title: CYP2B6 haplotype and biological factors responsible for hepatotoxicity in HIV-infected patients receiving efavirenz-based antiretroviral therapy.
abstract: Data on the pharmacogenetic markers of CYP2B6 and biological factors associated with hepatotoxicity in HIV-infected patients receiving an efavirenz-based antiretroviral therapy (ART) regimen are very limited. A total of 134 HIV-infected Thai adults were prospectively enrolled to receive a once-daily regimen of efavirenz 600 mg/tenofovir/lamivudine. Seven single nucleotide polymorphisms (SNPs) within CYP2B6 were genotyped using real-time PCR. At 12 weeks after ART, plasma efavirenz concentrations at 12h after dosing were measured. The mean ± standard deviation patient age was 37 ± 8 years, and 77.6% were male. The median (IQR) CD4 count was 43 cells/mm(3) (17-105 cells/mm(3)). Eighteen patients (13.4%) had positive anti-HCV and 5 patients (3.7%) had positive HBsAg. The frequencies of heterozygous/homozygous mutants of each SNP were 64C>T (11%), 499C>G (0%), 516G>T (55%), 785A>G (63%), 1375A>G (0%), 1459C>T (3%) and 21563C>T (62%). The three most frequent haplotypes identified included *1/*6 (40.3%), *1/*1 (34.3%) and *6/*6 (8.2%). The median (IQR) plasma efavirenz concentration was 2.3mg/L (1.4-3.7 mg/L). At 24 weeks, median (IQR) serum ALP was 98 mg/dL (73-133 mg/dL) and direct bilirubin was 0.11 mg/dL (0.10-0.19 mg/dL). The proportion of grade 1 and grade 2 elevated serum ALP was 12.7% and 1.5%, respectively. By multivariate analysis, factors associated with high ALP, total bilirubin and direct bilirubin included CYP2B6 haplotype *6/*6, high serum ALP at Week 0 and positive anti-HCV (all P<0.05). In summary, HIV-infected patients with the pharmacogenetic marker 'CYP2B6 haplotype *6/*6' may have increased susceptibility to hepatotoxicity with efavirenz-based ART.
authors.affiliation: Bamrasnaradura Infectious Diseases Institute, Ministry of Public Health, Nonthaburi, Thailand. Electronic address: drweerawat@hotmail.com.
authors.forename: Weerawat
authors.initials: W
authors.lastname: Manosuthi
authors.affiliation: Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Chonlaphat
authors.initials: C
authors.lastname: Sukasem
authors.affiliation: Bamrasnaradura Infectious Diseases Institute, Ministry of Public Health, Nonthaburi, Thailand.
authors.forename: Aroon
authors.initials: A
authors.lastname: Lueangniyomkul
authors.affiliation: Bamrasnaradura Infectious Diseases Institute, Ministry of Public Health, Nonthaburi, Thailand.
authors.forename: Wiroj
authors.initials: W
authors.lastname: Mankatitham
authors.affiliation: Bamrasnaradura Infectious Diseases Institute, Ministry of Public Health, Nonthaburi, Thailand.
authors.forename: Supeda
authors.initials: S
authors.lastname: Thongyen
authors.affiliation: Bamrasnaradura Infectious Diseases Institute, Ministry of Public Health, Nonthaburi, Thailand.
authors.forename: Samruay
authors.initials: S
authors.lastname: Nilkamhang
authors.affiliation: Bamrasnaradura Infectious Diseases Institute, Ministry of Public Health, Nonthaburi, Thailand.
authors.forename: Sukanya
authors.initials: S
authors.lastname: Manosuthi
authors.affiliation: Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Somnuek
authors.initials: S
authors.lastname: Sungkanuparph
mesh_terms: D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000009:adverse effects* / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects* / Q000379:methods; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D048588:Benzoxazines / Q000009:adverse effects* / Q000627:therapeutic use; D001685:Biological Factors; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics* / Q000473:pathology; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D005260:Female; D005787:Gene Frequency; D060005:Genotyping Techniques; D015658:HIV Infections / Q000188:drug therapy*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D060888:Real-Time Polymerase Chain Reaction; D013785:Thailand
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D001685:Biological Factors; D003521:Cyclopropanes; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; C098320:efavirenz
keywords: Antiretroviral therapy; CYP2B6; Efavirenz; HIV; Tuberculosis