A Phase I/II, open-label, single arm, two-stage trial to evaluate the single and multi-dose PK and safety of DTG in HIV-exposed neonates on ARV prophylaxis. HIV-exposed term neonates born mothers with HIV on DTG-based antiretroviral therapy with a birth weight ≥2000 g who are on ARV postnatal prophylaxis will be enrolled.

A Phase I/II, open-label, single arm, two-stage trial to evaluate the single and multi-dose PK and safety of DTG in HIV-exposed neonates on ARV prophylaxis. HIV-exposed term neonates born mothers with HIV on DTG-based antiretroviral therapy with a birth weight ≥2000 g who are on ARV postnatal prophylaxis will be enrolled.

Enrolment will be in two stages:

• Stage 1 will assess a single 5 mg dose of the DTG-DT in two sequential cohorts: Cohort 1A (n=8) and Cohort 1B (n=8).
• Stage 2 will assess multiple 5 mg doses of the DTG-DT and DTG-ODF in two parallel cohorts: Cohort 2A (n=20) and Cohort 2B (n=20).

Per national guidelines, all infants receive a birth HIV nucleic acid test (NAT). HIV NAT test results for the infant may or may not be available (HIV pending) at the time of study entry. HIV NAT results are typically available within 72 hours of the blood sample being taken and are checked and acted upon by the hospital HIV PMTCT service, as part of standard of care. If an HIV NAT result comes back positive whilst the neonate is on study, the neonate will not receive any further DTG doses, revert to standard of care antiretroviral therapy (ART), and be followed for safety for the duration of the study.

Primary Objectives:

• To evaluate the pharmacokinetics of dolutegravir (DTG) during the first 28 days of life in HIV-exposed term neonates (born to a mother with HIV) following administration of DTG dispersible tablet (DTG-DT) and DTG oral dispersible film (DTG-ODF)
• To determine the safety of DTG during the first 28 days of life in HIV-exposed term neonates following administration of DTG-DT and DTG-ODF

Secondary Objectives:

• To quantitatively and qualitatively assess the acceptability of DTG-DT and DTG-ODF for the neonate, the caregiver and health workers

Primary endpoints:

• DTG plasma pharmacokinetics parameters: area under the concentration time curve (AUC); maximum plasma concentration (Cmax), apparent clearance (CL/F), and trough concentration (Ctrough)
• Occurrence of the following events: adverse events of Grade 3 or higher; treatment-related adverse events of Grade 3 or higher; any adverse events

Secondary endpoints:

• Acceptability to caregivers and neonates of using DTG-DT will be measured by means of a questionnaire

Inclusion Criteria:

• Stage 1: Inclusion Criteria

  • HIV-exposed neonate (pending HIV status) born to a woman within HIV on DTG-based ART
  • Birth weight of ≥2000 g and on standard of care ARV prophylaxis

Cohort Specific Inclusion Criteria in Stage 1 must be met at Study Entry:

Cohort 1A: Infant <14 days of life Cohort 1B: Infant ≤3 days of life

Stage 2: Inclusion Criteria

• Low risk* HIV-exposed neonate (pending HIV status) born to a virologically suppressed woman on DTG-based ART

  *Neonate born to a woman with a documented plasma HIV-1 RNA result <50 copies/mL in the 4 weeks prior to delivery or between delivery and infant study entry

• Birth weight of ≥2000 g and on standard of care ARV prophylaxis

Cohort Specific Inclusion Criteria in Stage 2 must be met at Study Entry:

Cohort 2: Infant <7 days of life

Exclusion Criteria:

• • Less than 37 weeks gestational age at birth

  • Known blood group incompatibilities which can result in hemolytic disease of the newborn (e.g., Rh-negative mother, presence of antibodies on neonatal red blood cells, etc.)
  • Total bilirubin values approaching an exchange transfusion as defined by local guidelines (Section 18.2)
  • Haemoglobin value of <13.0 g/dL
  • Platelet count of less than 50,000 cells/mm3)
  • Decreased total white blood cell count (Grade 3 and above)
  • Creatinine value more than 1.3 the upper limit of normal (ULN) for gestational age and postnatal age (Grade 2 and above)
  • AST or ALT of more than 2.5 the ULN (Grade 2 and above)
  • Any other current Grade ≥3 event on the DAIDS toxicity table
  • Severe congenital abnormalities or critically ill neonates at discretion of the examining clinician
  • Receiving medicine(s) that can impact DTG pharmacokinetics (Section 8.7)
  • Participation in another clinical trial
  • HIV-infected neonates