OBJECTIVES: Efavirenz is extensively metabolized by CYP2B6, and associations between CYP2B6 polymorphisms and plasma efavirenz exposure have been reported. The objective of this study was to investigate CYP2B6 haplotype structure and functional consequences in a Latin American population. PATIENTS AND METHODS: Two hundred and nineteen patients were recruited at Fundación Arriarán, Chile, between September and December 2008. Plasma efavirenz concentrations were determined using liquid chromatography with mass spectrometry. Genotyping for 30 single nucleotide polymorphisms (SNPs) with a minor allele frequency of >0.05 in the HapMap CEU population at intervals of approximately 1 kb across the CYP2B6 locus was conducted using Sequenom iPLEX MALDI-TOF. RESULTS: Thirteen SNPs passed quality control and, of these, statistically significant associations (P < 0.001) with plasma efavirenz concentrations were observed for 11. Pairwise tagging SNP analysis (R(2) > 0.8) identified 3 SNPs (rs10403955, rs2279345 and rs8192719) representative of the 11 associated SNPs. A composite genetic model of these three alleles was constructed, and an association between carriers of four to six of these alleles and the risk of efavirenz plasma concentrations >4 microg/mL was identified with an odds ratio of 48.1 (95% confidence interval: 13.5-207.7). This represents a positive predictive value of 80.9% and a negative predictive value of 91.8%, with sensitivity of 57.9% and specificity of 97.2%. CONCLUSIONS: A composite genetic model of CYP2B6 SNPs in a Chilean HIV-positive cohort may have value in predicting concentrations of efavirenz associated with a higher likelihood of CNS toxicity. Further investigation of the functional basis of these associations is now required.
OBJECTIVES: Efavirenz is extensively metabolized by CYP2B6, and associations between CYP2B6 polymorphisms and plasma efavirenz exposure have been reported. The objective of this study was to investigate CYP2B6 haplotype structure and functional consequences in a Latin American population. PATIENTS AND METHODS: Two hundred and nineteen patients were recruited at Fundación Arriarán, Chile, between September and December 2008. Plasma efavirenz concentrations were determined using liquid chromatography with mass spectrometry. Genotyping for 30 single nucleotide polymorphisms (SNPs) with a minor allele frequency of >0.05 in the HapMap CEU population at intervals of approximately 1 kb across the CYP2B6 locus was conducted using Sequenom iPLEX MALDI-TOF. RESULTS: Thirteen SNPs passed quality control and, of these, statistically significant associations (P < 0.001) with plasma efavirenz concentrations were observed for 11. Pairwise tagging SNP analysis (R(2) > 0.8) identified 3 SNPs (rs10403955, rs2279345 and rs8192719) representative of the 11 associated SNPs. A composite genetic model of these three alleles was constructed, and an association between carriers of four to six of these alleles and the risk of efavirenz plasma concentrations >4 microg/mL was identified with an odds ratio of 48.1 (95% confidence interval: 13.5-207.7). This represents a positive predictive value of 80.9% and a negative predictive value of 91.8%, with sensitivity of 57.9% and specificity of 97.2%. CONCLUSIONS: A composite genetic model of CYP2B6 SNPs in a Chilean HIV-positive cohort may have value in predicting concentrations of efavirenz associated with a higher likelihood of CNS toxicity. Further investigation of the functional basis of these associations is now required.
Authors: Joel E Gallant; Edwin DeJesus; José R Arribas; Anton L Pozniak; Brian Gazzard; Rafael E Campo; Biao Lu; Damian McColl; Steven Chuck; Jeffrey Enejosa; John J Toole; Andrew K Cheng Journal: N Engl J Med Date: 2006-01-19 Impact factor: 91.245
Authors: M Rotger; H Tegude; S Colombo; M Cavassini; H Furrer; L Décosterd; J Blievernicht; T Saussele; H F Günthard; M Schwab; M Eichelbaum; A Telenti; U M Zanger Journal: Clin Pharmacol Ther Date: 2007-01-18 Impact factor: 6.875
Authors: Christoph Wyen; Heidy Hendra; Martin Vogel; Christian Hoffmann; Heribert Knechten; Norbert H Brockmeyer; Johannes R Bogner; Jürgen Rockstroh; Stefan Esser; Hans Jaeger; Thomas Harrer; Stefan Mauss; Jan van Lunzen; Nicole Skoetz; Alexander Jetter; Christiane Groneuer; Gerd Fätkenheuer; Saye H Khoo; Deirdre Egan; David J Back; Andrew Owen Journal: J Antimicrob Chemother Date: 2008-02-14 Impact factor: 5.790
Authors: Marco H Hofmann; Julia K Blievernicht; Kathrin Klein; Tanja Saussele; Elke Schaeffeler; Matthias Schwab; Ulrich M Zanger Journal: J Pharmacol Exp Ther Date: 2008-01-02 Impact factor: 4.030
Authors: Jose R Arribas; Anton L Pozniak; Joel E Gallant; Edwin Dejesus; Brian Gazzard; Rafael E Campo; Shan-Shan Chen; Damian McColl; Charles B Holmes; Jeffrey Enejosa; John J Toole; Andrew K Cheng Journal: J Acquir Immune Defic Syndr Date: 2008-01-01 Impact factor: 3.731
Authors: Miriam Polo; Fernando Alegre; Angela B Moragrega; Lara Gibellini; Alberto Marti-Rodrigo; Ana Blas-Garcia; Juan V Esplugues; Nadezda Apostolova Journal: Br J Pharmacol Date: 2017-11-07 Impact factor: 8.739
Authors: Jing Li; Vincent Menard; Rebekah L Benish; Richard J Jurevic; Chantal Guillemette; Mark Stoneking; Peter A Zimmerman; Rajeev K Mehlotra Journal: Pharmacogenomics Date: 2012-04 Impact factor: 2.533
Authors: M Polo; F Alegre; H A Funes; A Blas-Garcia; V M Victor; J V Esplugues; N Apostolova Journal: Br J Pharmacol Date: 2015-01-08 Impact factor: 8.739
Authors: C Sukasem; W Manosuthi; N Koomdee; S Santon; T Jantararoungtong; S Prommas; M Chamnanphol; A Puangpetch; S Sungkanuparph Journal: Infection Date: 2013-11-30 Impact factor: 3.553