Impact of pharmacogenetic markers of CYP2B6, clinical factors, and drug-drug interaction on efavirenz concentrations in HIV/tuberculosis-coinfected patients

Abstract

Comprehensive information on the effects of cytochrome P450 2B6 (CYP2B6) polymorphisms, clinical factors, and drug-drug interactions on efavirenz concentrations in HIV/tuberculosis-coinfected (HIV/TB) patients is unavailable.A total of 139 HIV/TB adults, 101 of whom received a rifampin-containing anti-TB regimen, were prospectively enrolled to receive efavirenz (600 mg)/ tenofovir/lamivudine.Nine single nucleotide polymorphisms (SNPs) within CYP2B6 were genotyped.Plasma efavirenz concentrations were measured at 12 weeks.The median (interquartile range [IQR]) efavirenz concentration was 2.3 (1.4 to 3.9) mg/liter.The SNPs (frequencies of heterozygous and homozygous mutants) were 64C>T (10% and 1%), 499C>G (0% and 0%), 516G>T (47% and 8%), 785A>G (54% and 10%), 1375A>G (0% and 0%), 1459C>T (3% and 0%), 3003C>T (44% and 27%), 18492T>C (39% and 6%), and 21563C>T (57% and 5%).The four most frequent CYP2B6 haplotypes identified were *1/*6 (41%), *1/*1 (35%), *1/*2 (7%), and *6/*6 (7%).The heterozygous/homozygous mutation associated with low efavirenz concentrations was 18492T>C (P<0.001), and those associated with high efavirenz concentrations were 516G>T, 785A>G, and 21563C>T (all P<0.05).Haplotype *1/*1 was associated with low efavirenz concentrations, and *6/*6, *1/*6, and *5/6 were associated with high efavirenz concentrations.As shown by multivariate analysis, low efavirenz concentrations were significantly associated with the *1/*1 haplotype (beta=-1.084, P=.027) and high body weight (beta=-0.076, P=.002).In conclusion, pharmacogenetic markers of CYP2B6 have the greatest impact with respect to inducing low plasma efavirenz concentrations in HIV/TB Thai patients.Copyright © 2013, American Society for Microbiology.All Rights Reserved.