title: Cytochrome P450 2B6 (CYP2B6) and constitutive androstane receptor (CAR) polymorphisms are associated with early discontinuation of efavirenz-containing regimens.
abstract: OBJECTIVE
  Cytochrome P450 2B6 (CYP2B6) is responsible for the metabolic clearance of efavirenz and single nucleotide polymorphisms (SNPs) in the CYP2B6 gene are associated with efavirenz pharmacokinetics. Since the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) correlate with CYP2B6 in liver, and a CAR polymorphism (rs2307424) and smoking correlate with efavirenz plasma concentrations, we investigated their association with early (<3 months) discontinuation of efavirenz therapy.
  
  
  METHODS
  Three hundred and seventy-three patients initiating therapy with an efavirenz-based regimen were included (278 white patients and 95 black patients; 293 male). DNA was extracted from whole blood and genotyping for CYP2B6 (516G → T, rs3745274), CAR (540C → T, rs2307424) and PXR (44477T → C, rs1523130; 63396C → T, rs2472677; and 69789A → G, rs763645) was conducted. Binary logistic regression using the backwards method was employed to assess the influence of SNPs and demographics on early discontinuation.
  
  
  RESULTS
  Of the 373 patients, 131 withdrew from therapy within the first 3 months. Black ethnicity [odds ratio (OR) = 0.27; P = 0.0001], CYP2B6 516TT (OR = 2.81; P = 0.006), CAR rs2307424 CC (OR = 1.92; P = 0.007) and smoking status (OR = 0.45; P = 0.002) were associated with discontinuation within 3 months.
  
  
  CONCLUSIONS
  These data indicate that genetic variability in CYP2B6 and CAR contributes to early treatment discontinuation for efavirenz-based antiretroviral regimens. Further studies are now required to define the clinical utility of these associations.
authors.affiliation: Department of Internal Medicine, University of Cologne, Cologne, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Wyen
authors.forename: Heidy
authors.initials: H
authors.lastname: Hendra
authors.forename: Marco
authors.initials: M
authors.lastname: Siccardi
authors.forename: Martin
authors.initials: M
authors.lastname: Platten
authors.forename: Hans
authors.initials: H
authors.lastname: Jaeger
authors.forename: Thomas
authors.initials: T
authors.lastname: Harrer
authors.forename: Stefan
authors.initials: S
authors.lastname: Esser
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Bogner
authors.forename: Norbert H
authors.initials: NH
authors.lastname: Brockmeyer
authors.forename: Bernhard
authors.initials: B
authors.lastname: Bieniek
authors.forename: Juergen
authors.initials: J
authors.lastname: Rockstroh
authors.forename: Christian
authors.initials: C
authors.lastname: Hoffmann
authors.forename: Albrecht
authors.initials: A
authors.lastname: Stoehr
authors.forename: Claudia
authors.initials: C
authors.lastname: Michalik
authors.forename: Verena
authors.initials: V
authors.lastname: Dlugay
authors.forename: Alexander
authors.initials: A
authors.lastname: Jetter
authors.forename: Heribert
authors.initials: H
authors.lastname: Knechten
authors.forename: Hartwig
authors.initials: H
authors.lastname: Klinker
authors.forename: Adriane
authors.initials: A
authors.lastname: Skaletz-Rorowski
authors.forename: Gerd
authors.initials: G
authors.lastname: Fätkenheuer
authors.forename: Deirdre
authors.initials: D
authors.lastname: Egan
authors.forename: David J
authors.initials: DJ
authors.lastname: Back
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000480:Alkynes; D000483:Alleles; D019380:Anti-HIV Agents / Q000009:adverse effects* / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D048588:Benzoxazines / Q000009:adverse effects* / Q000627:therapeutic use; D015331:Cohort Studies; D000090702:Constitutive Androstane Receptor; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D004247:DNA / Q000235:genetics; D005006:Ethnicity; D005260:Female; D005838:Genotype; D005858:Germany; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011446:Prospective Studies; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D012307:Risk Factors; D012727:Sex Characteristics; D012907:Smoking; D012959:Socioeconomic Factors
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D000090702:Constitutive Androstane Receptor; D003521:Cyclopropanes; D018160:Receptors, Cytoplasmic and Nuclear; D004247:DNA; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; C098320:efavirenz