Drug-induced liver injury and COVID-19: A review for clinical practice

Table 1 Reports of drug-induced liver injury in patients with coronavirus disease 2019 (PubMed/Virtual Health Library)

Ref.	Study/site	Patient profile	Medication	DILI	Outcome
Muhović et al[23]	Case report; Montenegro	Man, 52-yr-old	Chloroquine, lopinavir/ritonavir, methylprednisolone, ceftriaxone and azithromycin. After 6 d: methylprednisolone, ceftriaxone, azithromycin	CIOMS/RUCAM: scored 8 points for a ‘probable’ cause of DILI by TCZ. Hepatocellular form of DILI diagnosed using the EASL guidelines	TCZ had a positive effect on clinical and laboratory parameters, with transaminases values normalizing in 10 d
Zampino et al[24]	Case series; Naples, Italy	None of the 5 treated patients had history of liver disease, visceral obesity, viral hepatitis, or prior hepatotoxic medication or alcohol intake. Liver ultrasound did not show signs of advanced liver disease. Patient 1 and 2 had history of hypertension and asthma	Before and during RDV treatment, 4 of 5 patients alsoreceived hydroxychloroquine patient 2 and 4 received ceftazidime–avibactam plus daptomycin and patient 3 meropenem and linezolid	Significant increase in AST/ALT	Adverse effect neither progressed to severe liver damage nor induced liver failure. In no cases, RDV was discontinued because of liver injury
Durante-Mangoni et al[25]	Case series; Naples, Italy	Four patients	All patients had been previously treated with LPV/r or darunavir/cobicistat (DRV/c) and also received hydroxychloroquine	3 patients experienced ALT and AST increase (5 times to 8 times the upper normal limit)	RDV was prematurely discontinued in patient 1 because of a torsade de pointes requiring cardiac resuscitation and in patient 3 because of death due to multiple organ failure. The study suggests a significant burden of adverse events
Montastruc et al[26]	Cross-sectional study; United States, Europe	387 reports with RDV side effects in VigiBase; 130 hepatic adverse effects, 87 from the United States; 43 from Europe; mostly men (81, 62%), mean age of 54.9 yr	In the majority of cases (122, 94%), RDV was the sole suspected drug	Increased hepatic enzymes (114, 88%), involving AST and ALT in 79 cases (61%) and bilirubin in 4 cases (3%). Other cases were reported as hepatic failure or hepatitis	Most cases were serious (94, 72%), resulting in hospitalization or prolongation of hospital stay. The use of RDV was associated with an increased risk of reporting hepatic disorders
Yamazaki et al[27]	Case reported; Japan	73-yr-old man. History of hypertension, hyperlipidemia, gastric ulcer, benign prostatic hyperplasia, and alcoholic hepatitis	Favipiravir was the suspected drug. Dosage was 6000 mg on day 1 and 2400 mg/d from day 2 onward, for a total of 14 d. Patient was using previously lopinavir/ritonavir combined with interferon β-1b, vancomycin and antithrombin III. After started fapinavir two more drugs were added Trimethoprim-sulfamethoxazole and micafungin	Transaminases were elevated until day 4: Aspartate aminotransferase (AST) from 70 U/L (day 0) to 112 U/L (day 4) and alanine aminotransferase (ALT) from 37 U/L to 59 U/L, respectively. Total bilirubin (T-BiL) increased until day 3 from 5.2 mg/dL to 12.6 mg/dL. On day 11, however, transaminases peaked again (AST, 268 U/L; ALT, 115 U/L) and total bilirubin was also rising	A case of cholestatic liver injury in the early stages of favipiravir treatment for COVID-19. Based on the CIMOS/RUCAM scoring system, it was classified as a cholestatic liver injury, with a score of 6 (possible)
Leegwater et al[28]	Case report; The Netherlands	A 64-yr-old male patient. History of hypertension and hypercholesterolemia	Remdesivir	5 d after start of remdesivir ALT was 1305 IU/L, AST 1461 U/L, alkaline phosphatase 269 U/L, total bilirubin 8 µmol/L, gammaglutamyltransferase 227 U/L and creatine kinase 103 U/L	Remdesivir toxicity was suspected based on the time-relation, the positive dechallenge, the known in vitro toxicity of remdesivir and the absence of alternative causes of hepatotoxicity. After stop of remdesivir the ALT/AST ratio reached normal values

CIOMS/RUCAM: Council for International Organizations of Medical Sciences/Roussel Uclaf Causality Assessment Method; DILI: Drug induce liver injury; EASL: European Association for the Study of the Liver; TCZ: Tocilizumab; RDV: Remdesivir.