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

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01780831
• Collaborator: (none)
• Enrollment: 52
• Locations: 15
• Arms: 2
• Actual Duration (Months): 50.7
• Patients Per Site: 3.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study was to evaluate the safety and pharmacokinetics (PK) of raltegravir (RAL) when given to HIV-1-exposed, normal birth weight newborn infants at risk of acquiring HIV-1 infection. (PK is the study of the time course of absorption, distribution, metabolism, and excretion of drugs in the body.) The primary goal of this study was to determine a dose of RAL that was safe and met the PK targets for infants when administered during the first 6 weeks of life in addition to standard of care antiretroviral (ARV) agents for prevention of perinatal transmission.

Condition or Disease	Intervention/Treatment	Phase
HIV Infections	Drug: Raltegravir	Phase 1

Detailed Description

This is a Phase I multi-center, open label, non-comparative study to evaluate the safety and PK of RAL administered to HIV-1-exposed full-term (≥37 weeks of gestation) infants when administered during the first 6 weeks of life in addition to the infants' standard HIV-1 ARV prophylaxis.

IMPAACT P1097 (NCT01828073) demonstrated that RAL crossed the placenta from mother to fetus after maternal dosing during pregnancy and RAL was slowly eliminated by the newborn after birth. Therefore, for P1110, within each cohort, infants were stratified into the "RAL-naive" or "RAL-exposed" groups depending on infants' in utero exposure to maternal RAL. The study stratification with respect to in utero RAL exposure allowed for adjustment of the initial RAL dosing (i.e. timing and/or dose size).

Study participants were enrolled in two sequential cohorts with the following actual dosing of RAL in addition to their local standard of care ARV agents for prevention of perinatal transmission. PK and safety data from Cohort 1 (two single doses) provided information for the starting dosing for Cohort 2 (daily dosing through 6 weeks of life).

Cohort 1: Two single RAL doses: first dose within 48 hours of birth and second dose at 7-10 days of life.

• Cohort 1, RAL-naive: 3 or 2 mg/kg within 48 hours of birth and 3 mg/kg at 7-10 days of life. (P1110 V1.0 Clarification Memorandum #3, dated January 15, 2015, adjusted the first dose from 3 mg/kg to 2 mg/kg based on available PK data.)

• Cohort 1, RAL-exposed: 1.5 mg/kg within 48 hours of birth and 3 mg/kg at 7-10 days of life.

Cohort 2: Daily RAL dosing through 6 weeks of life.

• Cohort 2, RAL-naive: Daily dosing through 6 weeks of life with initial RAL dosing 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: Daily dosing through 6 weeks of life with initial RAL dosing between 12-60 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.

Target enrollment was approximately 50 infants and their mothers in order to have a minimum of 12 and 20 PK evaluable infants in Cohorts 1 and 2, respectively. Cohort 1 and Cohort 2 RAL-naive infants (and their mothers) were enrolled under protocol Version 1.0. Cohort 2 RAL-exposed infants (and their mothers) were enrolled under protocol Version 2.0.

Infants and their mothers were enrolled within 48 and within 60 hours of delivery under protocol Versions 1.0 and 2.0, respectively. Infants were followed through 24 weeks of life and their mothers were followed until discharge from the labor and delivery unit.

Infant PK samples were collected as follows:

Cohort 1:

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

• One random PK sample at 3-4 days of life.

• Dose #2 (7-10 days of life) limited PK sampling: Within 30 min pre-dose, and 1-2 hours post-dose and 24 (±1) hours post-dose.

Cohort 2:

• Initial dose (within 48 and 12-60 hours of birth for RAL-naive and RAL-exposed infants, respectively) intensive PK sampling: Within 1 hour pre-dose, and 1-2 hours, 6-10 hours, 20-24 hours post-dose.

• PK sampling for second dose: 3-6 hours post-dose.

• PK sampling at 6-9 days of life: Within 1 hour pre-dose of initiating 3mg/kg twice daily.

• Intensive PK sampling at 15-18 days of life: Within 1 hour pre-dose, and 1-2 hours post-dose, 4-6 hours post-dose, and 8-12 hours post-dose.

• PK sampling at 28-32 days of life: Within 1 hour pre-dose of initiating 6 mg/kg twice daily.

• PK sampling at 33-42 days of life done at Week 5-6 visit: Within 1 hour pre-dose, and 3-6 hours post-dose.

Protocol defined infant safety evaluations were done at:

Cohort 1: Entry, 3-4 days of life, 7-10 days of life, 2 weeks of life, 6 weeks of life and 24 weeks of life.

Cohort 2: Entry, 2-4 days of life, 6-9 days of life, 15-18 days of life, 28-32 days of life, 5-6 weeks of life, 8-10 weeks of life and 24 weeks of life.

Infant safety data included death, signs/symptoms, diagnoses and laboratory test results. Laboratory test results included results from evaluations specified in the protocol and evaluations done as part of the infant's clinical care which the sites considered relevant.

PK evaluable infants were those determined by the protocol pharmacologist to have PK results which provide analyzable data on the primary PK parameters of interest. Infants who were PK unevaluable were replaced for PK analysis but continued with the study safety follow-up visits.

Infants were evaluable for safety analysis if they received at least one dose of RAL. The safety analyses were based on data from all safety evaluable infants, regardless of whether they were evaluable for PK analysis.

The study initially opened accrual to Cohort 1 RAL-naive group. The PK and safety data from IMPAACT P1110 Cohort 1 RAL-naive group and from IMPAACT P1097 were used to determine the starting dose for the Cohort 1 RAL-exposed group. Opening accrual to the Cohort 2 RAL-naive group was contingent upon infants enrolled in Cohort 1 RAL-naive and RAL-exposed groups successfully meeting safety criteria and providing adequate PK data to determine a regimen to be tested for daily dosing through 6 weeks of life for the Cohort 2 RAL-naive group. The initial dosing regimen for the Cohort 2 RAL-naive group was determined using population PK modeling and simulations incorporating IMPAACT P1110 Cohort 1 data, along with data from the following IMPAACT studies: P1097, P1066 (NCT00485264) (Cohorts IV and V) and P1026s (NCT00042289). Since the PK results of Cohort 1 RAL-naive and exposed groups were similar except in the first 1-2 days of life and P1097 Cohort 1 results suggested that maternal RAL readily crosses the placenta and results to washout RAL exposure in neonates, Cohort 2 RAL-exposed group was determined to receive the same dose of RAL as Cohort 2 RAL-naive group, except the initial dose for RAL-exposed was delayed to within 12 to 60 hours of life.

Study Design

• Study Type: Interventional
• Actual Enrollment: 52 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I Trial to Evaluate the Safety and Pharmacokinetics of Raltegravir in HIV-1-Exposed Neonates at Risk of Acquiring HIV-1 Infection
• Actual Study Start Date: Jan 28, 2014
• Actual Primary Completion Date: Dec 14, 2017
• Actual Study Completion Date: Apr 20, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1 HIV-1-exposed full-term infants. Infants received two single doses of RAL: first dose within 48 hours of birth and second dose at 7-10 days of life: RAL-naive: 3 or 2 mg/kg within 48 hours of birth and 3 mg/kg at 7-10 days of life. RAL-exposed: 1.5 mg/kg within 48 hours of birth and 3 mg/kg at 7-10 days of life.	Drug: Raltegravir; RAL was given as oral granules for suspension.; Other Names: ISENTRESS
Experimental: Cohort 2 HIV-1-exposed full-term infants. Daily RAL through 6 weeks of life with first dosing within 48 hours of birth and between 12-60 hours of birth for in utero RAL-naive and RAL-exposed infants, respectively. Daily RAL through 6 weeks of life: 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.	Drug: Raltegravir; RAL was given as oral granules for suspension.; Other Names: ISENTRESS

Outcome Measures

Primary Outcome Measures

1. Number of Infants Who Died or Had Grade 3/4 Adverse Event Through 6 Weeks of Life [From first dosing of RAL through 6 weeks of life]

   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.

2. AUC24 for Cohort 1 RAL Dose #1 (Within 48 Hours of Birth) [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.]

   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)

3. Cmax for Cohort 1 RAL Dose #1 (Within 48 Hours of Birth) [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.]

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

4. AUC24 for Cohort 2 Initial RAL Dose (Within 48 and 12-60 Hours of Birth for RAL-naive and RAL-exposed Groups, Respectively) [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.]

   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).

5. Clast for Cohort 2 Initial RAL Dose (Within 48 and Between 12-60 Hours of Birth for RAL-naïve and RAL-exposed Groups, Respectively) [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.]

   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.

6. RAL AUC12 for Cohort 2 at 15-18 Days of Life [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.]

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

7. RAL C12 for Cohort 2 at 15-18 Days of Life [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.]

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

Secondary Outcome Measures

1. Number of Infants Who Died or Had Grade 3/4 Adverse Event Through 24 Weeks of Life [From first RAL dose through 24 weeks of life]

   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.

2. Number of Infants Who Died or Had SADR of Grade 3 or 4 Through 6 Weeks of Life [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.

3. Number of Infants Who Died or Had SADR of Grade 3 or 4 Through 24 Weeks of Life [From first RAL dose through 24 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.

4. Cohort 1 Dose #1 Neonatal RAL Elimination (CL/F) by UGT1A1 Genotype Group [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.]

   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) .

5. Cohort 2 Initial Dose Neonatal RAL Elimination (CL/F) by UGT1A1 Genotype Group [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.]

   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) .

6. Cohort 2 Neonatal RAL Elimination (CL/F) at 15-18 Days of Life by UGT1A1 Genotype Group [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.]

   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) .

7. Number of Cohort 1 Infants With Hyperbilirubinemia by UGT1A1 Genotype [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.]

   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.

8. Number of Cohort 2 Infants With Hyperbilirubinemia by UGT1A1 Genotype [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.]

   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.

9. Number of Cohort 1 Infants With Hyperbilirubinemia by SLCO1B3 Genotype [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.]

   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.

10. Number of Cohort 2 Infants With Hyperbilirubinemia by SLCO1B3 Genotype [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.]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Maternal Inclusion Criteria:

• Mother is living with HIV and either i) known to have HIV diagnosis 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 having HIV diagnosis at the time of labor or in the immediate postpartum period. More information on this criterion can be found in the protocol.

• Risk of mothers transmitting HIV to their infants:

• Cohort 1 and Cohort 2 (RAL-naive): Mother living with HIV 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; or mother has documented drug resistant virus to at least one class of ARV drugs.

• Cohort 2 RAL-exposed: there was no requirement that the mother living with HIV is at "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 will be receiving RAL as part of her combination antiretroviral (cART) regimen after delivery and intending to breastfeed her infant

• For Cohort 1 and Cohort 2 RAL-naive groups:

• Cohort 1 RAL-naive: Mother who received RAL prior to and through delivery unless last RAL dosing during prenatal period was >7 days prior to delivery

• Cohort 2 RAL-naive: Mother who received RAL prior to and through delivery

Infant Inclusion Criteria:

• Age at enrollment (Note: The full-term infants were HIV-exposed and may have received standard of care ARV prophylaxis/treatment before enrollment):

• Cohort 1 and Cohort 2 RAL-naive: Aged 48 hours or less.

• Cohort 2 RAL-exposed: Aged 60 hours or less.

• 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 1 and Cohort 2 RAL-exposed groups:

• Cohort 1 RAL-exposed: Infants born to mothers who received RAL during pregnancy with last dose taken within 7 days before delivery.

• Cohort 2 RAL-exposed: Infants born to a mother who received at least one dose of RAL within 2 to 24 hours prior to delivery.

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.

• Receipt of disallowed medications (phenytoin, phenobarbital, or rifampin).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Usc La Nichd Crs	Los Angeles	California	United States	90089
2	Children's National Med. Ctr. Washington DC NICHD CRS	Washington	District of Columbia	United States	20010
3	Univ. of Florida Jacksonville NICHD CRS	Jacksonville	Florida	United States	32209
4	Rush Univ. Cook County Hosp. Chicago NICHD CRS	Chicago	Illinois	United States	60612
5	Lurie Children's Hospital of Chicago (LCH) CRS	Chicago	Illinois	United States	60614-3393
6	Boston Medical Center Ped. HIV Program NICHD CRS	Boston	Massachusetts	United States	02118
7	Bronx-Lebanon Hospital Center NICHD CRS	Bronx	New York	United States	10457
8	St. Jude Children's Research Hospital CRS	Memphis	Tennessee	United States	38105-3678
9	Hospital Federal dos Servidores do Estado NICHD CRS	Rio de Janeiro		Brazil	20221-903
10	Hosp. Geral De Nova Igaucu Brazil NICHD CRS	Rio de Janeiro		Brazil	26030
11	Univ. of Sao Paulo Brazil NICHD CRS	Sao Paulo		Brazil	14049-900
12	University of Puerto Rico Pediatric HIV/AIDS Research Program CRS	San Juan		Puerto Rico	00935
13	Umlazi CRS	Durban	KwaZulu-Natal	South Africa	4001
14	Fam-Cru Crs	Cape Town		South Africa	7505
15	Siriraj Hospital ,Mahidol University NICHD CRS	Bangkok	Bangkoknoi	Thailand	10700

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Study Chair: Diana F. Clarke, PharmD, Section of Pediatric Infectious Diseases, Boston Medical Center

Study Documents (Full-Text)

• Study Protocol - Jan 18, 2017
• Statistical Analysis Plan - Jan 3, 2017

More Information

Additional Information:

• DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, dated December 2004, Clarification August 2009

Publications

• Nielsen-Saines K, Watts DH, Veloso VG, Bryson YJ, Joao EC, Pilotto JH, Gray G, Theron G, Santos B, Fonseca R, Kreitchmann R, Pinto J, Mussi-Pinhata MM, Ceriotto M, Machado D, Bethel J, Morgado MG, Dickover R, Camarca M, Mirochnick M, Siberry G, Grinsztejn B, Moreira RI, Bastos FI, Xu J, Moye J, Mofenson LM; NICHD HPTN 040/PACTG 1043 Protocol Team. Three postpartum antiretroviral regimens to prevent intrapartum HIV infection. N Engl J Med. 2012 Jun 21;366(25):2368-79. doi: 10.1056/NEJMoa1108275.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT01780831
• Other Study ID Numbers: P1110; 11891; IMPAACT P1110
• First Posted: Jan 31, 2013
• Last Update Posted: Nov 5, 2021
• Last Verified: Jul 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Infections; Communicable Diseases; Raltegravir Potassium

Study Results

Participant Flow

Recruitment Details	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.

Arm/Group Title	Cohort 1 RAL-naive	Cohort 1 RAL-exposed	Cohort 2 RAL-naive	Cohort 2 RAL-exposed
Arm/Group Description	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.	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.	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.	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.
Period Title: Overall Study
STARTED	10	6	26	10
COMPLETED	10	6	22	9
NOT COMPLETED	0	0	4	1

Baseline Characteristics

Arm/Group Title	Cohort 1 RAL-naive	Cohort 1 RAL-exposed	Cohort 2 RAL-naive	Cohort 2 RAL-exposed	Total
Arm/Group Description	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.	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.	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.	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 of all reporting groups
Overall Participants	10	6	26	10	52
Age (Count of Participants)
<=18 years	10 100%	6 100%	26 100%	10 100%	52 100%
Between 18 and 65 years	0 0%	0 0%	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%
Age, Customized (weeks) [Median (Full Range) ]
Gestational age at birth	39	38	38	39	39
Sex: Female, Male (Count of Participants)
Female	6 60%	2 33.3%	12 46.2%	4 40%	24 46.2%
Male	4 40%	4 66.7%	14 53.8%	6 60%	28 53.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 30%	3 50%	19 73.1%	5 50%	30 57.7%
Not Hispanic or Latino	7 70%	2 33.3%	7 26.9%	4 40%	20 38.5%
Unknown or Not Reported	0 0%	1 16.7%	0 0%	1 10%	2 3.8%
Birth weight (grams) [Median (Full Range) ]
Median (Full Range) [grams]	3020	2948	2930	3085	3000
Apgar score at 1 minute (Scores on a scale) [Median (Full Range) ]
Median (Full Range) [Scores on a scale]	8	9	9	9	9

Outcome Measures

1. Primary Outcome

Title	Number of Infants Who Died or Had Grade 3/4 Adverse Event Through 6 Weeks of Life
Description	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.
Time Frame	From first dosing of RAL through 6 weeks of life

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Cohort 1 RAL-naive	Cohort 1 RAL-exposed	Cohort 1 Total	Cohort 2 RAL-naive	Cohort 2 RAL-exposed	Cohort 2 Total
Arm/Group Description	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.	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.	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.	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.	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.	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.
Measure Participants	10	6	16	25	10	35
Count of Participants [Participants]	2 20%	2 33.3%	4 15.4%	7 70%	4 7.7%	11 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 Total
	Comments
	Type of Statistical Test	Other
	Comments	Point and 90% CI estimates of percentage Cohort 1 infants who died or had grade 3/4 AE through 6 weeks of life.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Clopper-Pearson Confidence Interval (CI)
	Estimated Value	25
	Confidence Interval	(2-Sided) 90%; 9 to 48.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 2 Total
	Comments
	Type of Statistical Test	Other
	Comments	Point and 90% CI estimates of percentage Cohort 2 infants who died or had grade 3/4 AE through 6 weeks of life.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Clopper-Pearson Confidence Interval (CI)
	Estimated Value	31
	Confidence Interval	(2-Sided) 90%; 18.7 to 46.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	AUC24 for Cohort 1 RAL Dose #1 (Within 48 Hours of Birth)
Description	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)
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Cohort 1 RAL-naive: 3 mg/kg for First Dose	Cohort 1 RAL-naive: 2 mg/kg for First Dose	Cohort 1 RAL-exposed 1.5 mg/kg
Arm/Group Description	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 RAL doses: first dose (3 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	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 RAL doses: first dose (2 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	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 RAL doses: first dose (1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.
Measure Participants	6	3	6
Geometric Mean (Geometric Coefficient of Variation) [mg*h/L]	53.88 (34.6)	44.26 (71.9)	37.42 (92.7)

3. Primary Outcome

Title	Cmax for Cohort 1 RAL Dose #1 (Within 48 Hours of Birth)
Description	Maximum concentration (Cmax) for Cohort 1 dose #1 (within 48 hours of birth)
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Cohort 1 RAL-naive: 3 mg/kg for First Dose	Cohort 1 RAL-naive: 2 mg/kg for First Dose	Cohort 1 RAL-exposed: 1.5 mg/kg for First Dose
Arm/Group Description	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: first dose (3 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	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: first dose (2 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	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: first dose (1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.
Measure Participants	6	3	6
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	3360.89 (35.5)	3405.24 (38.1)	2188.82 (73.3)

4. Primary Outcome

Title	AUC24 for Cohort 2 Initial RAL Dose (Within 48 and 12-60 Hours of Birth for RAL-naive and RAL-exposed Groups, Respectively)
Description	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).
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Cohort 2 RAL-naive: 1.5 mg/kg Once Daily on Days 1-7 of Life	Cohort 2 RAL-exposed: 1.5mg/kg Once Daily on Days 1-7 of Life
Arm/Group Description	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 lifes 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.	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
Measure Participants	24	10
Geometric Mean (Geometric Coefficient of Variation) [mg*h/L]	38.2 (42)	42.89 (25.3)

5. Primary Outcome

Title	Clast for Cohort 2 Initial RAL Dose (Within 48 and Between 12-60 Hours of Birth for RAL-naïve and RAL-exposed Groups, Respectively)
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Cohort 2 RAL-naive: 1.5 mg/kg Once Daily on Days 1-7 of Life	Cohort 2 RAL-exposed: 1.5 mg/kg Once Daily on Days 1-7 of Life
Arm/Group Description	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.	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.
Measure Participants	25	10
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	947.90 (84)	946.24 (74)

6. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Cohort 2 RAL-naive: 3 mg/kg Twice Daily on Days 8-18 of Life	Cohort 2 RAL-exposed: 3 mg/kg Twice Daily on Days 8-28 of Life
Arm/Group Description	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.	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 to 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.
Measure Participants	23	9
Geometric Mean (Geometric Coefficient of Variation) [mg*h/L]	14.3 (49.5)	18.25 (62.8)

7. Primary Outcome

Title	RAL C12 for Cohort 2 at 15-18 Days of Life
Description	RAL concentration at 12 hours (C12) for Cohort 2 at 15-18 days of life.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Cohort 2 RAL-naive: 3 mg/kg Twice Daily on Days 8-28 of Life	Cohort 2 RAL-exposed: 3 mg/kg Twice Daily on Days 8-28 of Life
Arm/Group Description	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.	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 to 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
Measure Participants	23	9
Geometric Mean (Geometric Coefficient of Variation) [mg*h/L]	176.11 (162.1)	273.59 (176.4)

8. Secondary Outcome

Title	Number of Infants Who Died or Had Grade 3/4 Adverse Event Through 24 Weeks of Life
Description	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.
Time Frame	From first RAL dose through 24 weeks of life

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Cohort 1 RAL-naive	Cohort 1 RAL-exposed	Cohort 1 Total	Cohort 2 RAL-naive	Cohort 2 RAL-exposed	Cohort 2 Total
Arm/Group Description	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: 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.	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: first dose (1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	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: 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.	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.	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 to 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	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 dosing 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.
Measure Participants	10	6	16	25	10	35
Count of Participants [Participants]	2 20%	2 33.3%	4 15.4%	11 110%	4 7.7%	15 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 Total
	Comments
	Type of Statistical Test	Other
	Comments	Point and 90% CI estimates of percentage Cohort 1 infants who died or had grade 3/4 AE through 24 weeks of life.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Clopper-Pearson Confidence Interval (CI)
	Estimated Value	25
	Confidence Interval	(2-Sided) 90%; 9 to 48.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 2 Total
	Comments
	Type of Statistical Test	Other
	Comments	Point and 90% CI estimates of percentage Cohort 2 infants who died or had grade 3/4 AE through 24 weeks of life.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Clopper-Pearson Confidence Interval (CI)
	Estimated Value	43
	Confidence Interval	(2-Sided) 90%; 28.6 to 58.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Number of Infants Who Died or Had SADR of Grade 3 or 4 Through 6 Weeks of Life
Description	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.
Time Frame	From first RAL dose through 6 weeks of life

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Cohort 1 RAL-naive	Cohort 1 RAL-exposed	Cohort 1 Total	Cohort 2 RAL-naive	Cohort 2 RAL-exposed	Cohort 2 Total
Arm/Group Description	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 RAL doses: 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.	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 RAL doses: first dose (1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	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 RAL doses: 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.	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.	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 to 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	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 dosing through 6 weeks of life starting within 48 hours of birth and between 12 to 60 hours of birth for 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.
Measure Participants	10	6	16	25	10	35
Count of Participants [Participants]	1 10%	0 0%	1 3.8%	0 0%	0 0%	0 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 Total
	Comments
	Type of Statistical Test	Other
	Comments	Point and 90% CI estimates of percentage Cohort 1 infants who died or had SADR of Grade 3 or 4 through 6 weeks of life.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Clopper-Pearson Confidence Interval (CI
	Estimated Value	6
	Confidence Interval	(2-Sided) 90%; 0.3 to 26.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 2 Total
	Comments
	Type of Statistical Test	Other
	Comments	Point and 90% CI estimates of percentage Cohort 2 infants who died or had SADR of Grade 3 or 4 through 6 weeks of life.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Clopper-Pearson Confidence Interval (CI)
	Estimated Value	0
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	CI is not provided since the estimation parameter is 0.

10. Secondary Outcome

Title	Number of Infants Who Died or Had SADR of Grade 3 or 4 Through 24 Weeks of Life
Description	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.
Time Frame	From first RAL dose through 24 weeks of life

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Cohort 1 RAL-naive	Cohort 1 RAL-exposed	Cohort 1 Total	Cohort 2 RAL-naive	Cohort 2 RAL-exposed	Cohort 2 Total
Arm/Group Description	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 RAL doses: first dose (3 mg/kg or 2 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	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 RAL doses: first dose (1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.	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 RAL doses: 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.	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.	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 to 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.	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 dosing through 6 weeks of life starting within 48 hours of birth and between 12 to 60 hours of birth for 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.
Measure Participants	10	6	16	25	10	35
Count of Participants [Participants]	1 10%	0 0%	1 3.8%	0 0%	0 0%	0 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 Total
	Comments
	Type of Statistical Test	Other
	Comments	Point and 90% CI estimates of percentage Cohort 1 infants who died or had SADR of Grade 3 or 4 through 24 weeks of life.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Clopper-Pearson Confidence Interval (CI)
	Estimated Value	6
	Confidence Interval	(2-Sided) 90%; 0.3 to 26.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 2 Total
	Comments
	Type of Statistical Test	Other
	Comments	Point and 90% CI estimates of percentage Cohort 2 infants who died or had SADR of Grade 3 or 4 through 24 weeks of life.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Clopper-Pearson Confidence Interval (CI)
	Estimated Value	0
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	CI is not provided since the estimation parameter is 0.

11. Secondary Outcome

Title	Cohort 1 Dose #1 Neonatal RAL Elimination (CL/F) by UGT1A1 Genotype Group
Description	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) .
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	(TA)6(TA)6	(TA)6(TA)7
Arm/Group Description	Cohort 1 infants whose UGT1A1 genotype were (TA)6(TA)6 (wildtype).	Cohort 1 infants whose UGT1A1 genotype were (TA)6(TA)7.
Measure Participants	6	6
Median (Inter-Quartile Range) [L/hr]	0.11	0.06

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 RAL-naive, Cohort 1 RAL-exposed
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.298
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

12. Secondary Outcome

Title	Cohort 2 Initial Dose Neonatal RAL Elimination (CL/F) by UGT1A1 Genotype Group
Description	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) .
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	(TA)6(TA)6 Wildtype	Mutation
Arm/Group Description	Cohort 2 infants whose UGT1A1 genotype were (TA)6(TA)6 (wildtype).	Cohort 2 infants whose UGT1A1 genotype were mutation: (TA)5(TA)5, (TA)5(TA)6, (TA)5(TA)7, (TA)6(TA)7, or (TA)7(TA)7.
Measure Participants	15	12
Median (Inter-Quartile Range) [L/hr]	0.1	0.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 RAL-naive, Cohort 1 RAL-exposed
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.37
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

13. Secondary Outcome

Title	Cohort 2 Neonatal RAL Elimination (CL/F) at 15-18 Days of Life by UGT1A1 Genotype Group
Description	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) .
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	(TA)6(TA)6 Wildtype	Mutation
Arm/Group Description	Cohort 2 infants whose UGT1A1 genotype were (TA)6(TA)6 (wildtype).	Cohort 2 infants whose UGT1A1 genotype were mutation: (TA)5(TA)5, (TA)5(TA)6, (TA)5(TA)7, (TA)6(TA)7, or (TA)7(TA)7.
Measure Participants	14	11
Median (Inter-Quartile Range) [L/hr]	0.5	0.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 RAL-naive, Cohort 1 RAL-exposed
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.98
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

14. Secondary Outcome

Title	Number of Cohort 1 Infants With Hyperbilirubinemia by UGT1A1 Genotype
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	(TA)5(TA)6	(TA)6(TA)6	(TA)6(TA)7
Arm/Group Description	Cohort 1 infants whose UGT1A1 genotype were (TA)5(TA)6.	Cohort 1 infants whose UGT1A1 genotype were (TA)6(TA)6 (wildtype).	Cohort 2 infants whose UGT1A1 genotype were (TA)6(TA)7.
Measure Participants	0	0	0

15. Secondary Outcome

Title	Number of Cohort 2 Infants With Hyperbilirubinemia by UGT1A1 Genotype
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	(TA)6(TA)6	(TA)5(TA)5	(TA)5(TA)6	(TA)5(TA)7	(TA)6(TA)7	(TA)7(TA)7
Arm/Group Description	Cohort 2 infants whose UGT1A1 genotype were (TA)6(TA)6 (wildtype).	Cohort 2 infants whose UGT1A1 genotype were (TA)5(TA)5.	Cohort 2 infants whose UGT1A1 genotype were (TA)5(TA)6.	Cohort 2 infants whose UGT1A1 genotype were (TA)5(TA)7.	Cohort 2 infants whose UGT1A1 genotype were (TA)6(TA)7.	Cohort 2 infants whose UGT1A1 genotype were (TA)7(TA)7.
Measure Participants	0	0	0	0	0	0

16. Secondary Outcome

Title	Number of Cohort 1 Infants With Hyperbilirubinemia by SLCO1B3 Genotype
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	C / C	C / T	T / T
Arm/Group Description	Cohort 1 infants whose SLCO1B3 genotype were C/C (wildtype).	Cohort 1 infants whose SLCO1B3 genotype were C/T.	Cohorts infants whose SLCO1B3 genotype were T/T.
Measure Participants	0	0	0

17. Secondary Outcome

Title	Number of Cohort 2 Infants With Hyperbilirubinemia by SLCO1B3 Genotype
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	C / C	C / T	T / T
Arm/Group Description	Cohort 2 infants whose SLCO1B3 genotype was C/C (wildtype).	Cohort 2 infants whose SLCO1B3 genotype was C/T.	Cohort 2 infants whose SLCO1B3 genotype was T/T.
Measure Participants	0	0	0

Adverse Events

Time Frame	From first RAL dose through 24 weeks of life
Adverse Event Reporting Description	All Adverse Events (AEs) including diagnoses, signs/symptoms and abnormal laboratory test results mentioned in the "Study Description" section. Events with onset dates prior to first RAL dose and congenital anomalies assessed as baseline by the study team were considered baseline events and not AEs.
Arm/Group Title	Cohort1 RAL-naive		Cohort1 RAL-exposed		Cohort2 RAL-naive		Cohort2 RAL-exposed
Arm/Group Description	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 RAL doses: first dose (3 mg/kg or 2 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.		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 RAL doses: first dose (1.5 mg/kg) within 48 hours of birth and second dose (3 mg/kg) at 7-10 days of life.		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.		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 to 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.
All Cause Mortality
	Cohort1 RAL-naive		Cohort1 RAL-exposed		Cohort2 RAL-naive		Cohort2 RAL-exposed
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/6 (0%)		0/25 (0%)		0/10 (0%)
Serious Adverse Events
	Cohort1 RAL-naive		Cohort1 RAL-exposed		Cohort2 RAL-naive		Cohort2 RAL-exposed
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/10 (30%)		1/6 (16.7%)		7/25 (28%)		2/10 (20%)
Blood and lymphatic system disorders
Anaemia neonatal	0/10 (0%)		1/6 (16.7%)		0/25 (0%)		0/10 (0%)
Congenital, familial and genetic disorders
Congenital syphilis	0/10 (0%)		0/6 (0%)		1/25 (4%)		0/10 (0%)
Gastrointestinal disorders
Vomiting	1/10 (10%)		0/6 (0%)		0/25 (0%)		0/10 (0%)
Infections and infestations
Bronchiolitis	0/10 (0%)		0/6 (0%)		1/25 (4%)		0/10 (0%)
Cellulitis	0/10 (0%)		0/6 (0%)		1/25 (4%)		0/10 (0%)
Pneumonia bacterial	0/10 (0%)		0/6 (0%)		1/25 (4%)		0/10 (0%)
Respiratory syncytial virus bronchiolitis	0/10 (0%)		0/6 (0%)		1/25 (4%)		0/10 (0%)
Injury, poisoning and procedural complications
Craniocerebral injury	0/10 (0%)		0/6 (0%)		1/25 (4%)		0/10 (0%)
Investigations
Aspartate aminotransferase increased	0/10 (0%)		0/6 (0%)		0/25 (0%)		1/10 (10%)
Blood glucose decreased	0/10 (0%)		0/6 (0%)		1/25 (4%)		0/10 (0%)
Haematocrit decreased	0/10 (0%)		0/6 (0%)		1/25 (4%)		0/10 (0%)
Hepatic enzyme increased	0/10 (0%)		0/6 (0%)		1/25 (4%)		0/10 (0%)
Neutrophil count decreased	1/10 (10%)		0/6 (0%)		0/25 (0%)		1/10 (10%)
Weight decreased	0/10 (0%)		0/6 (0%)		1/25 (4%)		0/10 (0%)
Vascular disorders
Hypertension neonatal	1/10 (10%)		0/6 (0%)		0/25 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Cohort1 RAL-naive		Cohort1 RAL-exposed		Cohort2 RAL-naive		Cohort2 RAL-exposed
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/10 (100%)		6/6 (100%)		24/25 (96%)		9/10 (90%)
Congenital, familial and genetic disorders
Atrial septal defect	1/10 (10%)		0/6 (0%)		0/25 (0%)		1/10 (10%)
Congenital umbilical hernia	0/10 (0%)		0/6 (0%)		3/25 (12%)		0/10 (0%)
Craniosynostosis	0/10 (0%)		1/6 (16.7%)		0/25 (0%)		0/10 (0%)
Laryngomalacia	1/10 (10%)		0/6 (0%)		0/25 (0%)		0/10 (0%)
Pulmonary artery stenosis congenital	1/10 (10%)		0/6 (0%)		0/25 (0%)		0/10 (0%)
Eye disorders
Eye discharge	0/10 (0%)		0/6 (0%)		1/25 (4%)		1/10 (10%)
Gastrointestinal disorders
Constipation	0/10 (0%)		0/6 (0%)		2/25 (8%)		0/10 (0%)
Gastrooesophageal reflux disease	1/10 (10%)		0/6 (0%)		2/25 (8%)		3/10 (30%)
Infantile spitting up	0/10 (0%)		0/6 (0%)		0/25 (0%)		2/10 (20%)
Infantile vomiting	0/10 (0%)		0/6 (0%)		2/25 (8%)		0/10 (0%)
Oral mucosal discolouration	0/10 (0%)		1/6 (16.7%)		0/25 (0%)		0/10 (0%)
Umbilical hernia	1/10 (10%)		0/6 (0%)		1/25 (4%)		0/10 (0%)
Vomiting	1/10 (10%)		1/6 (16.7%)		3/25 (12%)		1/10 (10%)
General disorders
Pyrexia	1/10 (10%)		0/6 (0%)		7/25 (28%)		1/10 (10%)
Vessel puncture site bruise	0/10 (0%)		1/6 (16.7%)		0/25 (0%)		0/10 (0%)
Hepatobiliary disorders
Hyperbilirubinaemia neonatal	1/10 (10%)		0/6 (0%)		0/25 (0%)		0/10 (0%)
Jaundice	1/10 (10%)		0/6 (0%)		2/25 (8%)		0/10 (0%)
Infections and infestations
Folliculitis	1/10 (10%)		0/6 (0%)		0/25 (0%)		0/10 (0%)
Genital candidiasis	0/10 (0%)		0/6 (0%)		3/25 (12%)		1/10 (10%)
Oral candidiasis	0/10 (0%)		1/6 (16.7%)		8/25 (32%)		1/10 (10%)
Otitis media acute	0/10 (0%)		1/6 (16.7%)		1/25 (4%)		0/10 (0%)
Skin candida	1/10 (10%)		0/6 (0%)		0/25 (0%)		0/10 (0%)
Tinea versicolour	0/10 (0%)		0/6 (0%)		0/25 (0%)		1/10 (10%)
Upper respiratory tract infection	0/10 (0%)		0/6 (0%)		5/25 (20%)		1/10 (10%)
Investigations
Alanine aminotransferase increased	1/10 (10%)		0/6 (0%)		1/25 (4%)		0/10 (0%)
Aspartate aminotransferase increased	2/10 (20%)		0/6 (0%)		2/25 (8%)		1/10 (10%)
Blood albumin decreased	1/10 (10%)		0/6 (0%)		0/25 (0%)		0/10 (0%)
Blood alkaline phosphatase increased	0/10 (0%)		1/6 (16.7%)		1/25 (4%)		0/10 (0%)
Blood bilirubin increased	1/10 (10%)		1/6 (16.7%)		4/25 (16%)		2/10 (20%)
Blood creatinine increased	1/10 (10%)		0/6 (0%)		6/25 (24%)		1/10 (10%)
Blood glucose decreased	0/10 (0%)		1/6 (16.7%)		0/25 (0%)		0/10 (0%)
Blood potassium increased	0/10 (0%)		1/6 (16.7%)		1/25 (4%)		0/10 (0%)
Blood pressure increased	1/10 (10%)		0/6 (0%)		1/25 (4%)		0/10 (0%)
Blood sodium decreased	1/10 (10%)		0/6 (0%)		0/25 (0%)		0/10 (0%)
Cardiac murmur	0/10 (0%)		0/6 (0%)		1/25 (4%)		1/10 (10%)
Haemoglobin decreased	4/10 (40%)		5/6 (83.3%)		20/25 (80%)		7/10 (70%)
Neutrophil count decreased	5/10 (50%)		4/6 (66.7%)		10/25 (40%)		1/10 (10%)
Nervous system disorders
Fontanelle bulging	0/10 (0%)		0/6 (0%)		0/25 (0%)		1/10 (10%)
Hypertonia	0/10 (0%)		1/6 (16.7%)		0/25 (0%)		0/10 (0%)
Pregnancy, puerperium and perinatal conditions
Jaundice neonatal	0/10 (0%)		0/6 (0%)		4/25 (16%)		2/10 (20%)
Reproductive system and breast disorders
Acquired hydrocele	1/10 (10%)		0/6 (0%)		0/25 (0%)		0/10 (0%)
Breast induration	0/10 (0%)		1/6 (16.7%)		0/25 (0%)		0/10 (0%)
Penile erythema	1/10 (10%)		0/6 (0%)		0/25 (0%)		0/10 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	2/10 (20%)		1/6 (16.7%)		9/25 (36%)		1/10 (10%)
Cyanosis neonatal	0/10 (0%)		0/6 (0%)		0/25 (0%)		1/10 (10%)
Dyspnoea	0/10 (0%)		0/6 (0%)		2/25 (8%)		0/10 (0%)
Nasal congestion	4/10 (40%)		0/6 (0%)		5/25 (20%)		1/10 (10%)
Oropharyngeal plaque	0/10 (0%)		0/6 (0%)		0/25 (0%)		1/10 (10%)
Rhinorrhoea	2/10 (20%)		0/6 (0%)		1/25 (4%)		0/10 (0%)
Skin and subcutaneous tissue disorders
Dermatitis	1/10 (10%)		0/6 (0%)		1/25 (4%)		0/10 (0%)
Dermatitis allergic	0/10 (0%)		0/6 (0%)		2/25 (8%)		0/10 (0%)
Dermatitis diaper	0/10 (0%)		1/6 (16.7%)		0/25 (0%)		0/10 (0%)
Eczema	1/10 (10%)		0/6 (0%)		0/25 (0%)		1/10 (10%)
Erythema	0/10 (0%)		1/6 (16.7%)		1/25 (4%)		0/10 (0%)
Papule	1/10 (10%)		0/6 (0%)		0/25 (0%)		1/10 (10%)
Rash	1/10 (10%)		0/6 (0%)		3/25 (12%)		0/10 (0%)
Rash erythematous	0/10 (0%)		0/6 (0%)		0/25 (0%)		1/10 (10%)
Rash generalised	0/10 (0%)		0/6 (0%)		0/25 (0%)		1/10 (10%)
Seborrhoea	1/10 (10%)		0/6 (0%)		0/25 (0%)		0/10 (0%)
Seborrhoeic dermatitis	0/10 (0%)		0/6 (0%)		4/25 (16%)		0/10 (0%)
Vascular disorders
Pallor	0/10 (0%)		2/6 (33.3%)		2/25 (8%)		0/10 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.