Clinical characteristics and HLA associations of azithromycin‐induced liver injury

Summary Background Azithromycin (AZ) is a widely used antibiotic. The aim of this study was to characterise the clinical features, outcomes, and HLA association in patients with drug‐induced liver injury (DILI) due to AZ. Methods The clinical characteristics of individuals with definite, highly likely, or probable AZ‐DILI enrolled in the US Drug‐Induced Liver Injury Network (DILIN) were reviewed. HLA typing was performed using an Illumina MiSeq platform. The allele frequency (AF) of AZ‐DILI cases was compared to population controls, other DILI cases, and other antibiotic‐associated DILI cases. Results Thirty cases (4 definite, 14 highly likely, 12 probable) of AZ‐DILI were enrolled between 2004 and 2022 with a median age of 46 years, 83% white, and 60% female. Median duration of AZ treatment was 5 days. Latency was 18.5 days. 73% were jaundiced at presentation. The injury pattern was hepatocellular in 60%, cholestatic in 27%, and mixed in 3%. Ten cases (33%) were severe or fatal; 90% of these were hepatocellular. Two patients required liver transplantation. One patient with chronic liver disease died of hepatic failure. Chronic liver injury developed in 17%, of which 80% had hepatocellular injury at onset. HLA‐DQA1*03:01 was significantly more common in AZ‐DILI versus population controls and amoxicillin‐clavulanate DILI cases (AF: 0.29 vs. 0.11, p = 0.001 and 0.002, respectively). Conclusion Azithromycin therapy can lead to rapid onset of severe hepatic morbidity and mortality in adult and paediatric populations. Hepatocellular injury and younger age were associated with worse outcomes. HLA‐DQA1*03:01 was significantly more common in AZ cases compared to controls.