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Please use this identifier to cite or link to this item: http://hdl.handle.net/123456789/13404

Title: Pharmacogenetic associations with plasma efavirenz concentrations and clinical correlates in a retrospective cohort of Ghanaian HIV-infected patients
Authors: Sarfo, Fred Stephen
Zhang, Yuan
Vegan, Deirdre
Tetteh, Lambert A.
Phillips, Richard
Bedu-Addo, George
Sarfo, Maame Anima
Khoo, Saye
Owen, Andrew
Chadwick, David R
Keywords: Non-nucleoside reverse transcriptase inhibitors
Issue Date: 2014
Publisher: Journal of Antimicrobial Chemotherapy
Citation: Journal of Antimicrobial Chemotherapy ,2014; 69: 491–499 doi:10.1093/jac/dkt372
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 in Journal of Antimicrobial Chemotherapy ,2014; 69: 491–499 doi:10.1093/jac/dkt372
URI: http://hdl.handle.net/123456789/13404
Appears in Collections:College of Health Sciences

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