Once-daily dolutegravir/lamivudine fixed-dose formulations in children living with HIV: a pharmacokinetic and safety sub-study nested in the open-label, multicentre, randomised, non-inferiority D3/PENTA 21 trial

Background: Two-drug regimen dolutegravir/lamivudine (DTG/3TC) is recommended as an alternative to standard three-drug regimens in adult treatment guidelines. This nested pharmacokinetic sub-study within the D3/Penta 21 randomised trial (#NCT04337450) assessed DTG and 3TC concentrations and safety in virologically-suppressed children, switching to once-daily DTG/3TC fixed-dose formulations. Methods: Children aged 2–<15 years received either 5/30 mg DTG/3TC dispersible tablets (DT) or 50/300 mg film-coated tablets (FCT), using WHO weight band (WB)-aligned dosing: 10–<14 kg 4 DTs; 14–<20 kg 5 DTs; 20–<25 kg 6 DTs or 1 FCT; 25–<40 kg 1 FCT. A minimum of 8-evaluable pharmacokinetic curves per WB/formulation were targeted for 24 h pharmacokinetic profiling (t = 0, 1, 2, 3, 4, 6, and 24 h post-dosing) at steady state. The number of children with DTG C_trough <0.32 mg/L (EC90) and <0.064 mg/L (PA-IC90) were summarised. Safety was evaluated through 48 weeks in eligible children consented to the pharmacokinetic sub-study. Findings: Between 11th May 2022 and 31st May 2023, 82 children consented for the sub-study. Seventy-two were included in the pharmacokinetic analysis; median (IQR) age was 7.1 (4.9–10.0) years and weight 21.6 (17.7–24.8) kg. DTG geometric mean (GM) (%CV) C_trough and AUC_{0–24 h} were 0.82 (54) mg/L and 66.2 (35) h∗mg/L. 3TC GM-AUC_{0–24 h} was 16.2 (45) h∗mg/L. Three children had DTG C_trough<0.32 mg/L, all had DTG C_trough ≥0.064 mg/L. In children weighing 20–<25 kg WB and taking 1 FCT (50/300 mg) 3TC GM AUC_{0–24 h} was 19% higher than in children ≥25 kg (1 FCT). Of 82 children, 3 had 4 serious adverse events (SAEs) and 5 had 6 grade ≥3 adverse events (AEs). No AEs were related to DTG/3TC or resulted in treatment discontinuation. No 3TC-related AEs or laboratory abnormalities were observed in children taking FCT in the 20–<25 kg WB. PK parameters were comparable to historical paediatric data from ODYSSEY (DTG) and IMPAACT2019 (3TC) trials. Interpretation: The study demonstrated adequate DTG and 3TC exposures with reassuring safety profiles using WB-based dosing, supporting licencing applications for dispersible and film-coated DTG/3TC formulations for paediatric use. Funding: The D3/Penta 21 trial is sponsored by Fondazione Penta Onlus ETS (Penta) and funded by ViiV Healthcare.