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

• Published in: Antimicrobial agents and chemotherapy Vol. 58; no. 4; pp. 2268 - 2273
• Main Authors: MANOSUTHI, Weerawat, SUKASEM, Chonlaphat, THONGYEN, Supeda, NILKAMHANG, Samruay, MANOSUTHI, Sukanya, SUNGKANUPARPH, Somnuek
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for Microbiology 2014
• Subjects: Adult; Anti-HIV Agents - pharmacokinetics; Anti-HIV Agents - therapeutic use; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral Agents; Aryl Hydrocarbon Hydroxylases; Aryl Hydrocarbon Hydroxylases - genetics; Bacterial diseases; Benzoxazines; Benzoxazines - pharmacokinetics; Benzoxazines - therapeutic use; Biological and medical sciences; Coinfection; Cytochrome P-450 CYP2B6; Female; Haplotypes - genetics; HIV Infections; HIV Infections - blood; HIV Infections - drug therapy; Human bacterial diseases; Human viral diseases; Humans; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Infectious diseases; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Polymorphism, Single Nucleotide - genetics; Reverse Transcriptase Inhibitors; Reverse Transcriptase Inhibitors - pharmacokinetics; Reverse Transcriptase Inhibitors - therapeutic use; Tuberculosis; Tuberculosis - blood; Tuberculosis - drug therapy; Tuberculosis and atypical mycobacterial infections; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Antiretroviral agent; Benzoxazine derivatives; RNA-directed DNA polymerase; Mixed infection; Genetic variability; Acetylenic compound; Isozyme; Non nucleoside compound; Mycobacterial infection; Efavirenz; Reverse transcriptase inhibitor; Antiviral; Haplotype; Human; Immunopathology; Enzyme; Transferases; Cytochrome P450; Enzyme inhibitor; Genotype; AIDS; Concentration; Immune deficiency; Infection; Allosteric inhibitor; Nucleotidyltransferases; Tuberculosis; Viral disease; Bacteriosis; Polymorphism; Cytochrome P450 2B6
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.02384-13

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 HIV-infected 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 (β=-0.937, P=0.004) and high body weight (β=-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.