Lopinavir-ritonavir super-boosting in young HIV-infected children on rifampicin-based tuberculosis therapy compared with lopinavir-ritonavir without rifampicin: a pharmacokinetic modelling and clinical study.

BACKGROUND: Rifampicin reduces lopinavir concentrations in HIV and tuberculosis co-treated patients. We hypothesised that adding ritonavir to co-formulated lopinavir-ritonavir (4:1) to achieve a one-to-one ratio would overcome this drug-drug interaction in young children.

METHODS: We did a prospective, open-label, one-group, one-sequence study at five sites in three South African provinces. We included HIV-infected children with tuberculosis, a bodyweight of 3-15 kg, and a post-conceptional age of more than 42 weeks. Children received the standard four-to-one ratio of lopinavir-ritonavir in the absence of rifampicin-based anti-tuberculosis treatment, whereas super-boosting of lopinavir-ritonavir with additional ritonavir was given orally twice a day to achieve a one-to-one ratio during rifampicin treatment. The primary outcome was the comparison of the proportion of children with predicted lopinavir morning minimum concentrations (Cmin ) of more than 1·0 mg/L during super-boosting with the proportion of more than 1·0 mg/L during standard lopinavir-ritonavir treatment without rifampicin. Lopinavir concentrations were determined before and at 1, 2, 4, 6, and 10 h after the morning dose during the second and the last month of tuberculosis co-treatment, and 4-6 weeks after stopping rifampicin. A non-linear mixed-effects model was implemented to interpret the data and Monte Carlo simulations were used to compare the percentage of lopinavir with morning Cmin values of less than 1·0 mg/L for the two dosing schemes. A non-inferiority margin of 10% was used. This study is registered with ClinicalTrials.gov, number NCT02348177.

FINDINGS: Between Jan 30, 2013, and Nov 9, 2015, 96 children with a median age of 18·2 months (IQR 9·6-26·8) were enrolled. Of these 96 children, 80 (83%) completed the first three pharmacokinetic evaluations. Tuberculosis therapy was started before antiretrovirals in 70 (73%) children. The model-predicted percentage of morning Cmin of less than 1·0 mg/L after tuberculosis treatment without super-boosting was 8·8% (95% CI 0·6-19·8) versus 7·6% (0·4-16·2) during super-boosting and tuberculosis treatment. The difference of -1·1% (95% CI -6·9 to 3·2), at a non-inferiority margin of 10%, confirmed the non-inferiority of lopinavir trough concentrations during rifampicin co-treatment. 19 serious adverse events were reported in 12 participants. Three deaths and a temporary treatment interruption due to jaundice were unrelated to study treatment.

INTERPRETATION: Lopinavir exposure with ritonavir super-boosting in a one-to-one ratio during rifampicin-based tuberculosis treatment was non-inferior to the exposure with lopinavir-ritonavir without rifampicin. Safe and effective, field application of super-boosting is limited by poor acceptability. Access to better adapted solid formulations will most likely facilitate public health implementation of this strategy.

FUNDING: DNDi, French Development Agency, UBS Optimus Foundation, and Unitaid.