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

Haas DW, Kwara A, Richardson DM, Baker P, Papageorgiou I, Acosta EP, Morse GD, Court MH
J Antimicrob Chemother. 2014 69 (8): 2175-82

PMID: 24729586 · PMCID: PMC4100708 · DOI:10.1093/jac/dku110

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.

© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

MeSH Terms (21)

Adult African Continental Ancestry Group Alkynes Anti-HIV Agents Benzoxazines Cyclopropanes Cytochrome P-450 CYP2A6 Cytochrome P-450 CYP2B6 Cytochrome P-450 CYP2B6 Inducers European Continental Ancestry Group Female Gene Dosage Glucuronosyltransferase HIV-1 HIV Infections Humans Male Polymorphism, Single Nucleotide Prospective Studies Reverse Transcriptase Inhibitors Secondary Metabolism

Connections (1)

This publication is referenced by other Labnodes entities:

Links