title: Case report: Severe central nervous system manifestations associated with aberrant efavirenz metabolism in children: the role of CYP2B6 genetic variation.
abstract: BACKGROUND
  Efavirenz, widely used as part of antiretroviral drug regimens in the treatment of paediatric human immunodeficiency virus infection, has central nervous system side effects. We describe four children presenting with serious, persistent central nervous system adverse events who were found to have elevated plasma efavirenz concentrations as a result of carrying CYP2B6 single nucleotide polymorphisms, known to play a role in the metabolism of EFV. None of the children had a CYP2B6 wildtype haplotype. We believe this is the first case of cerebellar dysfunction associated with efavirenz use to be described in children.
  
  
  METHODS
  Four black African children, between the ages of 4 and 8 years presenting between 1 and 20 months post-efavirenz initiation, are described. Cerebellar dysfunction, generalised seizures and absence seizures were the range of presenting abnormalities. Plasma efavirenz levels ranged from 20-60 mg/L, 5-15 times the upper limit of the suggested reference range. All abnormal central nervous system manifestations abated after efavirenz discontinuation.
  
  
  CONCLUSIONS
  Efavirenz toxicity should always be considered in human immunodeficiency virus-infected children with unexplained central nervous system abnormalities. Our findings further our understanding of the impact of genetic variants on antiretroviral pharmacokinetics in children across various ethnic groups. Screening for potential EFV-toxicity based on the CYP2B6 c.516 SNP alone, may not be adequate.
authors.affiliation: Empilweni Services and Research Unit (ESRU), Rahima Moosa Mother and Child Hospital, Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Francoise
authors.initials: F
authors.lastname: Pinillos
authors.affiliation: Pharmacogenetics and Cancer Research Group, Division of Human Genetics, Department of Pathology & Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Collet
authors.initials: C
authors.lastname: Dandara
authors.affiliation: Pharmacogenetics and Cancer Research Group, Division of Human Genetics, Department of Pathology & Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Marelize
authors.initials: M
authors.lastname: Swart
authors.affiliation: Empilweni Services and Research Unit (ESRU), Rahima Moosa Mother and Child Hospital, Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Renate
authors.initials: R
authors.lastname: Strehlau
authors.affiliation: Gertrude H. Sergievsky Center, College of Physicians and Surgeons; and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
authors.forename: Louise
authors.initials: L
authors.lastname: Kuhn
authors.affiliation: Empilweni Services and Research Unit (ESRU), Rahima Moosa Mother and Child Hospital, Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Faeezah
authors.initials: F
authors.lastname: Patel
authors.affiliation: Empilweni Services and Research Unit (ESRU), Rahima Moosa Mother and Child Hospital, Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Coovadia
authors.affiliation: ICAP, Mailman School of Public Health, and College of Physicians & Surgeons Columbia University, 722 W168th street, New York, NY, 10032, USA. eja1@columbia.edu.
authors.forename: Elaine
authors.initials: E
authors.lastname: Abrams
mesh_terms: D000480:Alkynes; D019380:Anti-HIV Agents / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity*; D048588:Benzoxazines / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity*; D002490:Central Nervous System / Q000187:drug effects*; D002648:Child; D002675:Child, Preschool; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006239:Haplotypes; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; C098320:efavirenz
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