HLA-B*57 Allele 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 of HLA-B*57 allele 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%). The HLA-B*57 allele frequency was significantly higher in cases (25%) than treatment tolerants (1.1%). In a multivariate logistic analysis, the proportion of patients carrying HLA-B*57 (P = 0.002) and HLA-B*14 (P = 0.014) alleles were significantly higher in DILI cases compared with treatment tolerants. HLA-B*57 was 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 all HLA-B*57 alleles detected, HLA-B*57:03 accounted 58.3% and HLA-B*57:02 accounted 41.7%. HLA-B*57:01 was not detected. The variant allele frequencies of HLA-B*57:03 (15.2 vs. 0%) and HLA-B*57:02 (9.8 vs. 1.1%) were significantly higher in the DILI cases than treatment tolerants (P < 0.03). We conclude that HLA-B*57 alleles (B*57:03 and B*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 of HLA-B*14 with anti-TB and ARV drugs co-treatment induced liver toxicity requires further investigations.

Shared Genetic Risk Factors Across Carbamazepine‐Induced Hypersensitivity Reactions

“…We also identified an association between CBZ‐induced SJS/TEN and HLA‐B*57:01 . This allele is a well‐known risk factor for other CD8+ T‐cell‐mediated reactions, including abacavir hypersensitivity syndrome and flucloxacillin‐induced DILI, and more recently, DILI induced by two other drug combinations, pazopanib and a combination of antituberculosis and anti‐HIV drugs . Given that the association with CBZ‐induced SJS/TEN was not genomewide significant, it needs replication in other cohorts.…”

“…This allele is a well-known risk factor for other CD8+ T-cell-mediated reactions, including abacavir hypersensitivity syndrome 24,25 and flucloxacillin-induced DILI, 26 and more recently, DILI induced by two other drug combinations, pazopanib and a combination of antituberculosis and anti-HIV drugs. 27,28 Given that the association with CBZ-induced SJS/ TEN was not genomewide significant, it needs replication in other cohorts. Interestingly, our finding of the association of valine 97 with CBZ-SJS/TEN is in line with the association of valine 97 with flucloxacillin-DILI, 29 suggesting that the binding site of HLA-B*57:01 may be promiscuous for a number of drugs, which would be in keeping with the increasing number of reports of immunemediated reactions associated with this allele.…”

Drug‐Induced Liver Injury due to Flucloxacillin: Relevance of Multiple Human Leukocyte Antigen Alleles

“…Based mainly on studies in vitro , alleles related closely to HLA‐B*57:01 , such as both HLA‐B*57:02 and HLA‐B*57:03 , are not risk factors for abacavir hypersensitivity . In view of a recent report involving an African population, which reports that HLA‐B*57:02 and HLA‐B*57:03 are risk factors for an unusual form of DILI seen when both antiretroviral and anti‐tuberculosis drugs are prescribed, as well as the strong homology in the amino acid sequence for the gene product, it is also possible that HLA‐B*57:02 and other rare B*57 alleles may be risk factors for flucloxacillin DILI. HLA‐B*57:02 , like HLA‐B*57:03 , is very rare in Northern Europeans and was not detected at all in our population but does code for V 97 in the HLA‐B gene product similar to both HLA‐B*57:01 and HLA‐B*57:03 .…”

Conference report: pharmacogenomics in special populations at WCP2018

“…PGx studies in genes coding for HLA revealed that HLA‐B*57 alleles ( B*57:03 and B*57:02 ) confer susceptibility to anti‐TB and antiretroviral drug‐induced liver toxicity . HLA‐B*57:03 is the most prevalent HLA‐B*57 subtype in black African populations, whereas HLA‐B*57:01 , which is strongly associated with abacavir‐induced hypersensitivity reaction, is absent in black Africans . HLA‐B*57:01 occurs with frequencies up to 5% in Asians and Caucasians, and prior screening for this allele is highly recommended in these populations.…”