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

Title
Suboptimal lopinavir exposure in infants 1-12 months on rifampicin treatment receiving double-dosed or semi-superboosted lopinavir/ritonavir; results from the EMPIRICAL trial
Presenter
Tom G. Jacobs
Authors
T.G. Jacobs * (1), V. Mumbiro (2), C. Moraleda (3), A. Colbers (1), A. Passanduca (4), S. Domínguez-Rodríguez (3), M. Chitsamatanga (2), A. Tagarro (3), A. Ballesteros (3), K.J. Nathoo (2), L. Madrid (3), N. Namuziya (5), B. Nduna (6), W.C. Buck (4,7), C. Chabala (5,8), H.A. Mujuru (2), D.M. Burger (1), P. Rojo (3), EMPIRICAL study team
Institutions
(1) Radboud university medical center, Clinical Pharmacy, Nijmegen, Netherlands, the, (2) University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe, (3) Hospital 12 de Octubre, Madrid, Spain, (4) Universidade Eduardo Mondlane Faculdade de Medicina, Maputo, Mozambique, (5) University Teaching Hospitals-Children''s Hospital, Lusaka, Zambia, (6) Arthur Davidson Children''s Hospital, Ndola, Zambia, (7) University of California Los Angeles, David Geffen School of Medicine, Pediatrics, Los Angeles, United States, (8) University of Zambia, School of Medicine, Lusaka, Zambia

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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