Expediting a UNIVERSAL first-line regimen of a dolutegravir-emtricitabine-tenofovir alafenamide fixed-dose ratio for children living with HIV older than 4 weeks: a 24-week, open-label, single-arm, phase 1-2, pharmacokinetic, safety, and antiviral activity trial.

BACKGROUND: Paediatric antiretroviral fixed-dose combination tablets remain limited. UNIVERSAL1 evaluated pharmacokinetics, short-term safety, and antiviral activity of novel fixed-dose ratios of dolutegravir, emtricitabine, and tenofovir alafenamide in children with HIV. METHODS: UNIVERSAL1 was an open-label, single-arm, phase 1-2, pharmacokinetic, safety, and antiviral activity study. Children with HIV aged between 28 days and 10 years with a bodyweight between 3 kg and less than 25 kg were enrolled at three clinical research centres (one in Harare, Zimbabwe, and two in Kampala, Uganda). Children were enrolled across five WHO bodyweight bands (ten children per weight band) and received dolutegravir, emtricitabine, and tenofovir alafenamide at the following respective doses according to weight band: 5 mg, 15 mg, 1·88 mg (3 kg to <6 kg band); 15 mg, 45 mg, 5·64 mg (6 kg to <10 kg band); 20 mg, 60 mg, 7·52 mg (10 kg to <14 kg band); 25 mg, 75 mg, 9·4 mg (14 kg to <20 kg band); and 50 mg, 200 mg, 25 mg (20 kg to <25 kg band). Children weighing 3 kg to less than 20 kg received dispersible tablets with 10 mg dolutegravir and tablets for oral suspension with emtricitabine (15 mg)-tenofovir alafenamide (1·88 mg); children weighing 20 kg to less than 25 kg received film-coated tablets containing 50 mg dolutegravir and emtricitabine (200 mg)-tenofovir alafenamide (25 mg). Primary pharmacokinetic outcomes were the areas under the concentration time curve over the dosing interval from time 0 h to 24 h (AUC0-24h) for dolutegravir, emtricitabine, and tenofovir, and from time 0 h to time of the last measurable concentration of the dosing interval (AUC0-last) for tenofovir alafenamide; maximum plasma concentration (Cmax) for all four compounds; and concentration at the end of the dosing interval (Ctrough for dolutegravir, emtricitabine, and tenofovir and Clast for tenofovir alafenamide). Primary safety outcomes were the occurrence of serious adverse events; new clinical and laboratory grade 3 and 4 adverse events; and adverse events of any grade leading to treatment interruption, discontinuation, or modification. Pharmacokinetic parameters were determined by non-compartmental analysis. The number of children with dolutegravir Ctrough lower than 0·32 mg/L (EC90), tenofovir alafenamide AUC0-last lower than 55 h × ng/mL (antiviral activity target), and tenofovir AUC0-24h higher than 2586 h × ng/mL (toxicity target) is reported. The trial is completed and registered with ClinicalTrials.gov, NCT05993767. FINDINGS: Between Jan 7 and June 5, 2025, 53 participants were enrolled (51 included in pharmacokinetic analysis, 53 included in safety analysis). Of these 53 children, 28 (53%) were female and 25 (47%) were male. Median age was 37 months (IQR 10-64), and median weight was 11·6 kg (7·9-16·8). Dolutegravir geometric mean (GM) value of AUC0-24h was 93·1 h × mg/L (percentage coefficient of variation 41), Cmax was 7·2 mg/L (44), and Ctrough was 1·7 mg/L (55). No child had dolutegravir Ctrough lower than 0·32 mg/L. Emtricitabine GM of AUC0-24h was 11·1 h × mg/L (60), Cmax was 1·6 mg/L (63), and Ctrough was 0·06 mg/L (46). Tenofovir alafenamide GM of AUC0-last was 207·1 h × ng/mL (101), Cmax 125·2 ng/mL (114), Clast 6·9 ng/mL (180). Three children had a tenofovir alafenamide AUC0-last lower than 55 h × ng/mL. Tenofovir GM of AUC0-24h was 219·0 h × ng/mL (53), Cmax 14·4 ng/mL (50), and Ctrough 6·9 ng/mL (66). None had tenofovir AUC0-24h higher than 2586 h × ng/mL. Adverse events were reported in 31 (58%) of the 53 participants. The overall incidence of adverse events was 3·7 events per 100 person-weeks (95% CI 2·5-5·2). Three (6%) participants experienced a serious adverse event (hospitalisation for severe malaria, severe acute malnutrition, and life-threatening anaemia); all serious adverse events were deemed unrelated to study drugs. One grade 3 adverse event (elevated aspartate aminotransferase) was considered possibly related to the study drugs. The patient with severe malnutrition (grade 4) had to have a dose reduction due to a change to a lower weight band; no other participants experienced adverse events that led to study drug withdrawal, interruption, or modification. INTERPRETATION: These data support proposed dosing of the dispersible fixed-dose combination (dolutegravir [5 mg]-emtricitabine [15 mg]-tenofovir alafenamide [1·88 mg]) for children weighing between 3 kg and less than 20 kg and extension of the licensed film-coated tablet (dolutegravir [50 mg]-emtricitabine [200 mg]-tenofovir alafenamide [25 mg]) for children weighing 20 kg or over. FUNDING: Second European and Developing Countries Clinical Trials Partnership (EDCTP2).