CYP2B6 18492T→C Polymorphism Compromises Efavirenz Concentration in Coinfected HIV and Tuberculosis Patients Carrying CYP2B6 Haplotype *1/*1

Abstract

Data regarding the effect of the CYP2B6 18492T¡C polymorphism on plasma efavirenz concentrations and 96-week virologic responses in patients coinfected with HIV and tuberculosis (TB) are still unavailable. A total of 139 antiretroviral-naive HIVinfected adults with active TB were prospectively enrolled to receive efavirenz 600 mg-tenofovir 300 mg-lamivudine 300 mg. Eight single nucleotide polymorphisms (SNPs) within CYP2B6 were genotyped. Seven SNPs, including 64C¡T, 499C¡G, 516G¡T, 785A¡G, 1375A¡G, 1459C¡T, and 21563C¡T, were included for CYP2B6 haplotype determination. The CYP2B6 18492T¡C polymorphism was studied in 48 patients who carried haplotype *1/*1. At 12 and 24 weeks after antiretroviral therapy, plasma efavirenz concentrations at 12 h after dosing were measured. Plasma HIV RNA was monitored every 12 weeks for 96 weeks. Of 48 patients {body weight [mean ؎ standard deviation (SD)], 56 ؎ 10 kg}, 77% received a rifampin-containing anti-TB regimen. No drug resistance-associated mutation was detected at baseline. The frequencies of the wild type (18492TT) and the heterozygous (18492TC) and homozygous (18492CC) mutants of the CYP2B6 18492T¡C polymorphism were 39%, 42%, and 19%, respectively. At 12 weeks, mean (؎SD) efavirenz concentrations of patients who carried the 18492TT, 18492TC, and 18492CC mutants were 2.8 ؎ 1.6, 1.7 ؎ 0.9, and 1.4 ؎ 0.5 mg/liter, respectively (P ‫؍‬ 0.005). At 24 weeks, the efavirenz concentrations of the corresponding groups were 2.4 ؎ 0.8, 1.7 ؎ 0.8, and 1.2 ؎ 0.4 mg/liter, respectively (P ‫؍‬ 0.003). A low efavirenz concentration was independently associated with 18492T¡C (␤ ‫؍‬ ؊0.937, P ‫؍‬ 0.004) and high body weight (␤ ‫؍‬ ؊0.032, P ‫؍‬ 0.046). At 96 weeks, 19%, 17%, and 28% of patients carrying the 18492TT, 18492TC, and 18492CC mutants, respectively, had plasma HIV RNA levels of >40 copies/ml and developed efavirenz-associated mutations (P ‫؍‬ 0.254). In summary, the CYP2B6 18492T¡C polymorphism compromises efavirenz concentrations in patients who carry CYP2B6 haplotype *1/*1 and are coinfected with HIV and tuberculosis.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2B6 and Efavirenz‐Containing Antiretroviral Therapy

“…Another CYP2B6 SNP, rs2279345 (g.18492T>C), has been associated with slightly decreased plasma efavirenz concentrations . This SNP is not part of any defined (*) alleles.…”

“…This SNP is not part of any defined (*) alleles. The presence of this SNP together with coadministration of a strong CYP inducer may increase the likelihood of subtherapeutic plasma efavirenz concentrations …”

“…Another CYP2B6 SNP, rs2279345 (g.18492T>C), has been associated with slightly decreased plasma efavirenz concentrations. [5][6][7][8][9] This SNP is not part of any defined (*) alleles. The presence of this SNP together with coadministration of a strong CYP inducer may increase the likelihood of subtherapeutic plasma efavirenz concentrations.…”

Drug disposition alterations in liver disease: extrahepatic effects in cholestasis and nonalcoholic steatohepatitis

“…Nonetheless, the accumulated amount evidence has resulted in the addition of a Black Box warning for clopidogrel alerting health care professionals of the decreased responsiveness to the drug in patients with CYP2C19 loss-of-function genotypes [11]. Additionally, it was recently shown that a specific polymorphism (18492T>C) occurring in the CYP2B6 gene is associated with decreased plasma levels of efavirnez in two separate patient populations infected with HIV [23;24]. It is interesting to note that the frequency of heterozygosity of this polymorphism was 42%, resulting in nearly a two-fold decrease in efavirnez plasma levels [23].…”

“…Additionally, it was recently shown that a specific polymorphism (18492T>C) occurring in the CYP2B6 gene is associated with decreased plasma levels of efavirnez in two separate patient populations infected with HIV [23;24]. It is interesting to note that the frequency of heterozygosity of this polymorphism was 42%, resulting in nearly a two-fold decrease in efavirnez plasma levels [23]. The CYP2D6*10 polymorphism was found to have a frequency of 51% in a Chinese population and patients homozygous for this allele had a significant reduction in tramadol clearance leading to an increased half-life and AUC [25].…”