title: Pharmacogenetics of long-term responses to antiretroviral regimens containing Efavirenz and/or Nelfinavir: an Adult Aids Clinical Trials Group Study.
abstract: BACKGROUND
  Efavirenz and nelfinavir are metabolized by cytochrome P-450 (CYP) 2B6 and CYP2C19, respectively, with some involvement by CYP3A. Nelfinavir is a substrate for P-glycoprotein, which is encoded by MDR1. The present study examined associations between genetic variants and long-term responses to treatment.
  
  
  METHODS
  Adult AIDS Clinical Trials Group study 384 randomized antiretroviral-naive subjects to receive efavirenz and/or nelfinavir plus 2 nucleoside analogues, with follow-up lasting up to 3 years. Population pharmacokinetics were estimated from a nonlinear mixed-effects model. Polymorphisms in CYP2B6, CYP2C19, CYP3A4, CYP3A5, and MDR1 were characterized.
  
  
  RESULTS
  The 504 participants in the genetic study included 340 efavirenz recipients and 348 nelfinavir recipients (184 of the 504 participants received both efavirenz and nelfinavir). Of the participants, 49% were white, 31% were black, and 19% were Hispanic. Plasma exposure to efavirenz and nelfinavir in each population was significantly associated with the polymorphisms CYP2B6 516G-->T and CYP2C19 681G-->A, respectively. Among efavirenz recipients, the MDR1 position 3435 TT genotype was associated with decreased likelihood of virologic failure and decreased emergence of efavirenz-resistant virus but not with plasma efavirenz exposure. Among nelfinavir recipients, a trend toward decreased virologic failure was associated with the polymorphism CYP2C19 681G-->A.
  
  
  CONCLUSIONS
  Genetic variants predict plasma exposure to efavirenz and nelfinavir, and they may predict virologic failure and/or emergence of drug-resistant virus. These associations with treatment responses must be validated in other studies.
authors.affiliation: Vanderbilt University School of Medicine, Nashville, TN 37203, USA. david.w.haas@vanderbilt.edu
authors.forename: David W
authors.initials: DW
authors.lastname: Haas
authors.forename: Laura M
authors.initials: LM
authors.lastname: Smeaton
authors.forename: Robert W
authors.initials: RW
authors.lastname: Shafer
authors.forename: Gregory K
authors.initials: GK
authors.lastname: Robbins
authors.forename: Gene D
authors.initials: GD
authors.lastname: Morse
authors.forename: Line
authors.initials: L
authors.lastname: Labbe
authors.forename: Grant R
authors.initials: GR
authors.lastname: Wilkinson
authors.forename: David B
authors.initials: DB
authors.lastname: Clifford
authors.forename: Richard T
authors.initials: RT
authors.lastname: D'Aquila
authors.forename: Victor
authors.initials: V
authors.lastname: De Gruttola
authors.forename: Richard B
authors.initials: RB
authors.lastname: Pollard
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Merigan
authors.forename: Martin S
authors.initials: MS
authors.lastname: Hirsch
authors.forename: Alfred L
authors.initials: AL
authors.lastname: George
authors.forename: John P
authors.initials: JP
authors.lastname: Donahue
authors.forename: Richard B
authors.initials: RB
authors.lastname: Kim
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D048588:Benzoxazines; D003521:Cyclopropanes; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics* / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D019888:Nelfinavir / Q000493:pharmacokinetics / Q000627:therapeutic use; D010078:Oxazines / Q000493:pharmacokinetics / Q000627:therapeutic use; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D010078:Oxazines; D018894:Reverse Transcriptase Inhibitors; D003577:Cytochrome P-450 Enzyme System; D019888:Nelfinavir; C098320:efavirenz