The purpose of this study was to evaluate the safety, tolerability, and pharmacokinetics (PK) of dolutegravir (DTG) in infants born to mothers living with HIV-1. The primary goal of the study was to propose a dose of DTG that is safe and meets PK targets when administered to infants through the first four weeks of life in addition to the infant's standard HIV-1 ARV prophylaxis. The study was expected to enroll a minimum of 36 and up to 108 mother-infant (M-I) pairs from Brazil, South Africa, Thailand, and the United States. Infants were followed through 16 weeks of life. Mothers did not receive study drug and were off study after completion of the Entry visit. A total of 48 M-I pairs were enrolled in the study.

This was a Phase I, multi-centered, open-label, non-comparative dose-finding study to evaluate the safety, tolerability, and PK of DTG when added to standard ARV prophylaxis in singleton full-term (≥ 37 weeks gestation at birth) infants born to mothers living with HIV-1, and to propose an appropriate DTG dosing regimen during the first four weeks of life for infants born to mothers living with HIV-1.

The infant and mother were enrolled as a pair, with the mother taken off study after completing the Entry visit and the infant followed through the Week 16 visit (Days 112-140 of life).

Infants were enrolled in two sequential dosing cohorts: Cohort 1 (two single DTG doses) and Cohort 2 (chronic DTG dosing through a Week 4 or 6 visit per local standard of care for ARV prophylaxis). Cohort 1 was intended to generate the PK and safety data that would inform DTG dose selection for Cohort 2.

At study entry in both cohorts, the participants were stratified based on the infant's in utero exposure to maternal DTG using the criteria below:

• DTG-naïve: Infant born to a mother who did not receive DTG during the two weeks immediately prior to delivery.
• DTG-exposed: Infant born to a mother who received at least one dose of DTG less than or equal to 72 hours prior to delivery.

Across the two cohorts and two in utero exposure groups there were five study strata.

Cohort 1: Two single DTG doses approximately seven days apart.

• Cohort 1 Stratum 1A (DTG-naïve): DTG-naïve infants receiving 2 doses of DTG liquid suspension, with 1st dose at 0-5 days of life and 2nd dose at the 7 Days (+3 days) Post Initial Dose visit.
• Cohort 1 Stratum 1B (DTG-exposed): DTG-exposed infants receiving 2 doses of DTG liquid suspension, with 1st dose at 2-5 days of life and 2nd dose at the 7 Days (+3 days) Post Initial Dose visit.
• Cohort 1 Stratum 1C (DTG-naïve): DTG-naïve infants receiving 2 doses of DTG dispersible tablets, with 1st dose at 0-5 days of life and 2nd dose at the 7 Days (+3 days) Post Initial Dose visit.

Cohort 2: Chronic DTG dosing through Week 4 or 6 visit based on the duration of local standard ARV prophylaxis.

• Cohort 2 Stratum 2A (DTG-naïve): DTG-naïve infants receiving DTG 5 mg dispersible tablets every 48 hours from the Entry visit (0-5 days of life) through Day 13 (week 2) of life; then every 24 hours from Day 14 of life through the Week 4 or Week 6 visit based on the duration of local standard ARV prophylaxis.
• Cohort 2 Stratum 2B (DTG-exposed): DTG-exposed infants receiving DTG 5 mg dispersible tablets every 48 hours from from the Entry visit (0-5 days of life) through Day 13 (week 2) of life; then every 24 hours from Day 14 of life through the Week 4 or Week 6 visit based on the duration of local standard ARV prophylaxis.

A minimum of 12 and up to 36 M-I pairs (across strata) were planned to be enrolled in Cohort 1 to achieve a target of six evaluable infants in each stratum to provide PK and safety data to determine the starting DTG dose for each stratum in Cohort 2. A minimum of 24 and up to 72 mother-infant pairs (across both strata) were planned to be enrolled in Cohort 2 to achieve a target of 12 evaluable infants in both Strata 2A and 2B receiving the final proposed chronic dose of DTG. Breastfeeding and formula-feeding infants were eligible for both Cohorts 1 and 2. At least eight breastfeeding and eight formula-feeding infants were planned to be enrolled in Cohort 2 across both strata.

Infant PK samples were collected as follows:

Cohort 1:

• Dose #1 (0-5 days of life) intensive PK sampling: prior to observed dose, 1-2 hours (±15 min) post-dose, 4-8 hours (±15 min) post-dose, 11-13 hours (±15 min) post-dose, 22-26 hours (±15 min) post-dose, 48-72 hours (±15 min) post-dose.
• Dose #2 [7 days post initial dose (+3 days)] intensive PK sampling: prior to observed dose, 1-2 hours (±15 min) post-dose, 22-26 hours (±15 min) post-dose.

Cohort 2:

• First intensive PK sampling [7 days post initial dose (+3 days)]: prior to observed dose, 1-2 hours (±15 min) post-dose, 6-10 hours (±15 min) post-dose, 22-26 hours (±15 min) post-dose (collect PK sample prior to administration of next DTG dose if every 24-hour dosing interval used), prior to administration of the next dose (a sample at this time point should only be collected for Cohort 2 infants with DTG dose regimen administered more than every 24 hours, e.g., every 48 or 72 hours).
• Second intensive PK sampling [Week 4 (23-33 days of life)]: prior to observed dose, 1-2 hours (±15 min) post-dose, 6-10 hours (±15 min) post-dose, 22-26 hours (±15 min) post-dose (collect PK sample prior to administration of next DTG dose if every 24-hour dosing interval used).

Infant safety evaluations were done at:

• Cohort 1: Entry, 7 days post initial dose, Week 4, Week 6, Week 16
• Cohort 2: Entry, 2 days post initial dose, 7 days post initial dose, Week 4, Week 6, Week 8, Week 12, Week 16.

Infant tolerability evaluations were done at:

• Cohort 1: Dose #1 (0-5 days of life), Dose #2 [7 days post initial dose (+3 days)]
• Cohort 2: Entry, 2 days post initial dose, 7 days post initial dose (+3 days), Week 4, Week 6

Safety data included infant clinical data, laboratory test results and information on any infant deaths. Laboratory test results included evaluations specified in the protocol and results from the infant's clinical care. Adverse events were graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. Adverse events were defined as the occurrence of at least one grade 1 (mild), 2 (moderate), 3 (severe), 4 (potentially life-threatening), or 5 (death) adverse event, during the study follow-up. In addition, grading of axillary measured fever and plasma creatinine grading in this study followed protocol section 7.3.3. The study site's assessment of adverse event attribution to study drug was used. For the final analysis, all infants who received at least one dose of DTG are safety evaluable (same as in the Regulatory Submission Report).

The protocol pharmacologists determined whether PK parameters can be estimated from the specimens collected, and as described in Protocol Section 3, these determinations were used to determine whether participants are PK evaluable.

Inclusion Criteria:

1. Mother is of legal age or circumstance to provide independent informed consent and is willing and able to provide written informed consent for her and permission for her infant's participation in this study.

2. Mother has confirmed HIV-1 infection based on positive test results from two samples collected from two separate blood collection tubes per Sample #1 and Sample #2 protocol requirements. Test results may be obtained from medical records or from testing performed during the study screening period:

   • For results obtained from medical records, adequate source documentation, including the date of specimen collection, date of testing or date of test result, name of test/assay performed, and test result, must be available in study records prior to study entry. Requirements related to laboratory operations (e.g., CLIA, GCLP, or VQA) and related to regulatory authority (e.g., FDA) approvals do not apply to results obtained from medical records.
   • If adequate source documentation is not available, Sample #1 and/or Sample #2 should be collected during the study screening period and tested in the site's designated testing laboratory. If both samples are tested using antibody tests, at least one of the samples must be tested in a laboratory that operates according to CLIA or equivalent (for US sites) or GCLP (for non-US sites) guidelines and participates in an appropriate external quality assurance program. If nucleic acid testing is used, at least one test must be performed in the site's CLIA-certified or equivalent (for US sites) or VQA-certified (for non-US sites) laboratory.
   • All study-specific samples tested to determine HIV-1 status must be whole blood, serum, or plasma. HIV testing methods and algorithms must be approved for each site by the IMPAACT Laboratory Center (for NIAID-funded sites) or Westat (for NICHD-funded sites). All test methods should be FDA-approved, if available.

3. At entry, infant meets DTG exposure requirements, based on mother's report and confirmed by medical records if available, as follows:

   • For Cohort 1, Strata 1A and 1C, and Cohort 2, Stratum 2A: Infant born to a mother who did not receive DTG during the two weeks immediately prior to delivery.
   • For Cohort 1, Stratum 1B, and Cohort 2, Stratum 2B: Infant born to a mother who received at least one dose of DTG less than or equal to 72 hours prior to delivery.

4. Infant was singleton with a gestational age at birth of at least 37 weeks.

5. At birth, infant's weight was as follows:

   • For Cohort 1, Strata 1A,1B, 1C, and Cohort 2, Strata 2A and 2B: At least 2 kg

6. At screening, infant has the following laboratory test results, based on severity grading specified in the protocol section 7.3.3:

   • ALT (normal)
   • AST (normal or Grade 1)
   • Total bilirubin (normal or Grade 1)
   • Hemoglobin (normal, Grade 1, or Grade 2)
   • White blood cells (normal, Grade 1, or Grade 2)
   • Platelets (normal, Grade 1, or Grade 2)
   • Creatinine (normal, Grade 1, or Grade 2)

7. At entry, infant is less than or equal to five days of life.

8. At entry, infant has initiated standard of care ARV prophylaxis (i.e., received at least one dose of ARV regimen prior to entry).

9. At entry, infant is generally healthy as determined by the site investigator based on review of all available medical history information and physical examination findings.

Exclusion Criteria:

1. Known maternal-fetal blood group incompatibility as evidenced by the presence of an unexpected clinically significant maternal red blood cell antibody that is known to cause hemolytic disease of the fetus and newborn.
2. Infant or breastfeeding mother is receiving any disallowed medicationlisted in protocol Section 5.8.1.
3. At entry, infant with a documented positive HIV nucleic acid test result.
4. Infants with prior exchange transfusion or with elevated bilirubin that would require exchange transfusion.
5. Mother or infant has any condition that, in the opinion of the site investigator or designee, would make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives.

Individual participant data that underlie results in the publication, after deidentification.

Beginning 3 months following publication and available throughout period of funding of the International Maternal Pediatric Adolescent AIDS Clinical Trial (IMPAACT) Network by NIH.

• With whom? Researchers who provide a methodologically sound proposal for use of the data that is approved by the IMPAACT Network.
• For what types of analyses? To achieve aims in the proposal approved by the IMPAACT Network.
• By what mechanism will data be made available? Researchers may submit a request for access to data using the IMPAACT "Data Request" form at: https://www.impaactnetwork.org/resources/study-proposals.htm. Researchers of approved proposals will need to sign an IMPAACT Data Use Agreement before receiving the data.