Secondary metabolism pathway polymorphisms and plasma efavirenz concentrations in HIV-infected adults with CYP2B6 slow metabolizer genotypes

J Antimicrob Chemother. 2014 Aug;69(8):2175-82. doi: 10.1093/jac/dku110. Epub 2014 Apr 11.

Abstract

Objectives: Efavirenz is widely prescribed for HIV-1 infection, and CYP2B6 polymorphisms 516G→T and 983T→C define efavirenz slow metabolizer genotypes. To identify genetic predictors of higher plasma efavirenz concentrations beyond these two common functional alleles, we characterized associations with mid-dosing interval efavirenz concentrations in 84 HIV-infected adults, all carrying two copies of these major loss-of-function CYP2B6 alleles.

Methods: Study participants had been randomized to efavirenz-containing regimens in prospective clinical trials and had available plasma efavirenz assay data. Analyses focused on secondary metabolism pathway polymorphisms CYP2A6 -48T→G (rs28399433), UGT2B7 735A→G (rs28365062) and UGT2B7 802T→C (rs7439366). Exploratory analyses also considered 196 polymorphisms and 8 copy number variants in 41 drug metabolism/transport genes. Mid-dosing interval efavirenz concentrations at steady-state were obtained ≥8 h but <19 h post-dose. Linear regression was used to test for associations between polymorphisms and log-transformed efavirenz concentrations.

Results: Increased efavirenz concentrations were associated with CYP2A6 -48T→G in all subjects (P = 3.8 × 10(-4)) and in Black subjects (P = 0.027) and White subjects (P = 0.0011) analysed separately; and with UGT2B7 735 G/G homozygosity in all subjects (P = 0.006) and in Black subjects (P = 0.046) and White subjects (P = 0.062) analysed separately. In a multivariable model, CYP2A6 -48T→G and UGT2B7 735 G/G homozygosity remained significant (P < 0.05 for each). No additional polymorphisms or copy number variants were significantly associated with efavirenz concentrations.

Conclusions: Among individuals with a CYP2B6 slow metabolizer genotype, CYP2A6 and possibly UGT2B7 polymorphisms contribute to even higher efavirenz concentrations.

Keywords: antiretroviral therapy; non-nucleoside reverse transcriptase inhibitor; pharmacogenetics; pharmacogenomics; pharmacokinetics.

Publication types

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

MeSH terms

  • Adult
  • African Continental Ancestry Group / genetics
  • Alkynes
  • Anti-HIV Agents / therapeutic use
  • Benzoxazines / blood*
  • Benzoxazines / metabolism
  • Benzoxazines / therapeutic use*
  • Cyclopropanes
  • Cytochrome P-450 CYP2A6 / genetics
  • Cytochrome P-450 CYP2B6 / genetics*
  • Cytochrome P-450 CYP2B6 Inducers / blood
  • Cytochrome P-450 CYP2B6 Inducers / therapeutic use
  • European Continental Ancestry Group / genetics
  • Female
  • Gene Dosage
  • Glucuronosyltransferase / genetics
  • HIV Infections / blood
  • HIV Infections / drug therapy*
  • HIV-1 / drug effects
  • Humans
  • Male
  • Polymorphism, Single Nucleotide
  • Prospective Studies
  • Reverse Transcriptase Inhibitors / blood
  • Reverse Transcriptase Inhibitors / therapeutic use
  • Secondary Metabolism / drug effects*

Substances

  • Alkynes
  • Anti-HIV Agents
  • Benzoxazines
  • Cyclopropanes
  • Cytochrome P-450 CYP2B6 Inducers
  • Reverse Transcriptase Inhibitors
  • CYP2A6 protein, human
  • Cytochrome P-450 CYP2A6
  • Cytochrome P-450 CYP2B6
  • UGT2B7 protein, human
  • Glucuronosyltransferase
  • efavirenz

Grant support