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

TitleSecondary metabolism pathway polymorphisms and plasma efavirenz concentrations in HIV-infected adults with CYP2B6 slow metabolizer genotypes.
Publication TypeJournal Article
Year of Publication2014
AuthorsHaas DW, Kwara A, Richardson DM, Baker P, Papageorgiou I, Acosta EP, Morse GD, Court MH
JournalJ Antimicrob Chemother
Volume69
Issue8
Pagination2175-82
Date Published2014 Aug
ISSN1460-2091
KeywordsAdult, African Continental Ancestry Group, Anti-HIV Agents, Benzoxazines, Cytochrome P-450 CYP2A6, Cytochrome P-450 CYP2B6, Cytochrome P-450 CYP2B6 Inducers, European Continental Ancestry Group, Female, Gene Dosage, Glucuronosyltransferase, HIV Infections, HIV-1, Humans, Male, Polymorphism, Single Nucleotide, Prospective Studies, Reverse Transcriptase Inhibitors, Secondary Metabolism
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.

DOI10.1093/jac/dku110
Alternate JournalJ. Antimicrob. Chemother.
PubMed ID24729586
PubMed Central IDPMC4100708
Grant ListAI-025859 / AI / NIAID NIH HHS / United States
AI-02586 / AI / NIAID NIH HHS / United States
AI-027658 / AI / NIAID NIH HHS / United States
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R01-GM061834 / GM / NIGMS NIH HHS / United States
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RR-000046 / RR / NCRR NIH HHS / United States
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TR-000445 / TR / NCATS NIH HHS / United States
UL1 TR000042 / TR / NCATS NIH HHS / United States
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