title: An Expanded Analysis of Pharmacogenetics Determinants of Efavirenz Response that Includes 3'-UTR Single Nucleotide Polymorphisms among Black South African HIV/AIDS Patients.
abstract: BACKGROUND
  Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor prescribed as part of first-line highly active antiretroviral therapy (HAART) in South Africa. Despite administration of fixed doses of EFV, inter-individual variability in plasma concentrations has been reported. Poor treatment outcomes such as development of adverse drug reactions or treatment failure have been linked to EFV plasma concentrations outside the therapeutic range (1-4 μg/mL) in some studies. The drug metabolizing enzyme (DME), CYP2B6, is primarily responsible for EFV metabolism with minor contributions by CYP1A2, CYP2A6, CYP3A4, CYP3A5, and UGT2B7. DME coding genes are also regulated by microRNAs through targeting the 3'-untranslated region. Expanded analysis of 30 single nucleotide polymorphisms (SNPs), including those in the 3'-UTR, was performed to identify pharmacogenetics determinants of EFV plasma concentrations in addition to CYP2B6 c.516G>T and c.983T>C SNPs.
  
  
  METHODS
  SNPs in CYP1A2, CYP2B6, UGT2B7, and NR1I2 (PXR) were selected for genotyping among 222 Bantu-speaking South African HIV-infected patients receiving EFV-containing HAART. This study is a continuation of earlier pharmacogenetics studies emphasizing the role of genetic variation in the 3'-UTR of genes which products are either pharmacokinetic or pharmacodynamic targets of EFV.
  
  
  RESULTS
  Despite evaluating thirty SNPs, CYP2B6 c.516G>T and c.983T>C SNPs remain the most prominent predictors of EFV plasma concentration.
  
  
  CONCLUSIONS
  We have shown that CYP2B6 c.516G>T and c.983T>C SNPs are the most important predictors of EFV plasma concentration after taking into account all other SNPs, including genetic variation in the 3'-UTR, and variables affecting EFV metabolism.
authors.affiliation: Division of Human Genetics, Department of Pathology and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town Cape Town, South Africa.
authors.forename: Marelize
authors.initials: M
authors.lastname: Swart
authors.affiliation: Division of Human Genetics, Department of Pathology and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town Cape Town, South Africa.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Evans
authors.affiliation: Division of Human Genetics, Department of Pathology and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town Cape Town, South Africa.
authors.forename: Michelle
authors.initials: M
authors.lastname: Skelton
authors.affiliation: Division of Clinical Pharmacology, Faculty of Health Sciences, University of Cape Town Cape Town, South Africa.
authors.forename: Sandra
authors.initials: S
authors.lastname: Castel
authors.affiliation: Division of Clinical Pharmacology, Faculty of Health Sciences, University of Cape Town Cape Town, South Africa.
authors.forename: Lubbe
authors.initials: L
authors.lastname: Wiesner
authors.affiliation: Division of Clinical Pharmacology, Faculty of Health Sciences, University of Cape Town Cape Town, South Africa.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Smith
authors.affiliation: Division of Human Genetics, Department of Pathology and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town Cape Town, South Africa.
authors.forename: Collet
authors.initials: C
authors.lastname: Dandara
keywords: 3′-UTR; HIV/AIDS; South Africa; efavirenz; pharmacogenetics; sensitivity; single nucleotide polymorphism; specificity