Pharmacokinetics of abacavir and lamivudine in infants living with HIV with and without rifampicin co-treatment

BACKGROUND: Lamivudine and abacavir are key components of first-line paediatric antiretroviral therapy (ART). Rifampicin is part of drug-sensitive TB treatment in children. Rifampicin induces UDP-glucuronosyltransferases and renal transporters and inhibits gastrointestinal transporters involved in the pharmacokinetics of abacavir and lamivudine, but pharmacokinetic data on this potential interaction in infants are scarce. OBJECTIVE: To evaluate the effect of rifampicin on the pharmacokinetics of abacavir and lamivudine in infants aged 28-365 days and weighing >3 kg. METHODS: This pharmacokinetic sub-study was nested within the EMPIRICAL trial (NCT03915366). Eighteen infants from Mozambique, Uganda, Zambia and Zimbabwe received once-daily fixed-dose abacavir/lamivudine with dolutegravir according to WHO guidelines. Five infants received ART alone and 13 received ART plus rifampicin-based tuberculosis treatment. Abacavir/lamivudine dosing was unchanged during rifampicin co-treatment. Six plasma concentrations were measured over 24 h and analysed using non-compartmental pharmacokinetic analysis. RESULTS: Median (IQR) age and weight were 6.8 (5.2-10.2) months and 6.0 (5.3-6.8) kg, respectively, and were comparable between groups. Abacavir exposure was comparable with and without rifampicin (AUC0-24h: 21.9 versus 21.0 h mg/L; Cmax: 6.2 versus 6.3 mg/L, respectively). Lamivudine exposure was also comparable (AUC0-24h: 12.6 versus 12.4 h mg/LL, respectively). The slightly higher Cmax (2.4 versus 1.9 mg/L) in the rifampicin group is probably due to interindividual variability or increased absorption from rifampicin's inhibition of gastrointestinal drug transporters, and considered not clinically relevant. CONCLUSIONS: Rifampicin co-treatment had minimal impact on abacavir and lamivudine pharmacokinetics in infants. Dose adjustment of abacavir/lamivudine is not required during rifampicin-containing tuberculosis treatment.