Highlight
– The PETITE‑DTG phase 1/2 randomized trial provides the first multidose pharmacokinetic and safety data for dolutegravir in term neonates from birth to 4 weeks of life.
– A regimen of 5 mg dolutegravir (half a 10 mg scored dispersible tablet or a 5 mg oral dispersible film) every 48 hours for the first 2 weeks, then daily until day 28, achieved geometric mean trough concentrations above the pre-specified target (0.67 μg/mL) and Cmax below the safety threshold (17.0 μg/mL).
– Both formulations produced similar pharmacokinetic profiles; no dolutegravir-related adverse events were observed and all infants completing follow-up were HIV-negative at study exit.
Background
Dolutegravir (DTG), an integrase strand transfer inhibitor with a high barrier to resistance and favourable tolerability in older children and adults, has transformed antiretroviral therapy (ART) policy globally. However, DTG has not been widely recommended for neonates (≤28 days) because of limited dosing guidance, immature drug-metabolizing systems in the neonatal period, and sparse safety data. The absence of practical neonatal formulations further constrained inclusion of DTG in early-life prevention and treatment strategies.
The PETITE‑DTG trial addresses an important clinical gap: generating evidence to inform safe, effective neonatal dosing and providing data on two practical paediatric formulations — a scored dispersible tablet and a novel oral dispersible film — that could facilitate bedside administration in resource-limited settings.
Study design
PETITE‑DTG was an open-label, single-centre, two-stage, randomized phase 1/2 trial conducted at Tygerberg Hospital, South Africa. Inclusion criteria for stage two (reported here) were term neonates (gestational age ≥37 weeks, birthweight ≥2 kg) born to mothers receiving DTG-based ART. Between Sept 15, 2023, and Nov 6, 2024, 41 neonates were randomized 1:1 to receive 5 mg DTG either as half of a scored 10 mg dispersible tablet or as a 5 mg oral dispersible film.
The dosing schedule was every 48 hours for the first 2 weeks of life, then daily through day 28. Intensive plasma pharmacokinetic (PK) sampling was performed at three visits: at entry (predose and 1–3 h post first dose), after at least three doses but before week 4 (predose and 1, 2, 4, 6, and 48 h postdose), and during week 4 (predose and 1–3 h postdose). Primary PK outcomes included AUC0–48, Cmax, apparent clearance (CL/F), and trough concentration (Ctrough). Safety endpoints captured adverse events (AEs) including grade ≥3 events. Target PK criteria were geometric mean Ctrough >0.67 μg/mL and individual Cmax <17.0 μg/mL. The trial registration number is NCT05590325.
Key findings
Participant characteristics and dosing timing
Forty-one neonates were enrolled and received at least one dose of DTG (21 dispersible tablets, 20 films). Median birthweight was 3235 g (range 2365–4330 g) and the median time to first DTG dose was 47 hours after birth (range 22–78 h). Males comprised 61% of participants.
Pharmacokinetics
Intensive PK profiles after at least three doses (6–10 days of life) were similar between the two formulations. Reported geometric mean AUC0–48 was 193.2 μg·h/mL and apparent clearance (CL/F) was 0.026 L/h (geometric mean). Both formulations achieved a geometric mean Ctrough above the prespecified target (0.67 μg/mL), and every measured Cmax for all neonates at each PK visit remained below the individual safety threshold of 17.0 μg/mL.
These results indicate that modest neonatal dosing — 5 mg administered every 48 hours initially — yields plasma exposures consistent with efficacious trough concentrations while avoiding high peak concentrations that could raise toxicity concerns in the early neonatal period when metabolic clearance is low.
Safety
No adverse events were attributed to dolutegravir. The most severe events observed were two grade 3 events in a single neonate with pneumonia; these were judged unrelated to the study drug. A total of 45 adverse events were reported across both arms (22 events in 12 of 21 neonates receiving dispersible tablets; 23 events in 14 of 20 neonates receiving films). Events were generally of low grade. All 39 neonates who completed study follow-up were HIV-negative at exit.
Formulation comparison and practical considerations
PK equivalence between the half-tablet and film formulations supports flexibility in paediatric product selection. The oral dispersible film provides an alternative that may reduce the need for tablet-splitting and improve dosing accuracy in busy clinical settings, but both options appear viable from a PK and safety standpoint in term neonates.
Expert commentary
Clinical relevance
PETITE‑DTG provides the first randomized, multidose PK and safety data to support neonatal DTG dosing from birth to 4 weeks for term infants. Achieving trough concentrations above the predefined pharmacodynamic target is reassuring for potential efficacy in preventing postnatal HIV acquisition when starting DTG shortly after birth or for neonatal treatment when maternal viral suppression is uncertain.
Biological plausibility and dosing rationale
Neonates have immature drug-metabolizing pathways (notably UGT1A1, the principal pathway for dolutegravir glucuronidation) and lower clearance than older infants; consequently, less frequent dosing early in life is pharmacologically sensible. PETITE‑DTG’s 48‑hour dosing interval during the first two weeks leveraged this physiology and was followed by daily dosing as clearance increases with maturation.
Limitations and remaining questions
Key limitations include single-centre conduct, modest sample size, and restriction to term neonates ≥37 weeks and ≥2 kg, which limits generalizability to preterm or low-birthweight infants. The short follow-up period (28 days) provides limited information on longer-term safety, neurodevelopmental outcomes, growth, and resistance emergence with any potential early virological failures. Mothers in the study were on DTG-based ART, which could influence baseline neonatal drug exposure and complicate attribution of in‑utero versus postnatal pharmacokinetics in some cases.
Translational considerations
Regulatory and guideline adoption will require synthesis of these PK/safety data with implementation feasibility and post-marketing pharmacovigilance. Additional studies are needed for preterm infants, prolonged neonatal treatment courses, and population PK modelling that integrates maternal dosing and breastfeeding exposure.
Conclusion
PETITE‑DTG delivers critical, practice‑ready pharmacokinetic and safety evidence supporting a 5 mg neonatal dose strategy — administered as either half a 10 mg dispersible tablet or a 5 mg oral dispersible film — given every 48 hours for the first 2 weeks, followed by daily dosing through day 28, in term neonates born to mothers on dolutegravir-based ART. The regimen achieved target troughs without excessive peak exposures and had no drug‑related adverse events in this cohort. These data support consideration of neonatal dolutegravir dosing in national and international ART guidelines for term infants, while highlighting the need for additional work in preterms, longer-term safety monitoring, and operational research to ensure safe programmatic adoption in diverse settings.
Funding and clinicaltrials.gov
The trial was funded by Unitaid. ClinicalTrials.gov identifier: NCT05590325.
References
Bekker A, Salvadori N, Rabie H, du Toit S, Than-In-At K, Groenewald M, Barnabas S, Ganger L, Luangcharoenkul T, Pingkarawat S, Capparelli EV, Owen A, Cressey R, Fry S, Le Roux G, Tawon Y, Kaewmalee J, Phitak T, Lallemant M, Cotton MF, Cressey TR. Safety and pharmacokinetics of dolutegravir dispersible tablets and oral films in term neonates exposed to HIV in South Africa (PETITE-DTG study): an open-label, randomised, phase 1/2 trial. Lancet HIV. 2025 Nov;12(11):e753-e762. doi: 10.1016/S2352-3018(25)00239-5. Epub 2025 Oct 8. PMID: 41075812.