Systematic Reviews
Copyright ©The Author(s) 2023.
World J Virol. Jan 25, 2023; 12(1): 53-67
Published online Jan 25, 2023. doi: 10.5501/wjv.v12.i1.53
Table 1 Drug induced hepatoxicity outcome and other relevant information in the included studies
Sr. No.
Ref.
Type of study
Location
Number of study participants
Medication
Outcome
1Grein et al[20], 2020Cross sectional/follow-up studyUnited States, Canada, Europe, Japan53RemdesivirElevation of liver enzymes in 12/53 patients
2Goldman et al[76], 2020Randomized, open-label, phase 3 trialUnited States, Italy, Spain, Germany, Hong Kong, Singapore, South Korea, Taiwan397RemdesivirElevated ALT in 26; elevated AST in 23; elevated bilirubin in 5
3Wang et al[1], 2020Randomized, double-blind, placebo-controlled, multicenter trialChina158RemdesivirElevated ALT in 2; elevated AST in 7, elevated bilirubin in 16, decreased albumin in 20
4Antinori et al[77], 2020Prospective (compassionate), open-label studyItaly35RemdesivirElevated transaminase in 15; elevated bilirubin in 7
5Leegwater et al[23], 2021Case studyNetherlands1RemdesivirElevated ALT, AST, ALP and GGT
6Lee et al[24], 2020Case seriesSouth Korea10RemdesivirElevated ALT in 5; elevated AST in 5
7Zampino et al[25], 2020Case seriesItaly5RemdesivirElevated ALT in 4; elevated AST in 4
8Carothers et al[26], 2020Case seriesUnited States2RemdesivirElevated ALT, AST, bilirubin, INR, ammonia in both patients; elevated ALP in 1
9Sun et al[27], 2020Active monitoring study by hospital pharmacovigilance systemChina217LPV/ritonavir, umifenovirElevated ALT in 30
10Fan et al[28], 2020Retrospective, single-center studyChina148LPV/ritonavirElevated ALT in 27; elevated AST in 32; elevated GGT in 26; elevated ALP in 6; elevated bilirubin in 18
11Cai et al[9], 2020Cross-sectional studyChina417LPV/ ritonavir, oseltamivir, interferon, NSAIDs, ribavirinElevated ALT in 167; elevated AST in 137; elevated GGT in 143; elevated ALP in 71; elevated bilirubin in 196
12Jiang et al[29], 2020Multicenter, retrospective, observational studyChina131LPV/ritonavirElevated ALT in 45; elevated AST in 4; elevated bilirubin in 43
13Serviddio et al[30], 2020Case seriesItaly7LPV/ritonavir, HCQ, azithromycinElevated ALT, AST, GGT in all patients
14Guaraldi et al[32], 2020Retrospective cohort studyItaly179TocilizumabNo elevation of ALT or bilirubin was noted
15Muhović et al[33], 2020Case reportMontenegro1TocilizumabElevated ALT and AST
16Hundt et al[34], 2020Retrospective observational cohort studyUnited States1827LPV/ritonavir, HCQ, remdesivir, tocilizumabElevated ALT in 1080 out of 1753; elevated AST in 1465 out of 1756; elevated ALP in 399 out of 1754; elevated total bilirubin in 284 out of 1747
17Kelly et al[35], 2021Retrospective analysis of hospitalized patientsIreland82HCQ, azithromycinElevation of LFTs of more than ULN after 5 d therapy in 51/85 patients
18Falcão et al[36], 2020Case reportBrazil1HCQElevated ALT and AST with normal bilirubin and GGT
19Yamazaki et al[38], 2021Case reportJapan1FavipiravirElevated ALT, AST, ALP, total bilirubin and LDH
20Aiswarya et al[49], 2021Observational prospective studyIndia48RemdesivirNo significant change in serum transaminases and LDH
22Kaur et al[78], 2022Case studyIndia1RemdesivirElevated ALT, AST and total bilirubin
23Gao et al[79], 2022Retrospective studyChina4010Oseltamivir, arbidol, interferon, ribavirin, LPV/ritonavir, HCQ/CQ, antibiotics, antifungals, corticosteroids395 out of 4010 developed DILI. 293 out of 395 received antibiotics, 25 out of 395 received antifungal, 42 out of 395 received oseltamivir, 52 out of 395 received ribavirin, 51 out of 395 received LPV/ritonavir, 47 out of 395 received interferon, 200 out of 395 received corticosteroid, 226 out of 395 received arbidol, 18 out of 395 received HCQ/CQ
24Naseralallah et al[80], 2022Retrospective studyQatar72Azithromycin, HCQ, LPVElevated ALT and AST was implicated in 24 patients due to azithromycin, in 11 patients due to HCQ and in 11 patients due to LPV
25Chew et al[21], 2021Retrospective studyUnited States834Tocilizumab, remdesivir105 out of 834 (12.6%) had elevated AST
26Delgado et al[22], 2021Retrospective observational studySpain8719Remdesivir, hydroxychloroquine, azithromycin, tocilizumab and ceftriaxone4.9% of 8719 patients developed DILI. Out of which remdesivir had the highest incidence of DILI per 10000 defined daily doses
27Durante-Mangoni et al[81], 2020Case reportItaly4Remdesivir3 out of 4 patients had elevated AST and ALT
28Wong et al[82], 2022Self-controlled case series studyChina860Remdesivir334 (38.8%) out of 860 had acute liver injury
29Montastruc et al[83], 2020Multicenter studyFrance387Remdesivir130 (34%) out of 387 developed liver injury
Table 2 Hepatoxicity and likelihood score of therapeutic agents of coronavirus disease 2019
Drug
Hepatotoxicity
Likelihood score
RemdesivirA duration of 7-14 d of administration caused elevation of serum aminotransferases up to > 5 times of ULN. Elevation of > 5 times ULN were reported in 9% of patients but returned to normal after discontinuation. Prolonged and more severe effects were seen in critically ill patients with multiorgan involvement, pre-existing comorbidities and who had received combination therapy with other hepatotoxic agents like amiodaroneD
Lopinavir/ritonavirA greater degree of rise in serum aminotransferase levels (> 5 times ULN) is mostly seen in association with immunodeficiency states. The pattern varies from hepatocellular to cholestatic or mixed type. Discontinuation leads to the normalization of enzyme levels. However, severe cases of acute liver failure or end stage liver disease are also reported with re-exposure of the drugD
TocilizumabReported to cause mild elevation of aminotransferases commonly, that is usually transient and asymptomatic, but rare instances of liver injury manifesting as jaundice and reactivation of hepatitis B are seen. ALT elevation (1-3 times ULN) was seen in 10%-50% of patients, which returned to baseline within 8 wk after stopping treatment. No effect on bilirubin or ALP levels were seenC
HydroxychloroquineClinically apparent liver injury is rare. In clinical trials for COVID-19 prevention and treatment, there were no reports of hepatotoxicity, and serum enzyme elevation was also lowC
CorticosteroidsLong-term use and high doses can result in hepatomegaly and steatosis. Can also trigger or exacerbate pre-existing or co-existing conditions like NASH, viral hepatitis or autoimmune hepatitis. Serum aminotransferase levels can rise up to 10-40 times ULNA
Enoxaparin4%-13% of patients showed mild elevation in serum aminotransferase levels. Rapid onset of liver injury symptoms after starting the drug (within 3-5 d) but rapid recovery (1-4 wk) after discontinuation of therapy is seenE
FavipiravirPretreatment with other hepatotoxic drugs like lopinavir/ritonavir and IF-β 1B lead to an increase in liver transaminase and bilirubin levels by manifold suggesting cholestatic injury. Isolated use is not known to cause any severe liver injuryD
Table 3 Mechanism of hepatic damage in severe acute respiratory syndrome coronavirus 2 infection
Proposed main mechanism
Explanation
Direct cytotoxicityActive SARS-CoV-2 replication in hepatic cells, which further binds to hepatic and biliary epithelial cells by angiotensin-converting enzyme 2 and damage them by direct infection[57]
Immunological damageSevere inflammatory response generated by SARS-CoV-2 further damages hepatic cells by immune mediated pathogenesis[58]
Drug-inducedAntiviral drugs such as remdesivir, chloroquine and ritonavir are possibly hepatotoxic[59]
Reactivation of pre-existing liver illnessIncreased risk to develop hepatotoxicity in the presence of pre-existing liver diseases. In addition, baricitinib also causes reactivation of hepatitis B virus infection[60]
AnoxiaAnoxia or hypoxia leads to respiratory failure in SARS-CoV-2, which further leads to hypoxic hepatitis[61]