Novel Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infection results predominantly in pulmonary involvement (Coronavirus disease 2019, COVID-19), but a direct, SARS-CoV-2-induced liver damage has also been described [1, 2]. Thus, it is important to monitor liver function and evaluate hepatic safety of drugs administered to COVID-19 patients. Remdesivir (RDV), a nucleotide analogue RNA polymerase inhibitor, originally developed and tested for Ebola virus disease, showed in vitro efficacy against SARS-CoV-2 [3], and experience on its efficacy and safety for COVID-19 is accumulating [4, 5]. However, hepatic safety of RDV in COVID-19 has not been the focus of detailed investigation. Here, we describe patterns of liver toxicity in 5 COVID-19 patients treated with RDV in the intensive care unit (ICU) of Monaldi Hospital, Naples, Italy, during March and April 2020. Overall, our Hospital cared for 32 critically ill COVID-19 patients.
Treatment was given in a compassionate use program (CPU) approved by our Ethics Committee. CPU was limited to the first 5 patients of our center who fulfilled all eligibility criteria (invasive mechanical ventilation, no multiorgan failure, no vasopressor requirement, ALT levels < 5 xULN, creatinine clearance > 30 mL/min). RDV was administered intravenously as a 200 mg loading dose, followed by 100 mg daily over 1 h for up to 9 days. According to the early recommendations of the Italian Society for Infectious Diseases, Lombardy section, all patients had been previously treated with lopinavir/ritonavir (LPV/r, 400/100 mg twice daily po). Before and during RDV treatment, 4 of 5 patients also received hydroxychloroquine (HCQ, 200 mg twice daily po). While on RDV, no patient received acetaminophen, patient 2 and 4 received ceftazidime–avibactam plus daptomycin and patient 3 meropenem and linezolid. None of the 5 treated patients had a previous 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 a history of hypertension and asthma, respectively, but were not receiving any relevant therapy in the ICU.
Figure 1 describes the dynamics of AST/ALT and bilirubin throughout the hospital stay, for each patient (Panels 1–5). In Panel 6, we report a comparison of median ALT and AST levels between RDV-treated patients and 5 COVID-19 patients who were treated in our Hospital ICU with the same schedule of LPV/r and HCQ, but without RDV. As shown in Panels 1–5, bilirubin increase occurred in 4 of 5 index patients on LPV/r. In contrast, the switch to RDV translated into a fast reduction of bilirubin and a significant increase in AST/ALT by day 3 of therapy in 4 of 5 patients. The single patient who did not receive HCQ with RDV (patient 4) did not show increase of ALT/AST levels. In no cases, RDV was discontinued because of liver injury. In patient 1, RDV was withdrawn at day 5 for a torsade de pointes requiring cardiac resuscitation, whereas patient 3 died on day 5 of RDV therapy. Final outcome was positive in 4/5 patients.
Our observation supports previous findings obtained in healthy volunteers (Gilead Sciences, data on file) and COVID-19 patients treated with RDV [4, 5], suggesting this antiviral may cause hepatocellular injury. In our patients, this adverse effect neither progressed to severe liver damage nor induced liver failure, although none had a prior chronic liver disease. Although SARS-CoV-2 infection can cause aminotransferase elevation per se, 4 of our 5 patients had normal or slightly elevated AST/ALT levels at RDV treatment start, suggesting a direct role of RDV in hepatocellular toxicity. Despite the overall low number of patients treated, we observed a clear trend of bilirubin elevation with LPV/r and ALT/AST elevation with RDV. Our observation suggests RDV can be used with close monitoring of liver function tests and with caution in subjects with prior liver disease.
References
Zhao D, Yao F, Wang L, Zheng L, Gao Y, Ye J, et al. A comparative study on the clinical features of COVID-19 pneumonia to other pneumonias. Clin Infect Dis. 2020. https://doi.org/10.1093/cid/ciaa247(pii:ciaa247).
Xu L, Liu J, Lu M, Yang D, Zheng X. Liver injury during highly pathogenic human coronavirus infections. Liver Int. 2020. https://doi.org/10.1111/liv.14435.
Chan KW, Wong VT, Tang SCW. COVID-19: an update on the epidemiological, clinical, preventive and therapeutic evidence and guidelines of integrative Chinese-western medicine for the management of 2019 novel coronavirus disease. Am J Chin Med. 2020;13:1–26. https://doi.org/10.1142/S0192415X20500378.
Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A, et al. Compassionate use of remdesivir for patients with severe covid-19. N Engl J Med. 2020. https://doi.org/10.1056/NEJMoa2007016.
Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020. https://doi.org/10.1016/S0140-6736(20)31022-9.
Acknowledgements
Authors thank Gilead Sciences for providing Remdesivir for compassionate use.
Funding
Remdesivir was provided by Gilead Sciences in a compassionate use program approved by EMA and our Institution Ethics Committee. No specific funding was received.
Author information
Authors and Affiliations
Contributions
RZ, AC, EDM worked on concept of the study; FM, LLF, LB, RA, MG worked on data collection and data interpretation; RDR, RZ and EDM drafted the manuscript; all authors critically revised the manuscript.
Corresponding author
Ethics declarations
Conflicts of interest
The authors declared that they have no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Zampino, R., Mele, F., Florio, L.L. et al. Liver injury in remdesivir-treated COVID-19 patients. Hepatol Int 14, 881–883 (2020). https://doi.org/10.1007/s12072-020-10077-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12072-020-10077-3