Double-dose lopinavir/ritonavir provides insufficient lopinavir exposure in children receiving rifampicin

Polly Clayden HIV i-Base

Rifampicin-based TB treatment is recommended for children (there is no formulation of rifabutin for young children nor is it widely available). In South Africa children with HIV who are <3 years old receive lopinavir/ritonavir-based antiretroviral 1st line regimens. Rifampicin reduces trough concentrations of lopinavir by more than 90%. Additional boosting with ritonavir to a 1:1 ratio during TB treatment provides adequate concentrations in adults and children but this strategy is complex with oral solutions and not always feasible.

Helen McIlleron from the University of Cape Town presented findings from a pharmacokinetic (PK) study using double dose lopinavir/r (LPV/r) (ratio 4:1) with rifampicin in young children who were >6 months of age. This strategy has achieved adequate concentrations in healthy adult volunteers.

In this study, children with TB/HIV (n=17), received 460/115mg/m2 LPV/r +2NRTIs, once established on rifampicin-based TB treatment. Children without TB (n=24) were used as a control group and received the standard dose LPV/r 230/57.5mg/m2 +2 NRTIs.

Table 1. Baseline characteristics and PK of children receiving LPV/r

TB/HIV n=17 Controls n=24 p-value
Male/female 4/13 16/8 0.007
Age (months) 15.0 (12.4-24.9) 19.1 (13.8-26.8) 0.615
Weight (kg) 8.64 (7.02-9.96) 10.55 (8.38 -12.55) 0.007
Cpre (mg/L) 0.76 (0.17-1.62) 4.25 (3.42-8.10) 0.0001
Cmax (mg/L) 4.45 (2.51-8.22) 7.94 (6.86-13.40) 0.008
AUC0-8h (mg.h/L) 22.29 (13.03-47.30) 45.15 (37.25-81.38) 0.010

Baseline characteristics and PK parameters are median (IQR).

Pre-dose sampling was performed at 2, 4, and 8 hours after dose and determined using LC-MSMS method.

Following an interim analysis and DSMB review of plasma levels in 15 children with TB/HIV the study was stopped.

The investigators reported a median (IQR) LPV dose of 486 mg/m2 (478-497) in cases and 234 mg/m2 (228-241) in controls.

Characteristics and PK of the children are shown in Table 1. There were more girls than boys with TB/HIV and children with TB weighed less than controls.

They noted that among a subgroup of 5 cases sampled 12 hours after the observed dose 12-hour LPV concentrations were 0.65 mg/L lower than Cpre showing that adherence to the previous dose is unlikely to be the reason for the low concentrations.

The investigators found high interpatient variability within both groups of children. The median LPV Cpre, Cmax and AUC0-8h were reduced by 82%, 44% and 51% respectively among children receiving double dose LPV/r with rifampicin-based TB treatment; 10(59%) had subtherapeutic LPV/r Cpre (<1mg/L) vs 2 (8%) controls.

They do not recommend this approach in young children and Dr McIlleron concluded: “There is an urgent need to establish safe, effective and feasible co-treatment for young children with HIV associated tuberculosis”.


These data are important to offer guidance for “what not to do” in this population. They also argue for easier to use solid paediatric formulations of LPV/r and RTV.


McIlleron et al. Double-dose lopinavir/ritonavir provides insufficient lopinavir exposure in children receiving rifampicin-based anti-TB treatment. 16th CROI. February 2009, Montreal. Oral abstract 98.

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