title: HLA-B*57Allele Is Associated with Concomitant Anti-tuberculosis and Antiretroviral Drugs Induced Liver Toxicity in Ethiopians.
abstract: Drug-induced liver injury (DILI) is a known adverse effect of both anti-tuberculosis (anti-TB) and antiretroviral (ARV) drugs. Recent studies highlight the implications of genetic predispositions to DILI. We performed a case-control study to identify Human Leukocyte Antigen-B (HLA-B) variant alleles associated with anti-TB and ARV co-treatment induced liver toxicity in Ethiopian TB and HIV co-infected patients. A total of 495 newly diagnosed TB and HIV co-infected patients were enrolled and received rifampicin based anti-TB and efavirenz based ARV therapy. Change in liver enzyme level from baseline was monitored 1st, 2nd, 4th, 8th, 12th, and 24th weeks after treatment initiation to identify patients who developed DILI (cases) and those who did not (treatment tolerants). Genomic DNA from 46 cases and 46 sex and age matched treatment tolerants were genotyped for HLA-B variant alleles using Olerup SSP®HLA-B DNA Typing Kits. The proportion ofHLA-B*57allele carriers in DILI cases (37.0%), particularly in those who developed cholestatic type of DILI (44.8%) was significantly higher compared with those who tolerated the treatment (2.2%). TheHLA-B*57allele frequency was significantly higher in cases (25%) than treatment tolerants (1.1%). In a multivariate logistic analysis, the proportion of patients carryingHLA-B*57(P= 0.002) andHLA-B*14(P= 0.014) alleles were significantly higher in DILI cases compared with treatment tolerants.HLA-B*57was significantly associated with cholestatic (P= 0.001) and mixed (P= 0.017) types of liver toxicity, and mild-to-moderate severity (P= 0.001). Of allHLA-B*57alleles detected,HLA-B*57:03accounted 58.3% andHLA-B*57:02accounted 41.7%.HLA-B*57:01was not detected. The variant allele frequencies ofHLA-B*57:03(15.2 vs. 0%) andHLA-B*57:02(9.8 vs. 1.1%) were significantly higher in the DILI cases than treatment tolerants (P< 0.03). We conclude thatHLA-B*57alleles (B*57:03andB*57:02) confer susceptibility to the development of anti-TB and ARV drugs co-treatment induced liver toxicity, which is mainly of cholestatic type. The possible association ofHLA-B*14with anti-TB and ARV drugs co-treatment induced liver toxicity requires further investigations.
authors.affiliation: Department of Pharmacology, School of Medicine, College of Health Sciences, Addis Ababa UniversityAddis Ababa, Ethiopia; Department of Laboratory Medicine, Karolinska Institutet-Karolinska University HospitalStockholm, Sweden.
authors.forename: Zelalem
authors.initials: Z
authors.lastname: Petros
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet-Karolinska University Hospital Stockholm, Sweden.
authors.forename: Junko
authors.initials: J
authors.lastname: Kishikawa
authors.affiliation: Department of Pharmacology, School of Medicine, College of Health Sciences, Addis Ababa University Addis Ababa, Ethiopia.
authors.forename: Eyasu
authors.initials: E
authors.lastname: Makonnen
authors.affiliation: Department of Pharmacology, School of Medicine, College of Health Sciences, Addis Ababa University Addis Ababa, Ethiopia.
authors.forename: Getnet
authors.initials: G
authors.lastname: Yimer
authors.affiliation: Department of Pharmacology, School of Medicine, College of Health Sciences, Addis Ababa University Addis Ababa, Ethiopia.
authors.forename: Abiy
authors.initials: A
authors.lastname: Habtewold
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet-Karolinska University Hospital Stockholm, Sweden.
authors.forename: Eleni
authors.initials: E
authors.lastname: Aklillu
keywords: DILI; Ethiopian; HIV; HLA; HLA-B*57; anti-tuberculosis; antiretroviral drugs; drug induced hepatotoxicity