Pharmacokinetics and safety of dolutegravir in term neonates exposed to HIV-1 (IMPAACT 2023): a phase 1, open-label, multicentre study.

BACKGROUND

Safe and effective antiretroviral options are needed for neonates exposed to HIV-1, but data supporting dolutegravir use from birth are scarce. The aim of this study was to evaluate dolutegravir pharmacokinetics, safety, and tolerability in term neonates, and to identify an appropriate dosing regimen.

METHODS

IMPAACT 2023 was a phase 1, open-label, multicentre study conducted at 15 IMPAACT sites in South Africa, Thailand, and the USA from Oct 5, 2022, to May 22, 2025. Full-term neonates weighing at least 2 kg born to women living with HIV-1 were enrolled between birth and 5 days of life. In cohort 1, infants received two single dolutegravir doses using liquid suspension or 5 mg dispersible tablets. In cohort 2, infants received dolutegravir 5 mg every 48 h until day 14 of life, then every 24 h up to week 4-6 depending on duration of local standard-of-care antiretroviral prophylaxis. In both cohorts, participants were stratified by antepartum maternal dolutegravir exposure. Intensive pharmacokinetic sampling was done around each of the two single doses in cohort 1 and at 7 days post initial dose and at week 4 of life in cohort 2. Safety and tolerability were assessed up to week 16. Primary pharmacokinetic outcomes were the last observed concentration of dolutegravir after each dose and area under the observed single-dose concentration-time curve in cohort 1, and concentration of dolutegravir at the end of the dosing interval (Ctrough) and area under the concentration-time curve over one dosing interval (AUC0-τ) in cohort 2. Pharmacokinetic parameters were estimated by non-compartmental analysis in infants who received the dolutegravir dose under evaluation and had evaluable pharmacokinetic data from intensive sampling. Primary safety outcomes were study drug-related safety failure and safety failure from initial dosing up to 2 weeks after permanent study drug discontinuation. Safety outcomes were assessed in all infants who received at least one dose of dolutegravir and were summarised descriptively. The study is registered with ClinicalTrials.gov, NCT05406583, and is complete.

FINDINGS: Of 73 screened mother-infant pairs, 48 were enrolled between Oct 5, 2022, and Jan 21, 2025. All 48 infants started the study drug and were safety-evaluable; 41 were pharmacokinetic-evaluable. In cohort 1, concentration-time profiles showed prolonged elimination and wide interindividual variability, with substantial overlap between neonates with and without antepartum maternal dolutegravir exposure. In cohort 2, geometric mean Ctrough and AUC0-τ at the day 7 post initial dose visit were within target ranges. At week 4 of life, geometric mean AUC0-τ remained within target range, whereas Ctrough exceeded the target range but remained acceptable. No infants in either cohort had a study drug-related safety failure during the primary safety window. Safety failure occurred in zero of 18 infants in cohort 1 and four of 30 infants in cohort 2. Two of 48 infants had grade 1-2 adverse events that were considered related to dolutegravir.

INTERPRETATION: These findings support dolutegravir as an option from birth for presumptive therapy or early treatment in term infants weighing at least 2 kg.

FUNDING: National Institutes of Health, ViiV Healthcare, and GlaxoSmithKline.