Background:
Dolutegravir (DTG) is recommended by WHO as first-line treatment option for children living with HIV. Rifampicin (RIF) interacts substantially with DTG by increasing DTG metabolism through induction of UGT1A1 and CYP3A4, thereby reducing its exposure resulting in potential treatment failure. Adapting the DTG dosing interval from once-daily (OD) to twice-daily (BID) was safe and effective in both adults and children. However, no pharmacokinetic (PK) data was available for children weighing < 14kg. The outcome of the RIF-DTG interaction may be different in infants as maturation of metabolic enzyme activity may not have been completed. PK data in infants receiving DTG and concomitant RIF is warranted and was identified as a knowledge gap by WHO. We evaluated plasma DTG concentrations in infants living with HIV receiving DTG BID with RIF-based TB-treatment.
Methods:
This is a 2-arm PK sub-study of the EMPIRICAL randomized controlled trial (#NCT03915366) for severe pneumonia in infants living with HIV. Eligible infants aged 1-11 months, weighing ≥3kg, receiving DTG OD (control) or DTG BID with RIF-based TB-treatment, were recruited in Mozambique, Uganda, Zambia, and Zimbabwe. Infants received DTG following WHO weight-band dosing. Six blood samples were taken over 12 (BID) or 24 (OD) hours30-90 days after start of RIF and at least 14 days after initiation of DTG. Relevant PK parameters and the proportion of infants with DTG Ctrough below the PK target (0.32 mg/L) were summarised per treatment arm. This project is part of the EDCTP2 programme supported by the European Union RIA2017MC-2013.
Results:
Of 30 enrolled infants, 27 had evaluable PK curves (Figure) of which 21 received concomitant RIF. The median (IQR) age was 7.1 (6.1 – 9.9) months, weight 7.1 (6.1 – 9.9) months, and 11/27 were female. DTG Ctrough, AUC0-24h and Cmax GM(%CV) were 1.05(82) mg/L, 49.7(70) h*mg/L, and 3.36(65) mg/L for children on RIF, and 1.11(46) mg/L, 54.4(39) h*mg/L, and 3.86 (38)mg/L for children in the control arm, respectively. Only 1/21 infants in the RIF arm had DTG Ctrough < 0.32mg/L vs none out of 6 in the control arm. Apparent oral DTG clearance was about 2-fold higher for infants receiving RIF.
Conclusions:
Consistent with data from older children and adults, BID dosing of DTG when administered in infants on RIF resulted in adequate DTG exposure. These PK data support the use of DTG BID for infants living with HIV receiving RIF.
Geometric mean dolutegravir concentration-time profiles for infants receiving rifampicin and the control arm. 