Pharmacogenetics of plasma efavirenz exposure after treatment discontinuation: an Adult AIDS Clinical Trials Group Study

Clin Infect Dis. 2006 Feb 1;42(3):401-7. doi: 10.1086/499364. Epub 2005 Dec 27.

Abstract

Background: Efavirenz has a long plasma half-life and a low genetic barrier to resistance. Simultaneously stopping treatment with all agents in efavirenz-containing regimens may result in functional efavirenz monotherapy that selects for drug-resistant human immunodeficiency virus type 1. Lower plasma efavirenz clearance is associated with a cytochrome P450 2B6 gene (CYP2B6) polymorphism (516G-->T) that is more frequent among African American individuals than among European American individuals.

Methods: We characterized relationships between this polymorphism and predicted plasma efavirenz concentration-time profiles after discontinuation of therapy with use of data obtained from subjects receiving therapy. Pharmacokinetic parameters were estimated using population-based methods. Concentrations after discontinuation of therapy were predicted from subject-specific estimates. RESULTS. Median estimated efavirenz half-lives were 23, 27, and 48 h for patients with CYP2B6 position 516 GG (78 patients), GT (60), and TT (14) genotypes, respectively (P<.001). After therapy was stopped, plasma efavirenz concentrations in patients with GG, GT, and TT genotypes were predicted to exceed 46.7 ng/mL (the estimated protein-adjusted 95% inhibitory concentration for wild-type virus) for a median of 5.8 days (interquartile range [IQR], 4.4-8.3 days), 7.0 days (IQR, 5.0-8.0 days), and 14 days (IQR, 11.1-21.2 days), respectively (P<.001). Plasma efavirenz levels were predicted to exceed 46.7 ng/mL for >21 days in 5% of subjects with GG genotype, 5% of subjects with GT genotype, and 29% of subjects with TT genotype.

Conclusions: The CYP2B6 position 516 TT genotype or a prolonged measured elimination half-life may predict increased risk of developing drug resistance among patients who discontinue efavirenz-containing regimens. This has implications for strategies to safely discontinue antiretroviral regimens while avoiding the emergence of drug resistance.

Publication types

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

MeSH terms

  • Acquired Immunodeficiency Syndrome / drug therapy*
  • Adult
  • African Americans
  • Alkynes
  • Anti-HIV Agents / administration & dosage
  • Anti-HIV Agents / blood
  • Anti-HIV Agents / pharmacokinetics
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Asian Continental Ancestry Group
  • Benzoxazines
  • Cyclopropanes
  • Cytochrome P-450 CYP2B6
  • European Continental Ancestry Group
  • Female
  • Genotype
  • Half-Life
  • Hispanic Americans
  • Humans
  • Male
  • Oceanic Ancestry Group
  • Oxazines / administration & dosage*
  • Oxazines / blood*
  • Oxazines / pharmacokinetics
  • Oxidoreductases, N-Demethylating / genetics*
  • Polymorphism, Genetic
  • Viral Load

Substances

  • Alkynes
  • Anti-HIV Agents
  • Benzoxazines
  • Cyclopropanes
  • Oxazines
  • Aryl Hydrocarbon Hydroxylases
  • CYP2B6 protein, human
  • Cytochrome P-450 CYP2B6
  • Oxidoreductases, N-Demethylating
  • efavirenz