Hepatic manifestations of COVID-19 and effect of remdesivir on liver function in patients with COVID-19 illness

Abstract

COVID-19 has emerged as a major global health crisis since the first cases were reported in China in December 2019. Remdesivir is the only broad-spectrum antiviral approved by the US Food and Drug Administration to treat hospitalized patients with COVID-19 infection. Although the adverse effects of remdesivir are largely unknown, data from randomized controlled trials have demonstrated its deleterious effect on the liver. This review briefly addresses the hepatic manifestations of COVID-19 infection and the data regarding the efficacy and adverse effects of remdesivir on liver function when used in patients hospitalized with COVID-19. Through a literature search, we identified five randomized controlled trials, two case reports, and one case series, including a total of 2375 patients. Although mild transaminase elevation has been reported as a feature of COVID-19, there has been a concern of hepatotoxicity associated with the use of remdesivir. Based on the limited available data regarding the adverse effects of remdesivir on hepatic function, it is prudent to exercise caution by evaluating baseline liver function, avoiding the use of potentially hepatotoxic drugs, and closely monitoring liver function when using remdesivir in patients hospitalized with COVID-19.

Keywords:

• Coronavirus
• COVID-19
• drug-induced liver injury
• elevated liver function tests
• hepatic dysfunction
• remdesivir
• SARS-CoV-2

Coronavirus disease 2019 (COVID-19), the illness caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), has emerged as the most significant global health crisis since the influenza pandemic of 1918. SARS-CoV-2 is a novel beta coronavirus belonging to the same subgenus as the severe acute respiratory syndrome (SARS-CoV) virus and Middle East respiratory syndrome coronavirus (MERS-CoV). It has a case fatality rate of 2.3% compared to 9.5% and 34.4% for SARS-CoV and MERS-CoV, respectively.¹ A meta-analysis of 50 studies reported that patients of Black and Asian ethnic minority groups are at increased risk of contracting SARS-CoV-2 infection compared with White patients.² The respiratory system is the primary organ system affected; however, COVID-19 is also frequently associated with the elevation of liver biochemistries in patients with or without clinical symptoms. Remdesivir is a broad-spectrum antiviral agent that is approved by the US Food and Drug Administration (FDA) for hospitalized patients with COVID-19. In this systematic review, we aim to present the latest data on hepatic manifestations of COVID-19 infection and the efficacy and potential hepatoxicity associated with remdesivir. We performed a literature search using Google Scholar and PubMed from January 2020 to October 2020 for studies describing hospitalized patients with COVID-19 who received remdesivir therapy.

PATHOGENESIS OF COVID-19–ASSOCIATED LIVER INJURY

COVID-19 is associated with elevation of liver biochemistries in 14% to 53% of patients; this elevation occurs more frequently in patients with severe COVID-19 illness than those with mild illness.^3–6 Numerous mechanisms have been hypothesized to explain the pathogenesis of liver injury associated with COVID-19, such as direct cytotoxicity due to virus replication in the liver, immune-mediated inflammatory response, hypoxia and ischemia due to severe sepsis, drug toxicity, and worsening of preexisting liver disease due to systemic illness.⁷

SARS-CoV-2 gains entry into host cells by binding of the SARS-CoV-2 spike protein to the angiotensin-converting enzyme 2 (ACE2) receptors.^8,9 However, the expression of ACE2 receptor in hepatocytes is limited.¹⁰ A recent study involving single-cell RNA sequential data analysis demonstrated the binding of the virus to ACE2 receptors in the cholangiocytes but not hepatocytes.¹¹ There was also significantly higher ACE2 expression in the cell clusters of cholangiocytes (59.7%) than hepatocytes (2.6%).¹¹ Contrary to the viral binding to the cholangiocytes, the liver injury in COVID-19 is primarily hepatocellular as opposed to a cholestatic, as evidenced by elevation in aspartate aminotransferase (AST) and alanine aminotransferase (ALT).¹² Viral hepatitis classically manifests with a hepatocellular injury that is ALT predominant; however, hepatocellular injury in COVID-19 appears to be AST predominant.¹²

Liver dysfunction has been reported in patients with severe bacterial sepsis.¹³ The hemodynamic compromise and severe systemic inflammation could contribute to the abnormal liver function noted in patients with severe COVID-19 infection. With the presence of other comorbid illnesses contributing to a higher risk of hospitalization, underlying metabolic syndrome and underrecognized nonalcoholic fatty liver disease could also be contributory factors. Also, COVID-19 patients with preexisting liver diseases are at a higher risk for decompensation and mortality based on the results of a US-based multicenter study that reported a mortality rate of 12% in COVID-19 patients with preexisting liver disease compared to 4% in those without.¹⁴ Various drugs (remdesivir, tocilizumab, acetaminophen, lopinavir-ritonavir, azithromycin, ivermectin) used in the management of COVID-19 are potential hepatoxic drugs, thus implying drug-induced liver injury in the pathogenesis. Notably, in a prospective multicenter study of liver transplant recipients, COVID-19 was associated with an overall and in-hospital fatality rate of 12% (95% CI 5%–24%) and 17% (95% CI 7%–32%), respectively.¹⁵

Postmortem histopathological examination of liver tissue in a deceased patient with COVID-19 demonstrated moderate microvesicular steatosis without any intranuclear or intracytoplasmic viral inclusions, which is not specific and can be attributable to sepsis or drug-induced liver injury or underlying nonalcoholic fatty liver disease.¹⁶ A prospective clinicopathologic case series study with postmortem histopathological exams of major organs of 11 deceased patients with COVID-19 reported findings of hepatic steatosis in all patients, with 73% of the liver specimens demonstrating chronic congestion. Different forms of hepatocyte necrosis were noted in four patients, and 70% of the patients’ liver specimens showed nodular proliferation. In summary, hepatic dysfunction in patients with COVID-19 is likely multifactorial and can be attributed to a combination of the hypotheses described above.

PHARMACODYNAMICS AND PHARMACOKINETICS OF REMDESIVIR

Remdesivir (GS-5734) is a pro-drug of a monophosphate nucleoside analog (GS-441524) and manifests as a viral RNA-dependent RNA polymerase (RdRp) inhibitor that targets the viral genome replication process. Hypothetically, nucleoside analogs are unable to permeate the cell wall easily. Upon gaining entry into the host cell, the adenosine nucleotide pro-drug is metabolized to a nucleoside monophosphate intermediate by carboxyesterase 1 and/or cathepsin A. The nucleoside monophosphate undergoes subsequent phosphorylation to produce nucleoside triphosphate, which resembles adenosine triphosphate and can be used by the RdRp enzymes or complexes for genome replication. After remdesivir is metabolized into the pharmacologic active analog adenosine triphosphate (GS-443902) by the host cells, it vies with adenosine triphosphate for integration by the RdRp complex into the nascent RNA strand and, upon subsequent integration of a few more nucleotides, results in termination of viral RNA synthesis.^17–21

The route of elimination, pharmacokinetics, drug-drug interactions, and safety of remdesivir in children and in women who are pregnant or breastfeeding is mostly unknown due to the absence of long-term studies. However, given the limited data available regarding the safety profile of remdesivir, clinicians should consider laboratory monitoring such as baseline renal function, hepatic function, and coagulation (prothrombin time) parameters before and after the initiation of remdesivir and closely monitor for any acute changes in clinical status and drug-drug reactions.¹⁹

EFFECT OF REMDESIVIR AGAINST SARS-COV-2

Remdesivir is an antiviral drug that has previously demonstrated broad-spectrum antiviral activity potential against SARS-CoV and MERS.²² In vitro and animal studies have also reported the potential benefit of remdesivir against SARS-CoV 2.²³ Based on data from three randomized controlled trials, remdesivir was approved by the FDA for treatment of hospitalized patients with COVID-19, both adults and pediatric patients 12 years of age or older and weighing at least 40 kg.²¹

EFFECT OF REMDESIVIR ON LIVER FUNCTION IN PATIENTS WITH COVID-19

Data regarding the potential hepatotoxicity of remdesivir is currently limited, and there are no specific studies conducted with its use in patients with hepatic impairment. On a cellular level, remdesivir has been demonstrated to be toxic to human hepatocytes, and the FDA has cautioned about the incidence of elevated liver enzymes in patients treated with remdesivir, indicating potential drug-induced liver injury.²⁴ Given the increase in the frequency of liver dysfunction in patients with COVID-19, the attribution of hepatotoxicity to remdesivir is indeed challenging. Mild (Grade 1) to moderate (Grade 2) transaminasemia was observed in healthy volunteers who received remdesivir, with resolution upon discontinuation of remdesivir.²⁵ Table 1 summarizes the published literature describing remdesivir-associated hepatotoxicity.^26–34

Table 1. Summary of the published literature describing remdesivir-associated hepatotoxicity

Author	Study design	Patients treated with RDV	Age (years)	Sex	IV RDV dose (mg)		Days of RDV exposure	Treatment of hepatotoxicity	Outcome
					Day 1	After
Holshue et al.^26	Case report	1	35	M	–	–	7	Supportive	Complete recovery
Carothers et al.^27	Case report	1	68	F	200	100	2	Acetylcysteine, withdrawal of medication	Complete recovery
Zampino et al.^28	Case series	5	NA	NA	200	100	10	NA	4 of 5 patients had normal or slight elevation in liver biochemistries with initiation of RDV
Grein et al.^29	Prospective study	53	64*	40 M 13 F	200	100	10	NA	RDV was discontinued in 2 patients due to significant elevation in aminotransferases
Antinori et al.^30	Prospective open-label	35	63*	26 M 9 F	200	100	10	NA	Grade 3–4 increase in transaminase levels observed in 42.8% of patients
Goldman et al.^31	Randomized, open label	397	61*	253 M 144 F	200	100	5 or 10	NA	RDV discontinued in 2.5% and 3.6% of patients in the 5-day and 10-day groups, respectively (grade 3–4 increase in transaminase levels)
Wang et al.^32	Randomized, double-blind, placebo-controlled	158	66*	89 M 69 F	200	100	10	NA	RDV discontinued in 2 patients due to grade 3 or 4 increase in ALT and in 1 patient due to increase in total bilirubin
Beigel et al.^33	Randomized, double-blind, placebo-controlled	541	59^†	352 M 189 F	200	100	10	NA	NA
Spinner et al.^34	Multicenter randomized, open-label	384	5-day group: 58* 10-day group: 56*	232 M 152 F	200	100	5 or 10	NA	Transaminase elevations were similar in all groups, with higher incidence of grade 3–4 elevation in standard-of-care treatment group

ALT indicates alanine aminotransferase; IV, intravenous; NA, not available; RDV, remdesivir.

* Median.

^† Mean.

Many case series and case reports have described mild elevation in transaminases with the use of remdesivir.^26–28 Increased liver transaminases were among the most common adverse effects noted in a prospective study examining the compassionate use of remdesivir in patients hospitalized with COVID-19 infection. In fact, remdesivir was discontinued in two patients due to significant elevation in serum aminotransferases.²⁹ Grade 3–4 elevation in serum transaminases occurred in 42.8% of patients treated with remdesivir in a prospective open-label study.³⁰ The SIMPLE-Severe trial (NCT04292899), which evaluated the efficacy and safety of 5- or 10-day dosing of remdesivir in patients hospitalized with severe COVID-19 disease, reported grade 3 and 4 elevation in serum transaminases with reported discontinuation of treatment in 2.5% and 3.6% of patients in the 5-day and 10-day groups, respectively.³¹

In a randomized, double-blind placebo-controlled multicenter trial that assessed the efficacy and safety of intravenous remdesivir in patients with severe COVID-19 infection, elevation in liver function tests was the most common adverse effect and remdesivir was discontinued in two patients due to grade 3 or 4 elevation in ALT.³² Findings from the ACTT-1(NTC04280705) trial, a multicenter randomized controlled trial to evaluate the therapeutic efficacy and safety of investigational therapeutic agents including remdesivir, reported an increase in aminotransferases in 4.1% of patients treated with remdesivir compared to 5.9% of patients who received placebo.³³ SIMPLE-Moderate trial (NCT04292730), a multicenter randomized controlled trial evaluating the efficacy and safety of remdesivir in a 5- or 10-day course of remdesivir or standard of care, reported that liver biochemistries were similar across all three groups, with a higher incidence of grade 3 and 4 transaminase elevation in patients who received standard-of-care treatment.³⁴

Before attributing the hepatic dysfunction to remdesivir, it is imperative to extensively evaluate other etiologies unrelated to COVID-19, such as viral hepatitis, potential hepatotoxic medications, and autoimmune disorders. Additionally, it is not recommended to presume disease flare or acute cellular rejection without a confirming biopsy in patients with preexisting liver disorders such as autoimmune hepatitis and liver transplant recipients, respectively.³⁵

In conclusion, the use of remdesivir in hospitalized patients with COVID-19 is associated with transient mild to moderate elevation in liver biochemistries with low discontinuation rates. It is prudent to perform baseline hepatic function testing in all patients before initiation of remdesivir, closely monitor liver function tests daily while on remdesivir therapy, and avoid using other potentially hepatotoxic drugs that can worsen liver function in patients hospitalized with COVID-19. The discontinuation of remdesivir infusions in de novo elevations in ALT or AST above 10 times the upper limit of normal should be considered.