ABSTRACT
BACKGROUND: Anti-tuberculosis drug-induced liver injury (AT-DILI) is one of the most common forms of drug-induced liver injury (DILI) in high tuberculosis (TB) burden countries. Among anti-tuberculosis drugs, isoniazid is the main cause of hepatotoxicity in patients with AT-DILI. OBJECTIVE: To investigate the association of AT-DILI with N-acetyltransferase 2 (NAT2) genotype status in Thai TB patients. METHODS: We enrolled 53 patients diagnosed with AT-DILI and 85 patients who tolerated anti-tuberculosis treatment as controls. Acetylator status was determined based on the inferred NAT2 haplotypes from four common single-nucleotide polymorphisms (SNPs) in Thais using Sanger sequencing. RESULTS: Phenotype frequencies of the NAT2 acetylator in AT-DILI patients were respectively 71.7%, 22.6% and 5.7% for slow, intermediate and rapid acetylators. Among slow, intermediate, and rapid acetylators in treatment tolerant controls, phenotype frequencies were respectively 22.4%, 62.4% and 15.3%. Slow NAT2 acetylators demonstrated a significant association with risk of AT-DILI. The odds ratio of comparing slow NAT2 acetylator in DILI patients and tolerance was 8.80 (95%CI 4.01-19.31, P = 1.53 × 10-8). CONCLUSIONS: Slow acetylator status in the NAT2 genotype is a significant risk factor for DILI in Thai patients with TB. This evidence provides confirmatory data in support of the role of NAT2 in AT-DILI in the Thai population.
Subject(s)
Antitubercular Agents/adverse effects , Arylamine N-Acetyltransferase/genetics , Chemical and Drug Induced Liver Injury/diagnosis , Tuberculosis/drug therapy , Acetylation , Adult , Aged , Antitubercular Agents/administration & dosage , Arylamine N-Acetyltransferase/metabolism , Case-Control Studies , Chemical and Drug Induced Liver Injury/genetics , Female , Gene Frequency , Genotyping Techniques , Haplotypes , Humans , Isoniazid/administration & dosage , Isoniazid/adverse effects , Male , Middle Aged , Polymorphism, Single Nucleotide , Prevalence , Risk Factors , Sequence Analysis, DNA , ThailandABSTRACT
A total of 755 highly active antiretroviral therapy (HAART)-naive HIV-infected patients were enrolled at a government hospital in Thailand from 1 June 2000 to 15 October 2002. Census dateo f survival was on 31 October 2004 or the date of HAART initiation. Of 700 (92.6%) patients with complete data, the prevalence of hepatitis B virus (HBV) surface antigen and anti-hepatitis C virus (HCV) antibody positivity was 11.9% and 3.3%, respectively. Eight (9.6%) HBV co-infected patients did not have anti-HBV core antibody (anti-HBcAb). During 1166.7 person-years of observation (pyo), 258 (36.9%) patients died [22.1/100 pyo, 95% confidence interval (CI) 16.727.8]. HBV and probably HCV co-infection was associated with a higher mortality with adjusted hazard ratios (aHRs) of 1.81 (95% CI 1.302.53) and 1.90 (95% CI0.983.69), respectively. Interestingly, HBV co-infection without anti-HBc Ab was strongly associated with death (aHR 6.34, 95% CI 3.9910.3). The influence of hepatitis co-infection on the natural history of HAART-naive HIV patients requires greater attention.
