In Africa, children carry a large proportion of the burden of tuberculosis (TB). Recent studies suggest that first line anti-TB drugs (isoniazid, rifampin, ethambutol and pyrazinamide) are often under-dosed in adults, especially with HIV, and children. In 2010, the World Health Organization (WHO) proposed a revised mg/kg dosing strategy for anti-TB drugs for children. The revised guidelines are based on a very limited body of data. As there is a non-linear relationship between weight and drug clearance, the standardized mg/kg dosing is likely to result in under-dosing in small children compared to larger children. The PIs propose to evaluate the 2010 WHO dosing guidelines by assessing the pharmacokinetics of first line anti-TB drugs in 240 children across pediatric populations (<12 years, HIV infected and uninfected, and varied nutritional status) and regions (Cape Town, South Africa and Blantyre, Malawi). Improving the understanding of the pharmacokinetics of first line anti-TB drugs in children will aid in the development of evidence-based guidelines for pediatric TB treatment. In sub-Saharan Africa, the burden of HIV infection in children remains high. Important management challenges in children with TB and HIV include drug-drug interactions and overlapping drug toxicities. Co-administration of rifampicin dramatically reduces the concentrations of protease inhibitors. Using double dose lopinavir/ritonavir (LPV/r) in the commercially available 4:1 ratio has been shown to be insufficient. LPV/r in a ratio of LPV/r=1:1 results in adequate pharmacokinetic parameters but is not feasible because of the complexity of dosing LPV/r and ritonavir separately, and the short shelf life of oral ritonavir solution. Alternative solutions for the management of HIV and TB concomitantly in children are thus urgently needed. The PIs propose to evaluate an 8-hourly weight band-based dosing strategy for LPV/r using commercially available LPV/r in children receiving rifampicin-based TB treatment. In many settings nevirapine (NVP)-based regimens remain the only effective ART available. Young children may be at high risk of subtherapeutic NVP in the presence of rifampin. The proposed research will define optimal dosing of anti-TB drugs in children and generate evidence for optimization TB/HIV co-infection in children.

Public Health Relevance

HIV and tuberculosis are a major public health problem in children. Challenges to treat children with tuberculosis include a lack of knowledge about optimal dosing of first line anti-tuberculosis drugs across ages, nutritional status and HIV infection status, the absence of an appropriate regimen to co-adminster rifampin and lopinavir/ritonavir, the key first line drugs for tuberculosis and HIV, and uncertainty about nevirapine exposure in young children during rifampin-based tuberculosis therapy.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Special Emphasis Panel (ZHD1-RRG-K (15))
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Worrell, Carol
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University of Cape Town
South Africa
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McIlleron, H; Hundt, H; Smythe, W et al. (2016) Bioavailability of two licensed paediatric rifampicin suspensions: implications for quality control programmes. Int J Tuberc Lung Dis 20:915-9
Bekker, A; Schaaf, H S; Draper, H R et al. (2016) Pharmacokinetics of Rifampin, Isoniazid, Pyrazinamide, and Ethambutol in Infants Dosed According to Revised WHO-Recommended Treatment Guidelines. Antimicrob Agents Chemother 60:2171-9
Moholisa, Retsilisitsoe R; Schomaker, Michael; Kuhn, Louise et al. (2014) Plasma lopinavir concentrations predict virological failure in a cohort of South African children initiating a protease-inhibitor-based regimen. Antivir Ther 19:399-406
Amlabu, V; Mulligan, C; Jele, N et al. (2014) Isoniazid/acetylisoniazid urine concentrations: markers of adherence to isoniazid preventive therapy in children. Int J Tuberc Lung Dis 18:528-30