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Effects of rifampin-based antituberculosis therapy on plasma efavirenz concentrations in children vary by CYP2B6 genotype

McIlleron, Helen M.a,b; Schomaker, Michaelc; Ren, Yuana; Sinxadi, Phumlaa; Nuttall, James J.C.d,e; Gous, Hermienf; Moultrie, Harryf; Eley, Briand,e; Merry, Conceptag,h; Smith, Petera; Haas, David W.i; Maartens, Garya,b

doi: 10.1097/QAD.0b013e328360dbb4
Clinical Science

Objectives: An efavirenz-based antiretroviral therapy (ART) regimen is preferred for children more than 3 years of age with tuberculosis. However, rifampin, a key component of antituberculosis therapy, induces CYP2B6. An increased dose of efavirenz is recommended in adults weighing more than 50 kg who require rifampin, but there is scant information in children being treated for tuberculosis.

Design: Plasma efavirenz concentrations were compared in 40 children during concomitant treatment for tuberculosis and HIV-1, after stopping rifampicin, and in a control group of children without tuberculosis. Associations with antituberculosis treatment, metabolizer genotype (based on CYP2B6 516G→T, 983T→C, and 15582C→T), weight, and time after dose were evaluated.

Results: Compared to children with extensive metabolizer genotypes, efavirenz concentrations were increased 1.42-fold (95% confidence interval, CI 0.94–2.15) and 2.85-fold (95% CI 1.80–4.52) in children with intermediate and slow metabolizer genotypes, respectively. Concomitant antituberculosis treatment increased efavirenz concentrations 1.49-fold (95% CI 1.10–2.01) in children with slow metabolizer genotypes, but did not affect efavirenz concentrations in extensive or intermediate metabolizer genotypes. After adjustment for dose/kg, each kilogram of weight was associated with a 2.8% (95% CI 0.9–4.7) decrease in efavirenz concentrations. Despite higher milligram per kilogram doses, a higher proportion of children in the lowest weight band (10–13.9 kg) had efavirenz concentrations less than 1.0 mg/l than larger children.

Conclusion: Antituberculosis treatment was not associated with reduced efavirenz concentrations in children, which does not support increased efavirenz doses. Children with slow metabolizer genotype have increased efavirenz concentrations during antituberculosis treatment, likely due to isoniazid inhibiting enzymes involved in accessory metabolic pathways for efavirenz.

aDivision of Clinical Pharmacology in the Department of Medicine

bInstitute of Infectious Disease and Molecular Medicine

cCenter for Infectious Disease Epidemiology and Research

dSchool of Child and Adolescent Health, University of Cape Town

ePaediatric Infectious Diseases Unit, Red Cross War Memorial Children's Hospital, Cape Town

fHarriet Shezi Children's Clinic, Wits Reproductive Health and HIV Institute, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

gInfectious Diseases Institute, Makerere University, Kampala, Uganda

hUniversity of Dublin School of Medicine, Trinity College, Dublin, Ireland

iDepartments of Medicine, Pharmacology, Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

Correspondence to H.M. McIlleron, K-45 Old Main Building, Groote Schuur Hospital, Observatory 7925, Cape Town, South Africa. E-mail: helen.mcilleron@uct.ac.za

Received 6 December, 2012

Revised 1 March, 2013

Accepted 4 March, 2013

© 2013 Lippincott Williams & Wilkins, Inc.