Impact of Pharmacogenetic Markers ofCYP2B6, Clinical Factors, and Drug-Drug Interaction on Efavirenz Concentrations in HIV/Tuberculosis-Coinfected Patients

Abstract

bComprehensive 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 ‫؍‬ 0.027) and high body weight (beta ‫؍‬ ؊0.076, P ‫؍‬ 0.002). In conclusion, pharmacogenetic markers of CYP2B6 have the greatest impact with respect to inducing low plasma efavirenz concentrations in HIV/TB Thai patients.

Pharmacokinetics of efavirenz in patients on antituberculosis treatment in high human immunodeficiency virus and tuberculosis burden countries: A systematic review

“…Ten studies, had proportions for both on and off RH, with nine reporting higher proportions of patients with EFV < 1000 ng ml –1 during RH coadministration than without RH, although the difference was highly variable, ranging between 1.1 and 21.1%. Only two studies, one in Thai patients and one in South Africans , reported a lower proportion of patients with EFV < 1000 ng ml –1 during RH coadministration than without RH, with a difference <5%.…”

“…Studies conducted among adult patients in Tanzania and Thailand or in children in South Africa highlight within country variability with regard to effect of RH on EFV concentrations , which could partially be explained by the small sample size, or differences in methodology used and the pharmacogenetics within different ethnic groups. As highlighted in the review by Colic et al .…”

Pharmacogenetics and Clinical Biomarkers for Subtherapeutic Plasma Efavirenz Concentration in HIV-1 Infected Thai Adults

“…31) In fact, there are multiple factors that could contribute to affect plasma efavirenz concentration, including gender, age, body weight, liver and renal impairment. 32) Thus, this study was also designed to investigate the various interactions of host genetics with clinical parameters and efavirenz concentration by univariate and multivariate analysis.…”

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

“…This study was a prospective open-label trial to evaluate the frequency of CYP2B6 single nucleotide polymorphisms (SNPs) and haplotypes in 139 adult Thai patients coinfected with HIV and tuberculosis at the Bamrasnaradura Infectious Diseases Institute, Ministry of Public Health, Nonthaburi, Thailand (16). The institutional ethics committees of the Bam-rasnaradura Infectious Diseases Institute and the Thai Ministry of Public Health approved the study.…”