants, respectively: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.
AUC24 for Cohort 1 RAL Dose #1 (Within 48 Hours of Birth)	53.88 mg*h/L Geometric Coefficient of Variation 34.6	44.26 mg*h/L Geometric Coefficient of Variation 71.9	37.42 mg*h/L Geometric Coefficient of Variation 92.7	—	—	—

PRIMARY outcome

Timeframe: Cohort 1 dose #1(within 48 hours of birth) intensive PK sampling: within 30 min pre-dose; and 1-2, 4-8, 12 (±1), 24 (±1) hours post-dose.

Population: All Cohort 1 infants who received the first RAL dosing within 48 hours of birth and had Cmax data for the dosing. Cmax was missing for one Cohort 1 RAL-naive infant whose PK samples were possibly switched.

Maximum concentration (Cmax) for Cohort 1 dose #1 (within 48 hours of birth)

Outcome measures

Outcome measures
Measure	Cohort 1 RAL-naive n=6 Participants Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg or 2mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 1 RAL-exposed n=3 Participants Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 1 Total n=6 Participants Full term Infants, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg, 2 mg/kg or 1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 2 RAL-naive Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Cohort 2 RAL-exposed Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting between 12 and 60 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Cohort 2 Total Full term Infants, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth and between 12 to 60 hours of birth for in utero RAL-naive and RAL-exposed infants, respectively: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.
Cmax for Cohort 1 RAL Dose #1 (Within 48 Hours of Birth)	3360.89 ng/mL Geometric Coefficient of Variation 35.5	3405.24 ng/mL Geometric Coefficient of Variation 38.1	2188.82 ng/mL Geometric Coefficient of Variation 73.3	—	—	—

PRIMARY outcome

Timeframe: Cohort 2 initial dose (within 48 and between 12-60 hours of birth for RAL-naive and RAL-exposed, respectively) intensive PK sampling: within 1 hour pre-dose; and 1-2, 6-10, 20-24 hours post-dose.

Population: All Cohort 2 infants who had AUC24 data for the initial RAL dosing. AUC24 were missing for 2 Cohort 2 RAL-naive infants: one was off-study right after study entry and had incomplete PK specimen collection; and one whose AUC24 could not be estimated due to possible administration of next dose before the 24 hr sample was collected.

Area Under the Concentration-time Curve at the 24-hour interval (AUC24) for Cohort 2 initial RAL dose (within 48 and between 12-60 hours of birth for RAL-naive and RAL-exposed, respectively).

Outcome measures

Outcome measures
Measure	Cohort 1 RAL-naive n=24 Participants Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg or 2mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 1 RAL-exposed n=10 Participants Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 1 Total Full term Infants, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg, 2 mg/kg or 1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 2 RAL-naive Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Cohort 2 RAL-exposed Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting between 12 and 60 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Cohort 2 Total Full term Infants, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth and between 12 to 60 hours of birth for in utero RAL-naive and RAL-exposed infants, respectively: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.
AUC24 for Cohort 2 Initial RAL Dose (Within 48 and 12-60 Hours of Birth for RAL-naive and RAL-exposed Groups, Respectively)	38.2 mg*h/L Geometric Coefficient of Variation 42	42.89 mg*h/L Geometric Coefficient of Variation 25.3	—	—	—	—

PRIMARY outcome

Timeframe: Cohort 2 initial dose (within 48 and between 12-60 hours of birth for RAL-naive and RAL-exposed groups, respectively) intensive PK sampling: within 1 hour pre-dose; and 1-2, 6-10, 20-24 hours post-dose.

Population: All Cohort 2 infants who had Clast data for the initial RAL dosing. Clast was missing for one Cohort 2 RAL-naive infant who was off-study right after study entry and had incomplete PK specimen collection.

Last concentration of the drug (Clast) at 24 hour interval post dosing for the Cohort 2 initial RAL dose (within 48 and at 12-60 hours of birth for RAL-naive and RAL-exposed, respectively). This is the plasma RAL concentration from a sample collected at or close to 24 hours post dose.

Outcome measures

Outcome measures
Measure	Cohort 1 RAL-naive n=25 Participants Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg or 2mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 1 RAL-exposed n=10 Participants Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 1 Total Full term Infants, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg, 2 mg/kg or 1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 2 RAL-naive Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Cohort 2 RAL-exposed Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting between 12 and 60 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Cohort 2 Total Full term Infants, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth and between 12 to 60 hours of birth for in utero RAL-naive and RAL-exposed infants, respectively: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.
Clast for Cohort 2 Initial RAL Dose (Within 48 and Between 12-60 Hours of Birth for RAL-naïve and RAL-exposed Groups, Respectively)	947.90 ng/mL Geometric Coefficient of Variation 84	946.24 ng/mL Geometric Coefficient of Variation 74	—	—	—	—

PRIMARY outcome

Timeframe: Intensive PK sampling for Cohort 2 at 15-18 days of life: within 1 hour pre-dose; and 1-2, 4-6, 8-12 hours post-dose.

Population: All infants who continued to receive RAL at or beyond Day 15-18 study visit and had AUC12 for the dosing. AUC12 were missing for 2 RAL-naive infants taken off study prior to Day 15-18 visit; 1 RAL-naive infant with delayed absorption for whom AUC12 could not be estimated; and 1 RAL-exposed infant who had incomplete PK sample collection.

Area Under the Concentration-time Curve at 12-hour interval (AUC12) of RAL for Cohort 2 at 15-18 days of life.

Outcome measures

Outcome measures
Measure	Cohort 1 RAL-naive n=23 Participants Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg or 2mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 1 RAL-exposed n=9 Participants Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 1 Total Full term Infants, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg, 2 mg/kg or 1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 2 RAL-naive Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Cohort 2 RAL-exposed Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting between 12 and 60 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Cohort 2 Total Full term Infants, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth and between 12 to 60 hours of birth for in utero RAL-naive and RAL-exposed infants, respectively: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.
RAL AUC12 for Cohort 2 at 15-18 Days of Life	14.3 mg*h/L Geometric Coefficient of Variation 49.5	18.25 mg*h/L Geometric Coefficient of Variation 62.8	—	—	—	—

PRIMARY outcome

Timeframe: Intensive PK sampling for Cohort 2 at 15-18 days of life: within 1 hour pre-dose; and 1-2, 4-6, 8-12 hours post-dose.

Population: All infants who continued to receive RAL at or beyond Day 15-18 study visit and had C12 for the dosing. C12 were missing for 2 RAL-naive infants taken off study prior to Day 15-18 visit; 1 RAL-naive infant with delayed absorption for whom C12 could not be estimated; and 1 RAL-exposed infant who had incomplete PK sample collection.

RAL concentration at 12 hours (C12) for Cohort 2 at 15-18 days of life.

Outcome measures

Outcome measures
Measure	Cohort 1 RAL-naive n=23 Participants Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg or 2mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 1 RAL-exposed n=9 Participants Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 1 Total Full term Infants, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg, 2 mg/kg or 1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 2 RAL-naive Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Cohort 2 RAL-exposed Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting between 12 and 60 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Cohort 2 Total Full term Infants, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth and between 12 to 60 hours of birth for in utero RAL-naive and RAL-exposed infants, respectively: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.
RAL C12 for Cohort 2 at 15-18 Days of Life	176.11 mg*h/L Geometric Coefficient of Variation 162.1	273.59 mg*h/L Geometric Coefficient of Variation 176.4	—	—	—	—

SECONDARY outcome

Timeframe: From first RAL dose through 24 weeks of life

Population: All infants who received at least one dose of RAL. Excluded was one Cohort 2 RAL-naive infant who received one dose of RAL at study entry but was off study right after study entry and thus had no post entry safety data.

Outcome measures

Outcome measures
Measure	Cohort 1 RAL-naive n=10 Participants Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg or 2mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 1 RAL-exposed n=6 Participants Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 1 Total n=16 Participants Full term Infants, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg, 2 mg/kg or 1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 2 RAL-naive n=25 Participants Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Cohort 2 RAL-exposed n=10 Participants Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting between 12 and 60 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Cohort 2 Total n=35 Participants Full term Infants, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth and between 12 to 60 hours of birth for in utero RAL-naive and RAL-exposed infants, respectively: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.
Number of Infants Who Died or Had Grade 3/4 Adverse Event Through 24 Weeks of Life	2 Participants	2 Participants	4 Participants	11 Participants	4 Participants	15 Participants

SECONDARY outcome

Timeframe: From first RAL dose through 6 weeks of life

Number of infants who died or had Suspected Adverse Drug Reaction (SADR) of Grade 3 or 4 as defined in DAIDS AE Grading Table. Events with onset dates prior to the first RAL dosing and congenital anomalies assessed as baseline by the study team were considered baseline events and not AEs. SADRs are AEs assessed as definitely related, probably related or possibly related to RAL.

Outcome measures

Outcome measures
Measure	Cohort 1 RAL-naive n=10 Participants Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg or 2mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 1 RAL-exposed n=6 Participants Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 1 Total n=16 Participants Full term Infants, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg, 2 mg/kg or 1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 2 RAL-naive n=25 Participants Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Cohort 2 RAL-exposed n=10 Participants Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting between 12 and 60 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Cohort 2 Total n=35 Participants Full term Infants, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth and between 12 to 60 hours of birth for in utero RAL-naive and RAL-exposed infants, respectively: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.
Number of Infants Who Died or Had SADR of Grade 3 or 4 Through 6 Weeks of Life	1 Participants	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: From first RAL dose through 24 weeks of life

Outcome measures

Outcome measures
Measure	Cohort 1 RAL-naive n=10 Participants Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg or 2mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 1 RAL-exposed n=6 Participants Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 1 Total n=16 Participants Full term Infants, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg, 2 mg/kg or 1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 2 RAL-naive n=25 Participants Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Cohort 2 RAL-exposed n=10 Participants Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting between 12 and 60 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Cohort 2 Total n=35 Participants Full term Infants, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth and between 12 to 60 hours of birth for in utero RAL-naive and RAL-exposed infants, respectively: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.
Number of Infants Who Died or Had SADR of Grade 3 or 4 Through 24 Weeks of Life	1 Participants	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Cohort 1 Dose #1 Intensive PK sampling: within 30 min pre-dose; and 1-2, 4-8, 12, 24 hours post-dose. Samples for UGT1A1 genotype testing were collected at study entry.

Population: All Cohort 1 infants with data on CL/F (for dose #1) and UGT1A1 genotype. Excluded were: 1 Cohort 1 RAL-naive infant with missing CL/F due to possible PK specimen switch; 2 Cohort 1 RAL-naive infants with no specimen for genotype testing; 1 Cohort 1 RAL-exposed infant with CL/F and genotype data but was the only infant with (TA)5(TA)6 genotype.

Cohort 1 Dose #1 neonatal RAL elimination was represented by Clearance (CL/F), which is the volume of plasma cleared of the drug per unit time. Genotyping for polymorphisms of UGT1A1 were performed on infants who were eligible for PK sampling and were consented by their mothers/guardians (i.e. genotyping was optional) .

Outcome measures

Outcome measures
Measure	Cohort 1 RAL-naive n=6 Participants Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg or 2mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 1 RAL-exposed n=6 Participants Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 1 Total Full term Infants, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg, 2 mg/kg or 1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 2 RAL-naive Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Cohort 2 RAL-exposed Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting between 12 and 60 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Cohort 2 Total Full term Infants, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth and between 12 to 60 hours of birth for in utero RAL-naive and RAL-exposed infants, respectively: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.
Cohort 1 Dose #1 Neonatal RAL Elimination (CL/F) by UGT1A1 Genotype Group	0.11 L/hr Interval 0.1 to 0.13	0.06 L/hr Interval 0.04 to 0.15	—	—	—	—

SECONDARY outcome

Timeframe: Intensive PK sampling for Cohort 2 initial dose: within 1 hour pre-dose; and 1-2, 6-10, 20-24 hours post-dose. Samples for UGT1A1 genotype testing were collected at study entry.

Population: All Cohort 2 infants w/ data on initial dose CL/F and UGT1A1 genotype. Exclusions: 1 RAL-naive infant who was off-study right after entry w/ incomplete PK specimens; 1 RAL-naive infant's CL/F can't be estimated due to possible administration of next dose before 24 hr sample collection; 3 RAL-naive and 4 exposed infants w/o genotype specimen.

Cohort 2 initial dose neonatal RAL elimination was represented by Clearance (CL/F), which is defined as the volume of plasma cleared of the drug per unit time. Genotyping for polymorphisms of UGT1A1 were performed on infants who were eligible for PK sampling and were consented by their mothers/guardians (i.e. genotyping was optional) .

Outcome measures

Outcome measures
Measure	Cohort 1 RAL-naive n=15 Participants Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg or 2mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 1 RAL-exposed n=12 Participants Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 1 Total Full term Infants, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg, 2 mg/kg or 1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 2 RAL-naive Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Cohort 2 RAL-exposed Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting between 12 and 60 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Cohort 2 Total Full term Infants, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth and between 12 to 60 hours of birth for in utero RAL-naive and RAL-exposed infants, respectively: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.
Cohort 2 Initial Dose Neonatal RAL Elimination (CL/F) by UGT1A1 Genotype Group	0.1 L/hr Interval 0.1 to 0.2	0.1 L/hr Interval 0.1 to 0.1	—	—	—	—

SECONDARY outcome

Timeframe: Intensive PK sampling for Cohort 2 at 15-18 days of life: within 1 hour pre-dose; and 1-2 hours post-dose, 4-6, 8-12 hours post-dose. Samples for UGT1A1 genotype testing were collected at study entry.

Population: All Cohort 2 infants with data on CL/F for Day 15-18 visit \& UGT1A1 genotype. Exclusions: 1 RAL-naive infant off-study right after entry w/ incomplete PK specimens; 1 RAL-naive infant withdrew consent; 1 RAL-naive infant stopped RAL after wk 4; 1 RAL-exposed infant w/ incomplete PK specimens; 3 RAL-naive and 4 exposed infants w/o genotype specimen.

Cohort 2 15-18 days of life dose neonatal RAL elimination was represented by Clearance (CL/F), which is defined as the volume of plasma cleared of the drug per unit time at 15-18 days of life when RAL dosing would have been 3 mg/kg twice daily. Genotyping for polymorphisms of UGT1A1 were performed on infants who were eligible for PK sampling and were consented by their mothers/guardians(i.e. genotyping was optional) .

Outcome measures

Outcome measures
Measure	Cohort 1 RAL-naive n=14 Participants Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg or 2mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 1 RAL-exposed n=11 Participants Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 1 Total Full term Infants, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: RAL was given as oral granules for suspension. Two single doses of RAL: first dose (3 mg/kg, 2 mg/kg or 1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	Cohort 2 RAL-naive Full term Infants not exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Cohort 2 RAL-exposed Full term Infants exposed in utero to maternal RAL, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting between 12 and 60 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.	Cohort 2 Total Full term Infants, ≥2000 grams and ≥37 weeks gestational age at birth, born to women living with HIV-1 infection and at risk of acquiring HIV-1 infection. Raltegravir: Daily RAL through 6 weeks of life starting within 48 hours of birth and between 12 to 60 hours of birth for in utero RAL-naive and RAL-exposed infants, respectively: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.
Cohort 2 Neonatal RAL Elimination (CL/F) at 15-18 Days of Life by UGT1A1 Genotype Group	0.5 L/hr Interval 0.4 to 1.0	0.5 L/hr Interval 0.4 to 0.8	—	—	—	—

SECONDARY outcome

Timeframe: Specimens for bilirubin testing were collected at study entry; Days 3-4, 7-10 of life; and Weeks 2, 6, 24 of life for Cohort 1. Specimen for genotype testing was collected at entry.

Population: The intent of this Outcome Measure was to investigate the association between UGT1A1 genotypes with hyperbilirubinemia, however no infants had hyperbilirubinemia.

Hyperbilirubinemia was defined as total bilirubin exceeding 16.0 mg/dL or receipt of phototherapy, or transfusion therapy, or other therapies for hyperbilirubinemia or elevated bilirubin.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Specimens for bilirubin testing were collected at study entry; after 2nd dose; Days 6-9, 15-18, 28-32 of life; and Weeks 5-6, 8-10, 24 of life for Cohort 2. Specimen for genotype testing was collected at study entry.

Population: The intent of this Outcome Measure was to investigate the association between UGT1A1 genotypes with hyperbilirubinemia, however no infants had hyperbilirubinemia.

Hyperbilirubinemia was defined as total bilirubin exceeding 16.0 mg/dL or receipt of phototherapy, or transfusion therapy, or other therapies for hyperbilirubinemia or elevated bilirubin.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Specimens for bilirubin test were collected at study entry; Days 3-4, 7-10 of life; and Weeks 2, 6, 24 of life for Cohort 1. Specimen for genotype testing was collected at study entry.

Population: The intent of this Outcome Measure was to investigate the association between SLCO1B3 genotypes with hyperbilirubinemia, however no infants had hyperbilirubinemia.

Hyperbilirubinemia was defined as total bilirubin exceeding 16.0 mg/dL or receipt of phototherapy, or transfusion therapy, or other therapies for hyperbilirubinemia or elevated bilirubin.

Outcome measures

Outcome data not reported

SECONDARY outcome

Population: The intent of this Outcome Measure was to investigate the association between SLCO1B3 genotypes with hyperbilirubinemia, however no infants had hyperbilirubinemia.

Hyperbilirubinemia was defined as total bilirubin exceeding 16.0 mg/dL or receipt of phototherapy, or transfusion therapy, or other therapies for hyperbilirubinemia or elevated bilirubin.

Outcome measures

Outcome data not reported

Adverse Events

Cohort1 RAL-naive

Serious events: 3 serious events

Other events: 10 other events

Deaths: 0 deaths

Cohort1 RAL-exposed

Serious events: 1 serious events

Other events: 6 other events

Deaths: 0 deaths

Cohort2 RAL-naive

Serious events: 7 serious events

Other events: 24 other events

Deaths: 0 deaths

Cohort2 RAL-exposed

Serious events: 2 serious events

Other events: 9 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Melissa Allen, Director, IMPAACT Operations Center

Family Health International (FHI 360)

Phone: (919) 405-1429

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee In accordance with the Clinical Trials Agreement between NIAID (DAIDS) and company collaborators, NIAID (DAIDS) provides companies with a copy of any abstract, press release, or manuscript prior to submission for publication with sufficient time for company review and comment. The publication/other disclosure can be delayed for up to 30 additional business days for manuscripts and five (5) business days for abstracts, to preserve U.S. or foreign patent or other intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER