title: 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 = 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.
authors.affiliation: Bamrasnaradura Infectious Diseases Institute, Ministry of Public Health, Thailand. drweerawat@hotmail.com
authors.forename: Weerawat
authors.initials: W
authors.lastname: Manosuthi
authors.forename: Chonlaphat
authors.initials: C
authors.lastname: Sukasem
authors.forename: Aroon
authors.initials: A
authors.lastname: Lueangniyomkul
authors.forename: Wiroj
authors.initials: W
authors.lastname: Mankatitham
authors.forename: Supeda
authors.initials: S
authors.lastname: Thongyen
authors.forename: Samruay
authors.initials: S
authors.lastname: Nilkamhang
authors.forename: Sukanya
authors.initials: S
authors.lastname: Manosuthi
authors.forename: Somnuek
authors.initials: S
authors.lastname: Sungkanuparph
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000097:blood* / Q000627:therapeutic use; D000995:Antitubercular Agents / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D048588:Benzoxazines / Q000097:blood* / Q000627:therapeutic use; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D004347:Drug Interactions; D004977:Ethambutol / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D007538:Isoniazid / Q000627:therapeutic use; D019259:Lamivudine / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000627:therapeutic use; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011718:Pyrazinamide / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000097:blood / Q000627:therapeutic use; D012293:Rifampin / Q000627:therapeutic use; D000068698:Tenofovir; D014376:Tuberculosis / Q000150:complications / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D011718:Pyrazinamide; D019259:Lamivudine; D004977:Ethambutol; D000068698:Tenofovir; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; D000225:Adenine; C098320:efavirenz; D007538:Isoniazid; D012293:Rifampin