title: A single-nucleotide polymorphism in CYP2B6 leads to >3-fold increases in efavirenz concentrations in plasma and hair among HIV-infected women.
abstract: BACKGROUND
  Efavirenz exhibits marked interindividual variability in plasma levels and toxicities. Prior pharmacogenetic studies usually measure exposure via single plasma levels, examine limited numbers of polymorphisms, and rarely model multiple contributors. We analyzed numerous genetic and nongenetic factors impacting short-term and long-term exposure in a large heterogeneous population of human immunodeficiency virus (HIV)-infected women.
  
  
  METHODS
  We performed 24-hour intensive pharmacokinetic studies in 111 women receiving efavirenz under actual-use conditions and calculated the area-under-the-concentration-time curve (AUC) to assess short-term exposure; the efavirenz concentration in hair was measured to estimate long-term exposure. A total of 182 single-nucleotide polymorphisms (SNPs) and 45 haplotypes in 9 genes were analyzed in relationship to exposure by use of multivariate models that included a number of nongenetic factors.
  
  
  RESULTS
  Efavirenz AUCs increased 1.26-fold per doubling of the alanine aminotransferase level and 1.23-fold with orange and/or orange juice consumption. Individuals with the CYP2B6 516TT genotype displayed 3.5-fold increases in AUCs and 3.2-fold increases in hair concentrations, compared with individuals with the TG/GG genotype. Another SNP in CYP2B6 (983TT) and a p-glycoprotein haplotype affected AUCs without substantially altering long-term exposure.
  
  
  CONCLUSIONS
  This comprehensive pharmacogenomics study showed that individuals with the CYP2B6 516TT genotype displayed >3-fold increases in both short-term and long-term efavirenz exposure, signifying durable effects. Pharmacogenetic testing combined with monitoring of hair levels may improve efavirenz outcomes and reduce toxicities.
authors.affiliation: Department of Medicine, University of California, San Francisco, CA, USA. monica.gandhi@ucsf.edu
authors.forename: Monica
authors.initials: M
authors.lastname: Gandhi
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Greenblatt
authors.forename: Peter
authors.initials: P
authors.lastname: Bacchetti
authors.forename: Chengshi
authors.initials: C
authors.lastname: Jin
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.forename: Kathryn
authors.initials: K
authors.lastname: Anastos
authors.forename: Mardge
authors.initials: M
authors.lastname: Cohen
authors.forename: Jack A
authors.initials: JA
authors.lastname: Dehovitz
authors.forename: Gerald B
authors.initials: GB
authors.lastname: Sharp
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Gange
authors.forename: Chenglong
authors.initials: C
authors.lastname: Liu
authors.forename: Susan C
authors.initials: SC
authors.lastname: Hanson
authors.forename: Bradley
authors.initials: B
authors.lastname: Aouizerat
mesh_terms: D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D048588:Benzoxazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D006197:Hair / Q000737:chemistry*; D006801:Humans; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D010949:Plasma / Q000737:chemistry*; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; C098320:efavirenz