Pharmacogenetic associations with plasma efavirenz concentrations and clinical correlates in a retrospective cohort of Ghanaian HIV-infected patients
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Date
2013-09-29
Journal Title
Journal ISSN
Volume Title
Publisher
Oxford University Press
Abstract
Objectives: Efavirenz is widely used in first-line antiretroviral therapy in sub-Saharan Africa. However, exposure to
efavirenz shows marked interindividual variability that is genetically mediated with potential for important pharmacodynamic
consequences. The aims of this study were to assess the frequencies of CYP2B6, CYP2A6, UGT2B7
and CAR single nucleotide polymorphisms (SNPs) and their impact on plasma efavirenz concentration and clinical/
immunological responses in Ghanaian patients.
Methods: Genomic DNA from 800 HIV-infected patients was genotyped for selected SNPs by real-time PCR-based
allelic discrimination. Mid-dose plasma efavirenz concentrations were measured for 521 patients using HPLC with
UVdetection. Clinical outcomes in 299 patients on efavirenzwere retrospectively assessed.Univariate andmultivariatelinear
regressionwereperformedusingbest subset selection.Time-to-eventoutcomeswereanalysedusingaCox
proportional hazards regressionmodel.
Results: The variant allele frequencies for CYP2B6 516G.T (rs3745274), CYP2B6 983T.C (rs28399499), CYP2A6
248T.G (CYP2B6*9B; rs28399433), UGT2B7 802C.T (UGT2B7*2; rs7439366), UGT2B7 735A.G (UGT2B7*1c;
rs28365062) and CAR 540C.T (rs2307424) were 48%, 4%, 3%, 23%, 15% and 7%, respectively. CYP2B6 516G.T,
CYP2B6 983T.C and CYP2A6 248T.G were associated with significantly elevated efavirenz concentrations. A
trend towards association between plasma efavirenz concentration and CAR 540C.T was observed. CYP2B6 516G
homozygosity was associated with immunological failure [adjusted hazards ratio compared with T homozygosity,
1.70 (1.04–2.76); P¼0.03].
Conclusions:CYP2B6andCYP2A6SNPswereassociatedwithhigher plasmaefavirenzconcentrationsduetoreduction
inmajor and minor phase I routes of elimination, respectively. Further prospective studies are needed to validate the
pharmacodynamic correlates of these polymorphisms in this population.
Description
An article published by Oxford University Press an is available at doi:10.1093/jac/dkt372
Keywords
non-nucleoside reverse transcriptase inhibitors, Africa, pharmacokinetics, pharmacodynamics
Citation
Oxford University Press 2014; 69: 491–499