Pharmacokinetics of Dolutegravir in Children with HIV with and without Tuberculosis Coinfection Treated According to World Health Organization Dosing Guidelines

BACKGROUND: The pharmacokinetics (PK) and safety of dolutegravir in children with HIV (CWH) weighing at least 20 kg with and without tuberculosis (TB) treated according to World Health Organization dosing guidelines was examined. METHODS: CWH on dolutegravir 50 mg once-daily and those with HIV/TB on 50 mg twice-daily with rifampin-based therapy were enrolled. Five to six blood samples were collected within the dosing interval after 4 weeks (period-1) and 7-8 months (period-2) of dolutegravir-based therapy. Dolutegravir concentrations were measured using LCMS/MS and PK parameters calculated by non-compartmental analysis. Geometric mean ratio (GMR) with 95% confidence interval (CI) was used to compare PK parameters on and off TB treatment and between the two groups. RESULTS: Of 25 participants, 52% had TB coinfection. Rifampin coadministration increased dolutegravir clearance by 86%. GMRs (95% CI) of area under the concentration-time curve (AUC0-24h) and trough concentration (Ctrough) of dolutegravir twice-daily with rifampin versus once-daily alone were 1.07 (0.79-1.44) and 1.45 (0.89-2.35), respectively. Comparing HIV/TB versus HIV, dolutegravir AUC0-24h and Ctrough GMRs (respectively) were 1.69 (0.99-2.90) and 2.50 (1.19-5.26) in period-1 and 1.26 (0.85-1.85) and 1.57 (0.53-4.68) in period-2. Two participants with HIV and none with HIV/TB had Ctrough <0.32mg/L. Overall, 92% of participants with HIV/TB and 82% with HIV achieved viral load <400 copies/mL at 6 months of dolutegravir-based therapy, with no dolutegravir discontinuations. CONCLUSIONS: Twice-daily dolutegravir with rifampin was associated with higher trough concentrations in children with HIV/TB than in controls. Standard dose of dolutegravir with rifampin needs to be investigated.