Impact of CYP2B6 983T>C polymorphism on non-nucleoside reverse transcriptase inhibitor plasma concentrations in HIV-infected patients

J Antimicrob Chemother. 2008 Apr;61(4):914-8. doi: 10.1093/jac/dkn029. Epub 2008 Feb 14.

Abstract

Objectives: The aim of this study was to investigate the frequency of CYP2B6 polymorphisms (according to ethnicity) and the influence of heterozygosity and homozygosity on plasma concentrations of efavirenz and nevirapine.

Methods: Following written informed consent, 225 Caucasians and 146 Blacks were recruited from the German Competence Network for HIV/AIDS. Plasma concentrations of efavirenz and nevirapine were assessed by HPLC, and genotyping for 516G>T, 983T>C and 1459T>C polymorphisms in CYP2B6 was conducted by real-time PCR-based allelic discrimination.

Results: The minor allele frequency for 516G>T, 983T>C and 1459T>C was 0.29, 0 and 0.08 in Caucasians and 0.34, 0.07 and 0.02 in Blacks, respectively. Two Black patients with the 983C allele receiving efavirenz were identified and both were withdrawn from therapy within 1 week of sampling due to toxicity. In multivariate analyses, efavirenz and nevirapine plasma concentrations were significantly associated with 983T>C (P < 0.0001 and P = 0.02, respectively), 516G>T (P < 0.0001 and P = 0.002, respectively) and time of drug analysis post-dose (P < 0.0001 for both). Body mass index was independently related to efavirenz (P = 0.04) but not nevirapine concentrations, and age was related to nevirapine (P = 0.05) but not efavirenz concentrations. Consistent with other studies, 1459C>T was not associated with plasma concentrations of either drug (P > 0.05 for both drugs).

Conclusions: This is the first report that the 983T>C genotype (part of the CYP2B6*18 haplotype) impacts on nevirapine plasma concentrations and the first study to assess the impact of 983C homozygosity on efavirenz concentrations. These data have implications for administration of non-nucleoside reverse transcriptase inhibitors to Black patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • African Continental Ancestry Group
  • Age Factors
  • Aged
  • Aged, 80 and over
  • Alkynes
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Benzoxazines / blood*
  • Benzoxazines / pharmacokinetics
  • Benzoxazines / therapeutic use
  • Body Mass Index
  • Chromatography, High Pressure Liquid
  • Cyclopropanes
  • Cytochrome P-450 CYP2B6
  • European Continental Ancestry Group
  • Female
  • Gene Frequency
  • HIV Infections / drug therapy*
  • Humans
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Nevirapine / blood*
  • Nevirapine / pharmacokinetics
  • Nevirapine / therapeutic use
  • Oxidoreductases, N-Demethylating / genetics*
  • Polymerase Chain Reaction
  • Polymorphism, Genetic*
  • Reverse Transcriptase Inhibitors / blood*
  • Reverse Transcriptase Inhibitors / pharmacokinetics
  • Reverse Transcriptase Inhibitors / therapeutic use

Substances

  • Alkynes
  • Benzoxazines
  • Cyclopropanes
  • Reverse Transcriptase Inhibitors
  • Nevirapine
  • Aryl Hydrocarbon Hydroxylases
  • CYP2B6 protein, human
  • Cytochrome P-450 CYP2B6
  • Oxidoreductases, N-Demethylating
  • efavirenz