Suboptimal lopinavir exposure in infants 1-12 months on rifampicin treatment receiving double-dosed or semi-superboosted lopinavir/ritonavir; results from the EMPIRICAL trial


BACKGROUND: Double-dosing of lopinavir/ritonavir (LPV/r) in infants and young children receiving rifampicin resulted in subtherapeutic LPV trough concentrations (<1.0mg/L) in 60% of children. However, only four infants <12 months old participated in that study while activity of LPV metabolism through CYP3A4 changes greatly during the first year of life. Super-boosted LPV/r to a 1:1 ratio is recommended for infants being co-treated with rifampicin. In clinical practice, however, double-dosed LPV/r is frequently given to infants receiving rifampicin due to limited availability of single formulation ritonavir syrup. We evaluated plasma LPV concentrations in infants with HIV receiving LPV/r according to local dosing guidelines with or without rifampicin-based TB-treatment.
METHODS: This is a 2-arm pharmacokinetic sub-study of the EMPIRICAL randomized controlled trial (#NCT03915366) for severe pneumonia in infants with HIV. Eligible infants aged 1-12 months, weighing '¥ 4kg, receiving LPV/r with or without (control) rifampicin-based TB-treatment, were recruited from hospitals in Mozambique, Zambia, and Zimbabwe. Infants received double-dosed or semi-superboosted LPV/r (adding a ritonavir 100mg crushed tablet to the evening LPV/r dose) during rifampicin co-treatment. Six blood samples were taken over 12 hours. This project is part of the EDCTP2 programme supported by the European Union RIA2017MC-2013.
RESULTS: In total, 13/15 included infants had evaluable pharmacokinetic curves; 8/13 had rifampicin co-treatment (5 received double-dosed and 3 semi-superboosted LPV/r). The median (IQR) weight was 5.7kg (5.3-6.7) and age 6.6 months (5.5-9.7), 9/13 were male. 5/8 infants in rifampicin arm had LPV Ctrough <1.0mg/L (equally divided over those receiving double-dosed and semi-superboosted LPV/r); median (IQR) AUC0-12h and Ctrough were 47.6 (7.7-96.1) h*mg/L and 0.25 (0.06-2.8) mg/L, respectively. In the control arm, 1/5 infants had Ctrough <1.0mg/L; AUC0-12h and Ctrough were 64.2 (61.8-237.2) h*mg/L and 3.4 (1.6-15.8) mg/L, respectively. LPV apparent oral clearance was 4-fold higher for infants receiving rifampicin.
CONCLUSIONS: Double-dosed or semi-superboosted LPV/r for infants 1-12 months old receiving rifampicin resulted in substantial proportions of subtherapeutic LPV levels. There is an urgent need for data on alternative ARVs in infants with HIV/TB co-infection, such as twice-daily dolutegravir which is being evaluated in an ongoing EMPIRICAL pharmacokinetic substudy.

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