title: Multilocus genetic interactions and response to efavirenz-containing regimens: an adult AIDS clinical trials group study.
abstract: OBJECTIVE
  For the HIV-1 reverse transcriptase inhibitor efavirenz, variant drug transporter gene ABCB1 may predict virologic response but not plasma efavirenz exposure. Conversely, variant drug metabolizing enzyme gene CYP2B6 predicts greater plasma efavirenz exposure but not virologic response. We examined whether long-term responses to efavirenz, and/or plasma efavirenz exposure, are better predicted by multilocus genetic interactions than by individual polymorphisms.
  
  
  METHODS
  We studied antiretroviral-naïve study participants randomized to receive efavirenz (with or without nelfinavir) plus two nucleoside analogues in study ACTG 384, and who had DNA available for analysis. Participants were followed up for up to 3 years. Nine single nucleotide polymorphisms in ABCB1, CYP2B6, CYP3A4, CYP3A5 and CYP2C19 were identified. Gene-gene interactions were identified using multifactor dimensionality reduction.
  
  
  RESULTS
  Among 340 efavirenz recipients, higher efavirenz AUC24 h values were associated with a single locus model involving CYP2B6 516G>T (73% accuracy; P<0.001). This was also the best model among blacks (69% accuracy; P<0.001), whereas among whites the best model involved a gene-gene interaction between CYP2B6 516G>T and ABCB1 2677G>T (82% accuracy, P<0.001). Among 155 participants who received efavirenz without nelfinavir, virologic failure was associated with a two-locus interaction between ABCB1 2677G>T and CYP2B6 516G>T (65% accuracy, P<0.001). Toxicity failure was best predicted by an interaction between ABCB1 2677G>T and ABCB1 3435C>T (71% accuracy, P<0.001).
  
  
  CONCLUSIONS
  Multilocus genetic interactions between variant drug metabolism and transporter genes may predict efavirenz pharmacokinetics and treatment responses. This finding may have implications for better individualizing antiretroviral therapy.
authors.affiliation: Vanderbilt University School of Medicine, Nashville, Tennessee 37203, USA.
authors.forename: Alison A
authors.initials: AA
authors.lastname: Motsinger
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
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: Victoria A
authors.initials: VA
authors.lastname: Johnson
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: John P
authors.initials: JP
authors.lastname: Donahue
authors.forename: Richard B
authors.initials: RB
authors.lastname: Kim
authors.forename: David W
authors.initials: DW
authors.lastname: Haas
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000235:genetics*; D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000627:therapeutic use; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D048588:Benzoxazines; D002986:Clinical Trials as Topic; D003521:Cyclopropanes; D020022:Genetic Predisposition to Disease; D006801:Humans; D008957:Models, Genetic; D010078:Oxazines / Q000097:blood / Q000627:therapeutic use*; D017211:Treatment Failure; D016896:Treatment Outcome
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D044966:Anti-Retroviral Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D010078:Oxazines; C098320:efavirenz