Pharmacogenetics of long-term responses to antiretroviral regimens containing Efavirenz and/or Nelfinavir: an Adult Aids Clinical Trials Group Study

J Infect Dis. 2005 Dec 1;192(11):1931-42. doi: 10.1086/497610. Epub 2005 Nov 1.

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • Adult
  • Anti-HIV Agents* / pharmacokinetics
  • Anti-HIV Agents* / therapeutic use
  • Benzoxazines
  • Cytochrome P-450 Enzyme System / genetics
  • Drug Resistance, Viral / genetics
  • Drug Therapy, Combination
  • Female
  • HIV Infections / drug therapy
  • HIV Infections / genetics*
  • HIV Infections / virology
  • Humans
  • Male
  • Middle Aged
  • Nelfinavir* / pharmacokinetics
  • Nelfinavir* / therapeutic use
  • Oxazines* / pharmacokinetics
  • Oxazines* / therapeutic use
  • Pharmacogenetics
  • Polymorphism, Genetic
  • Reverse Transcriptase Inhibitors* / pharmacokinetics
  • Reverse Transcriptase Inhibitors* / therapeutic use
  • Time Factors
  • Treatment Outcome

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Anti-HIV Agents
  • Benzoxazines
  • Oxazines
  • Reverse Transcriptase Inhibitors
  • Cytochrome P-450 Enzyme System
  • Nelfinavir
  • efavirenz