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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Remdesivir

Last Update: November 4, 2020.

OVERVIEW

Introduction

Remdesivir is an antiviral nucleotide analogue used for therapy of severe novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome (SARS) coronavirus 2 (CoV-2) infection. Remdesivir therapy is given intravenously for 5 to 10 days and is frequently accompanied by transient, reversible mild-to-moderate elevations in serum aminotransferase levels but has been only rarely linked to instances of clinically apparent liver injury, its hepatic effects being overshadowed by the systemic effects of COVID-19.

Background

Remdesivir (rem de’ si vir) is a phosphoramidate prodrug of a substituted nucleotide analogue of adenosine which has potent activity against the SARS-CoV-1 and SARS-CoV-2 encoded RNA dependent RNA polymerases. Remdesivir is not well absorbed orally and must be given by intravenous infusion. Once absorbed into cells, remdesivir is modified by cellular esterases and then converted by kinases to the active triphosphate, which competes with ATP for incorporation into the nascent viral RNA chain resulting in “delayed” chain termination. In animal models of SARS-CoV-2 infection, prophylactic or early treatment with remdesivir ameliorated the subsequent viral infection and clinical disease. In a large, multinational randomized, placebo-controlled trial in humans, remdesivir was found to shorten the time to clinical recovery in patients hospitalized with COVID-19, but had little effect on overall mortality. In other studies, the effects of remdesivir on time to recovery were less clear and mortality rates as well as SARS-CoV-2 RNA levels were similar to those on placebo or no therapy. Soon after the initial favorable reports of remdesivir therapy of severe COVID-19, it received emergency use authorization (EUA) approval for therapy of patients hospitalized with severe COVID-19 which was later extended to all hospitalized patients with COVID-19, both adults and children. After the final results were obtained and a more in-depth review, remdesivir was given formal approval for use in hospitalized adults and children (12 years of age or older and above 40 kilograms in weight) with COVID-19. Currently, it is being actively evaluated for efficacy and safety in treating milder and earlier stages of SARS-CoV-2 infection. In addition, an inhaled nebulized form of remdesivir is under development. Remdesivir is available in single-use vials of 100 mg, both as lyophilized powder and in solution (5 mg/mL) under the brand name Veklury. The typical intravenous dose in adults and children above the age of 12 is 200 mg on day one and 100 mg once daily thereafter for 5 to 10 days. Adverse events of remdesivir therapy include mild-to-moderate degrees of nausea and vomiting, headache, fatigue, renal dysfunction, serum aminotransferase elevations and rash. Rare instances of hypersensitivity reactions, acute renal dysfunction and liver injury have been reported.

Hepatotoxicity

In human volunteer studies, remdesivir therapy given for 7 to 14 days was associated with minor serum aminotransferase elevations (less than 5 times ULN) but without other evidence of hepatic injury. In controlled trials of remdesivir in patients hospitalized with COVID-19, rates of serum ALT elevations were similar or lower in patients receiving remdesivir than in those on placebo. Nevertheless, in most uncontrolled studies and case series, between 10% and 50% of patients treated with remdesivir developed transient, mild-to-moderate serum ALT and AST elevations within 1 to 5 days of starting therapy without changes in serum bilirubin or alkaline phosphatase levels. Elevations above 5 times ULN were reported in up to 9% of patients in several clinical trials, but the abnormalities resolved with discontinuation and were not associated with clinically apparent injury. With more widespread use of remdesivir for COVID-19, rare instances of marked ALT elevations with jaundice have been reported, but largely in patients who were critically ill with multi-organ failure or sepsis, or who had received other potentially hepatotoxic agents such as intravenous amiodarone (Case 2). Confounding the issue is that serum aminotransferase elevations are common during symptomatic SARS-CoV-2 infection (Case 1), present in up to 60% of patients and being more frequent in patients with severe disease and in those with the known risk factors for COVID-19 severity such as male sex, older age, higher body mass index and diabetes. Thus, serum aminotransferase elevations are common during remdesivir therapy but are generally asymptomatic, fully reversible and not associated with jaundice. With more widespread use of this antiviral in patients without severe or critical illness and with longer courses of therapy, features of hepatotoxicity may become more evident.

Likelihood score: D (possible uncommon cause of clinically apparent liver injury).

Mechanism of Injury

Serum aminotransferase elevations are not uncommon with parenterally administered remdesivir and may be caused by direct toxicity possibly due to inhibition of mitochondrial RNA polymerase. On the other hand, idiosyncratic injury due to remdesivir has not been clearly shown. SARS-CoV-2 virus may infect the liver and has been identified in hepatocytes by molecular techniques and electron microscopy, but the associated liver injury in these cases was mild. The receptor for SARS-CoV-2, the angiotensin-converting enzyme 2 (ACE2), is found on the surface of hepatocytes, although it is present in higher density on cholangiocytes. In the liver, remdesivir is metabolized by and is a substrate for CYP 3A4. It is also a substrate of the hepatocyte transporters p-glycoprotein and OATP1B1 and thus may be susceptible to drug-drug interactions with agents that inhibit or induce these enzymes and transporters.

Outcome and Management

The ALT and AST elevations associated with initiation of remdesivir therapy in patients with SARS-CoV-2 infection are generally mild-to-moderate in severity and self-limited in course without jaundice or symptoms. Careful monitoring of liver tests is recommended before and frequently during treatment. De novo elevations in ALT or AST above 10 times the upper limit of normal should lead to early discontinuation of the infusions. Restarting treatment can be considered once enzyme levels fall sufficiently, if there is no jaundice or symptoms and with careful monitoring. Use of other known hepatotoxins or potent inhibitors of p-glycoprotein should be avoided during remdesivir therapy.

Drug Class: Antiviral Agents; Nucleoside Analogues

CASE REPORTS

Case 1. Acute anicteric hepatitis attributed to SARS-CoV-2 infection.(1)

A 59 year old woman with HIV infection (well controlled on antiretroviral therapy), hypertension, hyperlipidemia and Graves disease presented to an emergency room with fatigue and dark urine. She denied jaundice, abdominal pain, itching, rash or fever. Laboratory evaluation showed elevations in liver tests that had previously been normal including ALT 617 U/L, AST 1230 U/L, alkaline phosphatase 141 U/L, bilirubin 0.6 mg/dL, albumin 3.1 g/dL and INR 1.7. She had no history of liver disease or known recent exposures to viral hepatitis. Her other medications included Genoya (elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide), clonidine, amlodipine, propranolol, hydrochlorothiazide, levothyroxine, fish oil and multivitamins. She was admitted for evaluation. She was afebrile and physical examination was normal. Tests for hepatitis A, B, C and E were negative as were assays for cytomegalovirus and Epstein Barr virus infection. Abdominal ultrasound showed a normal appearing liver without evidence of biliary obstruction or gallstones. A liver biopsy was not done. On hospital day 2 she developed fever and was found to have an oxygen saturation of 94% on room air. A nasopharyngeal swab was taken and proved to be positive for SARS-CoV-2 viral RNA. She was treated with hydroxychloroquine and remained minimally symptomatic and was discharged on hospital day 8, liver test abnormalities having improved but remaining mildly elevated.

Key Points

Medication:Not applicable
Pattern:Hepatocellular (R=12.3)
Severity:Mild (anicteric)
Latency:Not applicable
Recovery:Unclear
Other medications:Clonidine, hydrochlorothiazide, emtricitabine, tenofovir, elvitegravir, cobicistat

Laboratory Values

Day of
Hospitalization
ALT
(U/L)
AST
(U/L)
Alk P
(U/L)
Bilirubin
(mg/dL)
Other
169712301410.6INR 1.08
26751020145
36901125195
4640820201
5530605205
6480480230
7370205259
82271102500.6INR 1.13, discharged
Normal<50<50<125<1.2

Comment

This 59 year old woman developed an acute, mildly symptomatic hepatitis during an early, presymptomatic phase of SARS-CoV-2 infection. Other causes of acute liver injury were excluded and the episode was attributed to the SARS-CoV-2 infection. A striking finding was the predominance of AST over ALT elevations, a pattern that occurs with acute alcoholic hepatitis but is rare in acute hepatocellular injury due to medications or viral hepatitis. On the other hand, the aminotransferases were higher and the time to recovery was more rapid than occurs typically in acute alcoholic hepatitis. The case report did not mention alcohol use and liver biopsy was not done. One possible explanation for the prominent AST elevation was that part of the injury was due to muscle involvement. Transient elevations in serum aminotransferase levels are not uncommon during the course of symptomatic COVID-19 and in some cases AST elevations are greater than those of ALT. The degree of severity of the liver injury usually correlates with the degree of severity of the SARS-CoV-2 infection and occurs most frequently in men, the elderly and persons with obesity and diabetes. The occurrence of hepatic injury during the course of COVID-19 makes diagnosis of drug induced injury from therapies such as remdesivir challenging.

Case 2. Marked serum aminotransferase elevations and jaundice during remdesivir therapy of SARS-CoV-2 infection.(2)

A 68 year old woman with hypertension, diabetes, hyperlipidemia and coronary artery disease developed shortness of breath and chest pain and was hospitalized with suspected COVID-19 pneumonia. She was hypoxemic and had diffuse interstitial infiltrates but nasopharyngeal samples were negative for SARS-CoV-2 RNA. She had worsening symptoms and on day 4 underwent cardiac catheterization which showed severe, multivessel coronary artery disease. On day 6 she underwent successful 4-vessel coronary artery bypass surgery, but a repeat nasopharyngeal sample taken that day was positive for SARS-CoV-2, and she was transferred to a COVID-19 ward. Over the next few days, she had worsening oxygen requirements and pulmonary infiltrates and was started on remdesivir (200 mg loading dose followed by 100 mg daily intravenously). The following day she developed atrial fibrillation and was started on amiodarone infusions (150 mg loading dose, followed by 6 hours of 1.0 mg/min, followed by maintenance dosing of 0.5 mg/min). One day later serum ALT levels were above 5000 U/L and both remdesivir and amiodarone were stopped and intravenous N-acetyl cysteamine (iv NAC) was given. Her liver tests improved over the ensuing few days (Table) and she was discharged 2 weeks later.

Key Points

Medication:Remdesivir
Pattern:Hepatocellular (R=~100)
Severity:Moderate
Latency:2 days
Recovery:Improvements over next two weeks
Other medications:Amiodarone intravenously

Laboratory Values

Time After
Starting
ALT
(U/L)
AST
(U/L)
Bilirubin
(mg/dL)
Other
-7 days21Admitted with shortness of breath
-4 days15
Day 1-Started remdesivir
Day 2115Started amiodarone
Day 3>5000>50003.1INR 2.3: stopped drugs; IV NAC given
Day 42825>5000IV NAC given
Day 518611348
Day 79662352.1
Day 9469
Day 11211
Day 13120
Day 1750NormalINR normal, discharged
NormalNot givenNot given<1.2

Comment

A 68 year old woman suffered an acute coronary syndrome complicated by concurrent COVID-19. Therapy with remdesivir and amiodarone was rapidly followed by marked elevations in serum ALT and AST which fell after stopping both drugs (and administration of N-acetylcysteine). The marked elevations in both ALT and AST within 2 days of starting remdesivir is distinctly unusual and might well have been due to amiodarone that was started at about the same time. One possible explanation for the severity of the injury is that amiodarone altered the pharmacokinetics of remdesivir which is secreted from hepatocytes by p-glycoprotein, a hepatic transporter which is inhibited by amiodarone. A similar drug-drug interaction with precipitous adverse events occurs with the combination of sofosbuvir (another nucleoside analogue inhibitor of a viral RNA polymerase) and amiodarone, which results in severe bradycardia. Another explanation for the marked aminotransferase elevations would be shock, hypotension or hypoxemia which would cause acute hepatic necrosis. The case report is also somewhat unclear in regard to timing of the medications and the laboratory results.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Remdesivir – Veklury ®

DRUG CLASS

Antiviral Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Remdesivir1809249-37-3C27-H35-N6-O8-Pimage 328083432 in the ncbi pubchem database

CITED REFERENCES

1.
Wander P, Epstein M, Bernstein D. COVID-19 presenting as acute hepatitis. Am J Gastroenterol. 2020;115:941–2. [PMC free article: PMC7172489] [PubMed: 32301760]
2.
Carothers C, Birrer K, Vo M. Acetylcysteine for the treatment of suspected remdesivir-associated acute liver failure in COVID-19: a case series. Pharmacotherapy. 2020 Oct 2; Epub ahead of print. [PMC free article: PMC7537093] [PubMed: 33006138] [CrossRef]

ANNOTATED BIBLIOGRAPHY

References updated: 04 November 2020

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    (Among 584 patients hospitalized with confirmed SARS-CoV-2 pneumonia, clinical improvements at day 11 were more frequent in patients randomized to 5 days of remdesivir vs 10 days of remdesivir and vs standard of care [70% vs 65% vs 61%], while 28 day mortality was similar in all 3 groups [1% vs 2% vs 2%], although severe adverse events were less in those on remdesivir [5% vs 5% vs 9%] including any ALT elevation [34% vs 32% vs 39%] and those above 5 times ULN [2% vs 3% vs 8%]; no mention of clinically apparent hepatotoxicity).
  • Ferron PJ, Gicquel T, Mégarbane B, Clément B, Fromenty B. Treatments in COVID-19 patients with pre-existing metabolic dysfunction-associated fatty liver disease: a potential threat for drug-induced liver injury? Biochimie 2020: S0300-9084(20)30203-0. [PMC free article: PMC7468536] [PubMed: 32891697]
    (Commentary on possible hepatotoxicity of drugs used to treat SARS-CoV-2 infection and possible increase in risk for injury among patients with preexisting fatty liver disease).
  • Carothers C, Birrer K, Vo M. Acetylcysteine for the treatment of suspected remdesivir-associated acute liver failure in COVID-19: a case series. Pharmacotherapy. 2020 Oct 2; Epub ahead of print. [PMC free article: PMC7537093] [PubMed: 33006138] [CrossRef]
    (Two patients, ages 68 and 80, with severe SARS-CoV-2 pneumonia developed abnormal liver tests during or shortly after a course of remdesivir, one arising 2 days after starting remdesivir and 1 day after starting intravenous amiodarone [Case 2: bilirubin 3.1 mg/dL, ALT 2400 U/L, INR 2.3], and one arising 4 days after stopping a 5 day course of remdesivir and concurrent with suspected septic shock [bilirubin 2.1 mg/dL, ALT 1510 U/L, Alk P 151 U/L, INR 1.7], both treated with acetylcysteine infusions with apparent improvement).
  • FDA Fact Sheet for Health Care Providers. Emergency use authorization (EUA) of Veklury® (remdesivir) https://www​.fda.gov/media​/137566/download.
    (Fact sheet on remdesivir from the FDA recommends monitoring of routine liver tests before and daily during remdesivir therapy, not initiating therapy if values are above 5 times ULN and discontinuing therapy if they rise to above 5 times ULN, restarting when values fall below this level).
  • RECOVERY Collaborative Group, Horby P, Mafham M, Linsell L, Bell JL, Staplin N, Emberson JR, Wiselka M, et al. Effect of hydroxychloroquine in hospitalized patients with COVID-19. N Engl J Med 2020 Oct 8:NEJMoa2022926. Epub ahead of print. [PMC free article: PMC7556338] [PubMed: 33031652]
    (Among 1561 patients randomized to receive hydroxychloroquine vs 3155 randomized to standard care, the mortality rate was similar in the two groups [27% vs 25%] and cardiovascular toxicity was not increased with the active drug; no mention of ALT elevations or hepatotoxicity).
  • Dyer O. Covid-19: Remdesivir has little or no impact on survival, WHO trial shows. BMJ. 2020;371:m4057. [PubMed: 33077424]
    (Editorial on the results of the large WHO-supported Solidarity Trial comparing four different promising agents to no therapy in 11,266 adults hospitalized with COVID-19 demonstrating no difference in 28 day mortality with remdesivir therapy [301/2708: 11.1%] compared to no treatment [301/2743: 11.0%], nor in rates of requiring mechanical ventilation or in duration of hospitalization).
  • Baang JH, Smith C, Mirabelli C, Valesano AL, Manthei DM, Bachman M, Wobus CE, et al. Prolonged SARS-CoV-2 replication in an immunocompromised patient. J Infect Dis. 2020 Oct 22; Epub ahead of print. [PMC free article: PMC7797758] [PubMed: 33089317]
    (60 year old man with refractory lymphoma on chemotherapy [including mosunetuzumab] developed persistent SARS CoV-2 infection with repeated bouts of pulmonary symptoms and persistent nasopharyngeal RNA and virus [molecularly identical] despite two courses of remdesivir and convalescent plasma, being still SARS CoV-2 positive at 156 days when he was referred for hospice care).
  • Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, Hohmann E, et al. ACTT-1 Study Group Members. Remdesivir for the treatment of COVID-19 – final report. N Engl J Med. 2020;383:1813–26. [PMC free article: PMC7262788] [PubMed: 32445440]
    (Final report of a randomized, placebo controlled trial of remdesivir infusions for 10 days in 1062 adults hospitalized with COVID-19 pneumonia found treatment resulted in more rapid recovery time [10 vs 15 days] and slightly lower mortality at 29 days [11.4% vs 15.2%], while adverse events were less frequent with the active drug including serious adverse events [24% vs 32%], and elevations in serum ALT [2.3% vs 4.7%], AST [3.4% vs 6.4%] and bilirubin [1.7% vs 3.1%]; no mention of clinically apparent liver injury).
  • Goldman JD, Lye DCB, Hui DS, Marks KM, Bruno R, Montejano R, Spinner CD, et al. GS-US-540-5773 Investigators. Remdesivir for 5 or 10 days in patients with severe COVID-19. N Engl J Med. 2020;383:1827–37. [PMC free article: PMC7377062] [PubMed: 32459919]
    (Among 297 patients with severe SARS-CoV-2 pneumonia treated with 5 or 10 days of intravenous remdesivir, rates of clinical improvement were similar in the two groups and adverse events included nausea [9%], constipation [7%] and ALT elevations above 5 times ULN [7%]; therapy was discontinued early because of enzyme elevations in 3% but no mention of clinically apparent hepatotoxicity).
  • Humeniuk R, Mathias A, Cao H, Osinusi A, Shen G, Chng E, Ling J, Vu A, German P. Safety, tolerability, and pharmacokinetics of remdesivir, an antiviral for treatment of COVID-19, in healthy subjects. Clin Transl Sci. 2020;13:896–906. [PMC free article: PMC7361781] [PubMed: 32589775]
    (Results of phase 1 studies of remdesivir in healthy subjects, found ALT or AST elevations in 2 subjects treated for 7 days and 6 of 8 treated for 14 days, but all elevations were asymptomatic, mild [less than 5 times ULN], transient and not associated with bilirubin or alkaline phosphatase elevations).
  • Zeitlinger M, Koch BCP, Bruggemann R, De Cock P, Felton T, Hites M, Le J, et al. PK/PD of Anti-Infectives Study Group (EPASG) of the European Society of Clinical Microbiology, Infectious Diseases (ESCMID). Pharmacokinetics/pharmacodynamics of antiviral agents used to treat SARS-CoV-2 and their potential interaction with drugs and other supportive measures: a comprehensive review by the PK/PD of Anti-Infectives Study Group of the European Society of Antimicrobial Agents. Clin Pharmacokinet. 2020;59:1195–1216. [PMC free article: PMC7385074] [PubMed: 32725382]
    (Review of the pharmacology and potential of drug-drug interaction of remdesivir).
  • Sabers AJ, Williams AL, Farley TM. Use of remdesivir in the presence of elevated LFTs for the treatment of severe COVID-19 infection. BMJ Case Rep. 2020;13(10):e239210. [PMC free article: PMC7783372] [PubMed: 33130588]
    (82 year old man with COVID-19 treated initially with hydroxychloroquine and azithromycin was admitted with pulmonary symptoms and found to have abnormal liver tests [bilirubin 1.1 mg/dL, ALT 1075 U/L, Alk P not given], which worsened for one day and then improved rapidly despite initiation of therapy with remdesivir as well as use of convalescent plasma, dexamethasone, levofloxacin, ceftriaxone and amiodarone [while stopping hydroxychloroquine and azithromycin], with clinical improvement and near normal ALT levels by day 7).
  • Rahimi MM, Jahantabi E, Lotfi B, Forouzesh M, Valizadeh R, Farshid S. Renal and liver injury following the treatment of COVID-19 by remdesivir. J Nephropathol. 2021;10(2):e10. http://www​.nephropathol​.com/Files/Inpress/jnp-17106.pdf
    (Review of the renal handling of remdesivir and cautionary note on use of remdesivir in patients with renal dysfunction because of an increased risk of further renal dysfunction and hepatic adverse events).

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