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Impact of COVID-19 on the liver and on the care of patients with chronic liver disease, hepatobiliary cancer, and liver transplantation: An updated EASL position paper
Oxford Liver Unit, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UKNuffield Department of Medicine, Translational Gastroenterology Unit, University of Oxford, Oxford, UK
Center for Vaccinology and Neonatal Immunology, Department of Pathology and Immunology, University of Geneva, SwitzerlandDivision of General Pediatrics, Department of Woman, Child and Adolescent Medicine, Faculty of Medicine, University of Geneva, Center for Vaccinology, Geneva University Hospitals, Geneva, Switzerland
Liver Transplantation and Hepatology Unit and Ciberehd, IISLaFe and Hospital Universitario y Politécnico La Fe, Valencia, SpainDepartment of Medicine, Universitat de València, Valencia, Spain
Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London and European Foundation for the Study of Chronic Liver Failure, Barcelona
Division of Clinical Immunology and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo and Department of Internal Medicine and Therapeutics, University of Pavia, Italy
European Foundation for the Study of Chronic Liver Failure, Barcelona, SpainService d’Hépatologie, Hôpital Beaujon, APHP, Clichy, FranceCentre de Recherche sur l’Inflammation, INSERM and Université de Paris Cité, Paris, France
Centre for Individualised Infection Medicine (CiiM), a joint venture between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, GermanyDepartment of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, GermanyGerman Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Germany
The COVID-19 pandemic has presented a serious challenge to the hepatology community, particularly healthcare professionals and patients. While the rapid development of safe and effective vaccines and treatments has improved the clinical landscape, the emergence of the omicron variant has presented new challenges. Thus, it is timely that the European Association for the Study of the Liver provides a summary of the latest data on the impact of COVID-19 on the liver and issues guidance on the care of patients with chronic liver disease, hepatobiliary cancer, and previous liver transplantation, as the world continues to deal with the consequences of the COVID-19 pandemic.
Since the onset of the COVID-19 pandemic in early 2020, the European Association for the Study of the Liver (EASL) has published several position papers designed to provide guidance on the care of adult patients with liver diseases.
As the landscape of COVID-19 continues to change, particularly with the emergence of new strains of SARS-CoV-2 and the development of novel treatment and vaccination strategies, there is an urgent need to provide updated information for clinicians and researchers. By the end of 2021, the B.1.1.529 (omicron) SARS-CoV-2 variant displaced the B.1.617.2 (delta) variant as the predominant circulating strain in many countries.
Comparison of total and neutralizing SARS-CoV-2 spike antibodies against omicron and other variants in paired samples after two or three doses of mRNA vaccine.
Whilst our understanding of omicron continues to evolve rapidly, a majority of the EASL position statements in this document are based on data derived from the pre-omicron era. Therefore, at present, it is not clear whether all recommendations may also apply to omicron or indeed to any future variants or subvariants which may arise. Finally, prior infection with omicron may not provide adequate protection against earlier variants (such as delta) or new variants unless COVID-19 vaccination has been optimised.
Despite these caveats, this position paper seeks to review all the available data, comprehensively summarise the liver-specific effects of SARS-CoV-2 infection, and highlight important care considerations for patients with COVID-19 and chronic liver disease (CLD), hepatobiliary cancer, and previous liver transplantation.
Liver-related complications of SARS-CoV-2 infection
Acute liver injury during COVID-19
Acute liver injury indicated by abnormal liver biochemistry parameters is common (occurring in 10–65% of individuals) during the course of COVID-19.
These abnormalities are usually characterised by mild elevations in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), whereas severe liver injury with raised bilirubin and hepatic synthetic dysfunction is rare. The cause of liver injury during COVID-19 is likely multifactorial with contributions from systemic inflammation, cytokine signalling, ischaemia, and drug toxicity. Alongside this ‘bystander’ hepatitis, SARS-CoV-2 may cause direct liver injury via infection of hepatocytes. Multimodal investigations of autopsy liver tissue from patients with severe COVID-19 have convincingly demonstrated intrahepatic SARS-CoV-2 RNA alongside consistent molecular signatures associated with viral infections, suggesting that SARS-CoV-2 may trigger immunopathology directly in the liver.
although there is some inconsistency across studies. The longer-term trajectory of abnormal liver biochemistry following recovery from COVID-19 remains incompletely defined. In a large cohort of patients with COVID-19 who were hospitalised and then subsequently discharged, 43% had liver biochemistry abnormalities at the point of admission and 32% still showed abnormalities at the point of discharge suggesting that resolution of liver injury may lag behind recovery from respiratory symptoms.
The time taken for complete normalisation of liver biochemistry has not been systematically investigated but persisting abnormalities following complete recovery from COVID-19 may indicate undiagnosed pre-existing CLD.
EASL position
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Liver parameters (including AST, ALT, gamma-glutamyltransferase (GGT), alkaline phosphatase (ALP) and bilirubin should be regularly assessed during hospitalisation with COVID-19.
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Ongoing monitoring may be required after hospital discharge in patients with persistent elevations in liver biochemistry parameters.
Secondary sclerosing cholangitis after COVID-19
As discussed above, liver biochemistry abnormalities, particularly elevations in ALT and AST levels are common during the course of COVID-19 and are most likely multifactorial.
In contrast, cholestasis, characterised by elevated bilirubin and ALP is not typically identified during acute COVID-19. Interestingly, this is despite cholangiocytes exhibiting high SARS-CoV-2 entry receptor expression and viral permissibility in vitro.
However, over the course of the pandemic several case series have reported delayed-onset and progressive cholestasis as a unique clinical entity in patients following severe, and often critical, COVID-19. Furthermore, this may be a more frequent complication in patients with pre-existing CLD.
In a European cohort of 34 patients with COVID-19 who required admission to the intensive care unit (ICU), 9 (27%) developed severe cholestasis (total bilirubin ≥2x upper limit of normal [ULN]) of whom 4 (44%) subsequently developed features of secondary sclerosing cholangitis (SSC) defined by bile duct irregularities and strictures on magnetic resonance cholangiopancreatography (MRCP).
Of these 4 patients with SSC, 2 died from respiratory failure, 1 developed decompensated cirrhosis and was listed for transplantation, and 1 had persistently elevated ALP 9 months after discharge from ICU. Notably, in a historic cohort of 34 patients admitted to ICU with influenza A, only 6% developed severe cholestasis and none exhibited features of SSC.
Similarly, in a single-centre North American study, 12 patients admitted to the ICU with severe COVID-19 subsequently developed delayed-onset cholestasis (ALP >3x ULN) with associated MRCP abnormalities.
This clinical picture was present in <0.6% of all patients hospitalised with COVID-19. Five of these patients were ultimately referred for consideration of liver transplantation after experiencing persistent jaundice, hepatic insufficiency, and/or recurrent bacterial cholangitis. Across both cohorts, organ support requirements during COVID-19 were strongly associated with the development of cholestasis. Indeed, patients who developed SSC had protracted ICU stays (36-138 days) with long periods of prone ventilation, and high respiratory support and vasopressor requirements, with a substantial proportion receiving extracorporeal membrane oxygenation (ECMO). The mean interval between COVID-19 diagnosis and the onset of cholangiopathy was 93 and 118 days in European and American cohorts, respectively. In patients where a liver biopsy was performed, histological features included large duct obstruction (but without definite bile duct loss), portal tract oedema, lobular biliary infarcts, and hepatocellular cholestasis.
In a retrospective study from Austria, approximately 20% of patients with CLD developed progressive cholestasis following SARS-CoV-2 infection, with 10/65 (15%) meeting criteria for SSC. Seventy percent of these patients with SSC had non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), 90% were treated with ursodeoxycholic acid, all patients had severe COVID-19 requiring ICU admission and 50% died.
Notably in both European series, >90% of patients who developed severe cholestasis or SSC were exposed to ketamine as an anaesthetic agent in the ICU.
acute biliary injury in the context of critical illness is less well recognised. However, since the onset of the pandemic several case reports and series have postulated a mechanistic link between ketamine use and cholangiopathy following COVID-19.
Keta-Cov research group. Electronic address: [email protected], Keta-Cov research group Intravenous ketamine and progressive cholangiopathy in COVID-19 patients.
Critical illness-SSC has long been recognised as a distinct pathological entity typically developing after burns, polytrauma, complex surgery, hypovolemic shock or other life-threatening diseases including influenza-associated acute respiratory distress syndrome.
Abdominal obesity and prolonged prone positioning increase risk of developing sclerosing cholangitis in critically ill patients with influenza A-associated ARDS.
Whether SSC observed in the context of COVID-19 constitutes a distinct clinical entity or simply reflects a continuum of critical illness-SSC remains unclear. However, the relatively high prevalence of cholangiopathy following critical COVID-19 may implicate SARS-CoV-2-specific biliary tropism and injury.
EASL position
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Patients admitted to ICU with critical COVID-19 who develop severe cholestasis should undergo MRCP during the disease course (where possible) and monitoring of liver biochemistry for at least 3 months following ICU discharge to check for SSC.
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Where possible, ketamine may be avoided as a sedating agent in patients with CLD and critical COVID-19 who require ICU admission.
Autoimmune and autoimmune-like hepatitis after COVID-19
The relationship between autoimmunity and COVID-19 is complex.
Some of the clinical manifestations of COVID-19, including hyperinflammation and macrophage activation, can resemble the immunopathology of various autoimmune diseases such as juvenile idiopathic arthritis and systemic lupus erythematosus.
De novo autoimmunity following SARS-CoV-2 infection is also well recognised, manifesting in a range of clinical phenomena including systemic lupus erythematosus, immune thrombocytopenic purpura, Guillain-Barré syndrome, and autoimmune/autoimmune-like hepatitis (AIH).
(Table 1). In each case, a diagnosis of AIH was made based on characteristic laboratory parameters including elevated transaminases, IgG, and the presence of associated autoantibodies. Liver biopsy was performed in 3 patients, all of whom demonstrated typical histological features of AIH, including lymphoplasmacytic inflammation and interface hepatitis. Most cases occurred within 1 month of mild COVID-19 and responded well to immunosuppressive therapy. Beyond these isolated reports, the broader population-level epidemiology of autoimmune liver disease during the pandemic remains to be determined, including both the incidence of de novo AIH and flares in those with pre-existing AIH. Prospective series have demonstrated a high prevalence of tissue-specific autoantibodies during or soon after recovery from COVID-19, including smooth muscle antibody and antinuclear antibody positivity in up to 30% and 44%, respectively.
However, the longer-term clinical significance of these autoantibodies remains unclear. Given that new-onset clinically overt AIH appears rare and may occur even following mild COVID-19, we cannot currently recommend routine monitoring for this condition in all patients following SARS-CoV-2 infection.
EASL position
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De novo AIH may rarely occur following SARS-CoV-2 infection.
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Routine monitoring for this condition in all patients recovering from COVID-19 is not required.
Table 1Case reports of de novo AIH following COVID-19.
Risk stratification and disease course of SARS-CoV-2 infection in patients with CLD, hepatobiliary cancer, and liver transplant recipients
CLD and cirrhosis
During the first wave of the pandemic, patients with CLD and cirrhosis were not found to be over-represented in large COVID-19 case series and population studies, suggesting that these conditions were unlikely to increase susceptibility to infection.
Cirrhosis and severe acute respiratory syndrome coronavirus 2 infection in US veterans: risk of infection, hospitalization, ventilation, and mortality.
This most likely reflects heightened vigilance and greater patient adherence to public health advice although interpretations are limited by retrospective design and lack of adjustment for certain relevant cofactors including socioeconomic status and occupational exposure. However, once patients with cirrhosis acquire SARS-CoV-2 infection it has become clear that they are at increased risk of adverse COVID-19 outcomes including death.
Overall mortality in patients with cirrhosis following SARS-CoV-2 infection was found to be 32% in a large registry cohort of 729 predominantly hospitalised patients with CLD across 29 countries, with case fatality rates incrementally increasing with each Child-Pugh (CP) class (CLD without cirrhosis; 8%, CP-A; 19%, CP-B; 35%, CP-C; 51%).
Similar stepwise trends were observed in the rates of ICU admission, renal replacement therapy, and invasive mechanical ventilation. Furthermore, the risk of mortality in those with decompensated cirrhosis was significantly elevated compared to that in patients without CLD, after matching for age and comorbidity. Decompensated cirrhosis was also shown to be an independent risk factor for death based on outcome data from patients with CLD across 21 North American institutions.
Pre-existing liver disease is associated with poor outcome in patients with SARS CoV2 infection; the APCOLIS Study (APASL COVID-19 Liver Injury Spectrum Study).
Comparison of mortality risk in patients with cirrhosis and COVID-19 compared with patients with cirrhosis alone and COVID-19 alone: multicentre matched cohort.
This risk of death following SARS-CoV-2 infection appears to be higher compared to other infective insults including spontaneous bacterial peritonitis.
An analysis of >220,000 patients with CLD in North America further emphasized the negative impact of advanced liver disease at a population level, with cirrhosis being associated with a 2.38-fold adjusted hazard of mortality 30 days after SARS-CoV-2 infection.
Similarly, a retrospective French cohort of >259,000 inpatients with COVID-19 including >15,000 with pre-existing CLD, demonstrated that patients with decompensated cirrhosis were at an increased adjusted risk for mortality.
This is further corroborated by data derived from the electronic health records of >6 million UK adults which indicated an elevated adjusted hazard ratio for both hospitalisation and death related to COVID-19 in patients coded as having cirrhosis.
Living risk prediction algorithm (QCOVID) for risk of hospital admission and mortality from coronavirus 19 in adults: national derivation and validation cohort study.
These findings contrast with those from a nationwide Swedish CLD cohort which did not demonstrate associations between cirrhosis and COVID-19-related mortality.
However, this study was limited to patients with biopsy-proven CLD prior to 2017, and therefore more advanced liver disease may have been under-represented because these patients did not undergo biopsy or died before the onset of the pandemic. Lastly, meta-analysis of 63 outcome studies up until February 2021 revealed a pooled odds ratio for mortality of 2.48 (95% CI 2.02-3.04) in patients with cirrhosis and COVID-19.
It is important to recognise that our understanding of the disease course of COVID-19 in patients with cirrhosis is nearly exclusively derived from data collected in the era preceding COVID-19 vaccination and the emergence of viral variants of concern (e.g. omicron). However, in a retrospective analysis of US veterans with cirrhosis, receipt of even a single mRNA vaccine dose not only reduced rates of SARS-CoV-2 infection but markedly improved rates of hospitalisation and death in those developing breakthrough COVID-19.
The impact of the highly prevalent omicron variant including all subvariants in patients with CLD, as well as the modifying effect of COVID-19 vaccination, needs to be further investigated.
There are several clinical hallmarks of COVID-19 in patients with cirrhosis. Firstly, new or worsening acute hepatic decompensation, predominantly with ascites and/or hepatic encephalopathy, is a common presenting feature in up to 46% of patients.
and is thought to be secondary to greater gut permeability and systemic inflammation. Historic studies have shown a >30-fold increase in angiotensin-converting enzyme 2 (ACE2) receptor expression in cirrhotic vs. healthy livers, suggesting that patients with cirrhosis may be uniquely susceptible to SARS-CoV-2-mediated hepatic dysfunction.
In addition, Wanner et al. have shown clear evidence of specific SARS-CoV-2 hepatotropism, further indicating that the virus could trigger decompensation in patients with pre-existing CLD.
Pre-existing liver disease is associated with poor outcome in patients with SARS CoV2 infection; the APCOLIS Study (APASL COVID-19 Liver Injury Spectrum Study).
Comparison of mortality risk in patients with cirrhosis and COVID-19 compared with patients with cirrhosis alone and COVID-19 alone: multicentre matched cohort.
of decompensating patients. In this context, several scoring models have been applied, with the CLIF-C (Chronic Liver Failure-Consortium) ACLF and organ failure scores appearing to outperform model for end-stage liver disease, NACSELD (North American Consortium for the Study of End-stage Liver Disease), and CP scores.
Despite SARS-CoV-2 triggering acute hepatic decompensation and ACLF, the predominant cause of death remains respiratory failure (71%) followed by liver-related complications (19%).
The mechanistic links between hepatic dysfunction and subsequent lung injury are likely to be numerous and overlapping including cirrhosis-associated immune dysfunction, gut dysbiosis, altered pulmonary dynamics secondary to ascites and hepatic encephalopathy, and coagulopathy.
In a large nationwide cohort study in France, Mallet et al. described an associated between pulmonary embolism and COVID-19 mortality, and reported a modest but significant increase in rates of pulmonary emboli in patients with vs. without CLD.
In addition, this study introduced the concept of limited ‘therapeutic effort’ for patients with cirrhosis and alcohol-related liver disease (ALD), both of whom had a lower chance of mechanical ventilation and a higher risk of death. This suggests that there were barriers to patients with cirrhosis receiving invasive ventilation. Indeed, this may reflect a perception that patients with cirrhosis represent an underserved population analogous to racial and socioeconomic minorities who also exhibit a higher risk of severe COVID-19.
which may have become acutely unmasked during the COVID-19 pandemic.
EASL position
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Patients with CLD with or without cirrhosis do not appear at increased risk of SARS-CoV-2 infection. However, those with cirrhosis are at high risk of COVID-19-related mortality.
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Liver disease severity is a strong predictor of developing severe COVID-19 and preventing liver disease progression may protect patients from the adverse effects of future SARS-CoV-2 infection.
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Limited data are available on the impact of viral variants and COVID-19 vaccination on the clinical course of SARS-CoV-2 infection in patients with CLD.
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SARS-CoV-2 infection can precipitate new or worsening acute hepatic decompensation and ACLF in patients with cirrhosis.
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Patients with cirrhosis and SARS-CoV-2 infection often present without typical respiratory symptoms but subsequently deteriorate with the predominant cause of death being COVID-19-related respiratory failure.
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Limitations of access to care, including invasive ventilation, may contribute to adverse outcomes in hospitalised patients with cirrhosis and COVID-19. Consequently, every effort must be made to facilitate access to intensive care units when appropriate.
Alcohol-related liver disease
The immunomodulating effects of alcohol are well recognised,
A history of harmful alcohol use also appears to increase susceptibility to acute respiratory distress syndrome, a hallmark of severe COVID-19, in critically ill patients with sepsis.
Both registry data and multicentre studies have identified ALD as being independently associated with COVID-19 mortality after controlling for important cofactors including baseline liver disease severity.
However, alcohol consumption in patients with CLD, categorised as either social drinking or current daily drinking, was not associated with all-cause mortality compared to abstinence in a multivariable model.
The precise mechanisms through which ALD negatively impacts on prognosis in COVID-19 remain to be established although this may plausibly be underpinned by poor nutritional status and functional immunosuppression. In addition, patients with ALD and severe COVID-19 were significantly less likely to receive mechanical ventilation in a large French cohort.
The strength of this negative association exceeded that observed with any other individual comorbidity or category of Charlson comorbidity index, suggesting that mortality in hospitalised patients with ALD and COVID-19 may be partly explained by discrepancies in the allocation of healthcare resources. These findings are especially alarming given that the incidence of harmful drinking, ALD, and alcohol-related hospital admissions have dramatically increased since the onset of the pandemic (see below)
and collectively highlights the urgent need for concerted institutional and public health efforts to tackle the rise in alcohol-related harm.
EASL position
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Patients with ALD do not appear to have a higher risk of SARS-CoV-2 infection but are at increased risk of mortality following SARS-CoV-2 infection compared to patients with CLD of other aetiology.
NAFLD
The impact of NAFLD on COVID-19 outcomes has been closely scrutinised due to its association with well-established risk factors for severe COVID-19 including obesity, type 2 diabetes, cardiovascular disease, and hypertension.
However, it has been challenging to accurately decipher an independent effect of NAFLD on COVID-19 disease course due to confounding factors and heterogeneity in diagnostic criteria and populations investigated. Several observational cohorts have demonstrated a significant increase in the risk of severe COVID-19 in patients with NAFLD,
Mechanistically, this observation may be supported by gene expression datasets showing increased expression of key viral entry receptors (ACE2, FURIN, TMPRSS2) in patients with NAFLD and NASH.
In addition, ACE2 is upregulated in the liver, and in subcutaneous and visceral adipose tissue, in obese patients with NAFLD compared to obese controls without NAFLD.
This increased receptor expression strongly correlated with degree of insulin resistance. Collectively this indicates that NAFLD in the context of the wider metabolic syndrome likely contributes to more severe and multisystem involvement of COVID-19. However, in contrast, some groups have failed to draw a link between NAFLD with severe COVID-19 or death after controlling for relevant comorbidities.
NAFLD is a predictor of liver injury in COVID-19 hospitalized patients but not of mortality, disease severity on the presentation or progression - the debate continues.
Separate independent analyses using 2-step Mendelian randomisation techniques have also failed to identify a causal relationship between NAFLD and COVID-19 susceptibility and severity.
This approach attempts to overcome confounding by using genetic variants as instrument variables to draw causal inferences between risk factors and health outcomes.
In summary, from a purely epidemiological perspective it appears that patients with NAFLD are at increased risk of severe COVID-19. However, the extent to which this is driven by hepatic steatosis, or the presence of overlapping risk factors and comorbidities remains incompletely resolved.
EASL position
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Patients with NAFLD are at increased overall risk of developing severe COVID-19 which may be attributed to the presence of other high-risk comorbidities.
Autoimmune liver disease
Understanding the clinical impact of pre-existing immunosuppression on COVID-19 risk and severity remains complex. Various concerns have been raised in specific disease groups, e.g. regarding the use of maintenance corticosteroids and thiopurines in patients with rheumatoid conditions and inflammatory bowel disease, respectively.
Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry.
Conversely, the disease course in those on immunosuppression following solid organ transplantation appears comparable to non-immunosuppressed individuals.
A large-scale European survey of 1,752 individuals with AIH performed between June and October 2020 indicated low rates of self-reported COVID-19, providing reassuring real-world data that these patients are unlikely to be at significantly increased risk of severe disease.
Subsequently, in an international cohort of 70 patients with AIH and COVID-19, of whom 86% were immunosuppressed, no differences were found in the rates of adverse outcomes including hospitalisation, ICU admission, and death compared to those with other causes of CLD.
When compared to propensity score-matched patients without CLD, patients with AIH had no increased risk of ICU admission or death but did appear to have higher rates of hospitalisation which may have reflected heightened clinical concern. Age and baseline liver disease severity constituted independent risk factors for death in this analysis, but not the use of immunosuppressive medications. Similar findings were concurrently reported in a multicentre cohort of 110 patients with AIH who also had comparable outcomes to other liver disease types.
However, a larger retrospective study from the same group including 254 patients with AIH and COVID-19 did indicate that baseline treatment with systemic glucocorticoids (median dose 5 mg/day) or azathioprine (median dose 75 mg/day) was associated with more severe COVID-19
after adjusting for age, sex, comorbidities, and presence of cirrhosis. Data for patients with primary biliary cholangitis and primary sclerosing cholangitis are limited. One nationwide study in Spain did observe a higher cumulative incidence of hospitalisation and mortality in patients with primary biliary cholangitis compared with the general population although interpretations are limited by the lack of adjustment for comorbidities.
Patients with AIH on immunosuppression do not appear to be at a higher risk of SARS-CoV-2 infection or COVID-19-related mortality.
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However, baseline use of glucocorticoids or azathioprine may be associated with more severe COVID-19; yet, discontinuing, or reducing the dose of these agents should only occur following careful assessment of all risks and benefits.
Chronic viral hepatitis
Several studies have investigated the clinical impact of co-existing chronic HBV or HCV infection with SARS-CoV-2. A large territory-wide retrospective cohort study in Hong Kong
showed that COVID-19 outcomes were no different between 359 patients with previous exposure to HBV, 353 patients with HBV infection, and a comparator group of 4,927 individuals without HBV. In addition, the rates and pattern of acute liver biochemistry abnormalities during COVID-19 were the same across groups. Notably, 73 treatment-naïve patients with chronic HBV were started on HBV-targeted nucleoside analogues (NAs) during the course of COVID-19, either as a prophylactic measure against HBV reactivation due to the introduction of steroids (n = 48) or following marked elevations in ALT and HBV DNA levels (n = 16). Whilst patients who received NA treatment had a higher peak ALT than those who did not receive NAs, the ALT level at discharge was comparable between treated and untreated groups. A retrospective review of health insurance records in Korea also demonstrated that patients with chronic HBV did not have a significantly greater risk of severe COVID-19.
Furthermore, in those with COVID-19 the proportion of patients with chronic HBV was lower than the general population after adjusting for comorbidities and socioeconomic status, indicating that patients with HBV may be less susceptible to SARS-CoV-2 infection.
It has been suggested that this protective effect is mediated by the use of antiviral treatments, including tenofovir and entecavir, which have been shown to be associated with a reduced rate of SARS-CoV-2 positivity.
NAs may have immunomodulatory effects and possibly specific antiviral properties against SARS-CoV-2, as postulated in pilot studies and preclinical models.
Effect of Tenofovir Disoproxil Fumarate and Emtricitabine on nasopharyngeal SARS-CoV-2 viral load burden amongst outpatients with COVID-19: a pilot, randomized, open-label phase 2 trial.
Analysis from a large American Veterans dataset demonstrated that a greater proportion of HCV-positive patients (n = 975) with COVID-19 were hospitalised compared to propensity score-matched HCV-negative individuals, particularly among those with elevated non-invasive markers of advanced fibrosis. However, rates of ICU admission and mortality did not differ between those with and without HCV infection.
Two subsequent single-centre studies have indicated adverse outcomes in patients with co-existing HCV and SARS-CoV-2, including increased ICU admissions and mortality, particularly in those with elevated HCV RNA levels.
However, interpretations are limited by small sample sizes and the lack of adjustment for the presence of cirrhosis. The repurposing of direct-acting antivirals (DAAs) for the treatment of COVID-19 has been investigated but results remain contentious (discussed below).
The effect of sofosbuvir-based treatment on the clinical outcomes of patients with COVID-19: a systematic review and meta-analysis of randomized controlled trials.
Patients with chronic viral hepatitis (HBV or HCV) without cirrhosis do not appear to have an increased risk of SARS-CoV-2 infection or COVID-19-related mortality.
Hepatobiliary cancer
Accurate risk stratification of patients with malignancy and COVID-19 has remained challenging due to high rates of comorbidity and heterogeneity in cancer type, stage, and treatment modality. Nonetheless, overall, patients with malignancy do appear to be more susceptible to SARS-CoV-2 infection and death from COVID-19.
Living risk prediction algorithm (QCOVID) for risk of hospital admission and mortality from coronavirus 19 in adults: national derivation and validation cohort study.
Data related specifically to patients with hepatobiliary cancer are limited. In a large prospective UK cancer cohort, 95 patients were coded as having ‘non-colorectal digestive malignancy’ of whom 29% died following SARS-CoV-2 infection.
COVID-19 prevalence and mortality in patients with cancer and the effect of primary tumour subtype and patient demographics: a prospective cohort study.
In a multicentre North American study of patients with CLD and COVID-19, patients with hepatocellular carcinoma (HCC) (n = 22) had an all-cause mortality of 52%, approximately 7-fold higher than in patients without HCC, although whether cause of death was related to COVID-19 or HCC complications remains unclear.
This equated to HCC being an independent risk factor for COVID-19 mortality even after controlling for the presence of cirrhosis (hazard ratio 3.31 [1.53–7.16]). Within this HCC cohort, 8 (36.4%) had received locoregional therapy and 2 (9.1%) had received immunotherapy. Conversely, international registry data including 48 patients with HCC failed to show an independent association with death.
At present, there are no data providing risk estimates for adverse COVID-19 outcomes in patients with cholangiocarcinoma.
EASL position
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Patients with hepatocellular carcinoma may have an increased risk of mortality following SARS-CoV-2 infection.
Liver transplant recipients
Early in the pandemic, country-wide data from Spain and the UK suggested that diagnoses of SARS-CoV-2 infection were more frequent in LT recipients than in the general population.
Given that LT recipients have been shown to have diminished responses to COVID-19 vaccination these patients should continue to be considered as being particularly susceptible to SARS-CoV-2 acquisition
(discussed below). However, LT recipients who develop COVID-19 do not appear to have an increased risk of mortality compared to patients without LT after matching for relevant cofactors.
In line with the general population, the major risk factors for developing severe COVID-19 in LT recipients are advancing age and burden of comorbidity.
Concerns that immunosuppressive medications in LT recipients may increase susceptibility to SARS-CoV-2 infection must be balanced with their potential to positively influence the course of COVID-19 by suppressing inflammation in the later stages of the disease. Whilst antimetabolic drugs seem to have a negative effect,
Methylprednisolone pulses plus tacrolimus in addition to standard of care vs. standard of care alone in patients with severe COVID-19. A randomized controlled trial.
Therefore, adjustments to the dose and type of immunosuppression during SARS-CoV-2 infection should be individually tailored based on COVID-19 severity, the specific regimen used, time post-transplant, and the risk of allograft rejection. Clinical features of COVID-19 among solid organ transplant (SOT) recipients are variable. However, gastrointestinal symptoms including diarrhoea appear more frequent, particularly in patients receiving mycophenolate mofetil (MMF)
Protective role of tacrolimus, deleterious role of age and comorbidities in liver transplant recipients with Covid-19: results from the ELITA/ELTR multi-center European study.
At present, there is no convincing evidence that liver transplantation by itself is an independent risk factor for COVID-19-related mortality. However, liver transplant recipients should be considered at high-risk of SARS-CoV-2 infection because of their comorbidities, non- or hypo-responsiveness to COVID-19 vaccination and immunosuppression.
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In liver transplant recipients with COVID-19, a dose reduction or temporary discontinuation of anti-metabolites (e.g. azathioprine or MMF) may be considered.
Effects of the COVID-19 pandemic on incidence and management of CLDs
Impact on harmful alcohol use and ALD
COVID-19 has had a vast collateral impact on the incidence and severity of alcohol use disorder and ALD. Early on in the pandemic, an upsurge in harmful drinking was widely documented with large-scale survey data showing pervasive increases in both the frequency and severity of alcohol consumption across men, women, and the breadth of racial and socioeconomic backgrounds.
Mental health and health behaviours before and during the initial phase of the COVID-19 lockdown: longitudinal analyses of the UK Household Longitudinal Study.
These behaviours are likely to have been triggered by heightened anxiety, social isolation, deteriorating mental health, and disruption to alcohol support services.
Mental health and health behaviours before and during the initial phase of the COVID-19 lockdown: longitudinal analyses of the UK Household Longitudinal Study.
Furthermore, these early drinking trends appear to have persisted, with UK public health data compiled from 18 national surveys demonstrating a widespread increase in harmful alcohol consumption throughout 2020 and 2021.
Indeed, the proportion of respondents with high-risk drinking was consistently elevated, increasing by up to 58% compared to peak values recorded in 2019. In parallel, the epidemiology of ALD appears to have shifted. In a large study of electronic health records in Canada, the average number of monthly admissions due to alcoholic hepatitis was found to have doubled during the pandemic compared to the previous 2 years (22.1/10,000 admissions vs. 11.6/10,000 admissions; p <0.001).
Similarly, UK data have indicated unprecedented increases in the number of alcohol-related hospital admissions and alcohol-related deaths throughout 2020/21. Alarmingly, 80% of these alcohol-related deaths are accounted for by liver disease, representing an increase in 20% from pre-pandemic levels.
Alcohol consumption during the pandemic has also heavily influenced liver transplantation programmes, with ALD now accounting for 40% of transplant listings in North America, more than NASH and HCV combined.
Furthermore, the severity of liver disease at the time of transplantation was found to be significantly worse during the COVID-19-era, driven predominantly by higher model for end-stage liver disease-Na scores in patients with ALD.
Lastly, simulation modelling in the United States has estimated that a single year of increased alcohol consumption during the pandemic may result in 8,000 additional deaths from ALD, 18,700 cases of decompensated cirrhosis, 1,000 cases of HCC, and 8.9 million disability-adjusted life years between 2020 and 2040.
Collectively, these data paint a bleak picture and highlight the immense current and future burden of morbidity and mortality precipitated by COVID-19-associated alcohol consumption.
This should provide additional impetus to urgently re-establish alcohol support services and to implement evidence-based population-level interventions such as minimum unit pricing and taxation of alcohol,
There has been an unprecedented rise in the incidence and severity of ALD during the COVID-19 pandemic which requires urgent implementation of local and population-level interventions alongside clear public health messaging about the risks of harmful drinking.
Impact on NAFLD
The COVID-19 pandemic has led to the adoption of unhealthy lifestyles and has impeded strategies to manage obesity and metabolic dysfunction which may influence the development and progression of NAFLD. Several survey studies have documented increased consumption of unhealthy foods, excess calorie intake, and reduced physical activity during periods of enhanced social distancing.
Changes in physical activity levels, eating habits and psychological well-being during the Italian COVID-19 pandemic lockdown: impact of socio-demographic factors on the Florentine academic population.
This appears to have translated into an increased prevalence of obesity during the pandemic, particularly in paediatric and adolescent populations. According to figures from the Centers for Disease Control and Prevention, among a cohort of 432,302 individuals aged 2-19 years, the rate of increase in BMI approximately doubled during the pandemic compared to the period preceding it.
The greatest increase was observed in children aged 6-11 years and in those who were overweight at baseline. These data coincided with similar findings from electronic health records for 46,151 children in Massachusetts, USA, which identified a particularly high obesity risk in boys (aged 6-11 years), and Black and Hispanic subgroups.
Paradoxically, a study of primary care practices in the UK observed a 70% decrease in the rate of type 2 diabetes diagnoses in the initial months following the onset of the pandemic, reflecting reduced testing and limited population engagement with health services.
This subsequently normalised throughout 2020 and there are concerns that a rebound in the incidence of type 2 diabetes mellitus and its complications may be imminent.
Although no study has yet directly evaluated the epidemiology of NAFLD in the COVID-19 era, it is highly likely that the pandemic will have a detrimental effect on liver health via the negative impact on obesity, diabetes care, and patient lifestyle choices.
EASL position
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The pandemic has led to increased adoption of unhealthy lifestyles and a rise in the prevalence of obesity which is likely to drive the development and progression of NAFLD.
Impact on viral hepatitis elimination strategies
In 2016, the World Health Organization released a strategy aiming for elimination of viral hepatitis by 2030. Several countries introduced policies and strategies to meet this ambitious goal
A modelling study has predicted that a delay of just 1 year in hepatitis C diagnosis and treatment due to the pandemic could result in 44,800 additional liver cancer cases and 72,300 deaths worldwide by 2030.
Nevertheless, SARS-CoV-2 testing requirements and the roll-out of mass vaccination campaigns offer a unique opportunity to approach large parts of the population and offer screening for viral hepatitis.
Alliance for the Elimination of Viral Hepatitis in Spain. Let’s leverage SARS-CoV2 vaccination to screen for hepatitis C in Spain, in Europe, around the world.
efforts to meet the World Health Organization (WHO)’s goal of viral elimination should continue without further delay.
EASL position
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The WHO goal of viral hepatitis elimination by 2030 should be pursued without further delay.
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Diagnosis of viral hepatitis and linkage to care through SARS-CoV-2 testing and vaccination programmes are strongly encouraged.
Changes in the standard of care and adherence to surveillance programmes
In the early phases of the pandemic, when little was known about the transmissibility of SARS-CoV-2 and personal protective equipment was in short supply in many places, hospitals and other health care providers represented SARS-CoV-2 hotspots, prompting many medical associations, including EASL, to advocate for rapidly escalating telemedicine and postponing surveillance visits (e.g. ultrasound for HCC surveillance, endoscopy for surveillance of oesophageal varices) for selected patient cohorts in order to reduce the likelihood of nosocomial infections and to respond to the re-allocation of healthcare resources.
Indeed, the number of liver transplantations declined in 2020 compared to 2019 primarily in those countries that were most strongly affected by the first wave of the pandemic in early 2020.
Similarly, numbers of first HCC diagnosis declined from 2019 to 2020 and the percentage of patients in whom treatment initiation had to be delayed increased in that period.
More than 80% of European centres had to change their clinical practices because diagnostic procedures, screening programmes, curative and/or palliative treatments, and liver transplant programmes were affected by lockdown measures.
The pandemic profoundly altered the standard of care within hospitals and the outpatient setting. All efforts should be made to return to these standards and resume and improve surveillance programmes in order to reduce the backlog of deferred care for the future.
Treatment of COVID-19 in patients with CLD, transplant recipients and patients with hepatobiliary carcinoma
General concepts of COVID-19 treatment
The pathogenesis of COVID-19 is mainly determined by 2 main processes. Early in the clinical course, the disease is mainly triggered by SARS-CoV-2 replication. Later, the disease appears to be driven by a dysregulated immune/inflammatory response resulting in tissue injury. Based on this understanding, direct antiviral therapies should have the greatest effect when employed as early as possible in the disease course, whereas immune/inflammation-modulating therapies are likely to be more beneficial when SARS-CoV-2 infection has already reached a stage characterised by tissue damage and hypoxia (Fig. 1). In this section, we will review current COVID-19 treatment strategies (Table 2 and Table 3 show the currently recommended therapies) with a focus on considerations for patients with CLD, hepatobiliary cancer, and LT recipients.
Fig. 1Treatment options according to disease stage.
Indicated in high-risk patients (lack of immune protection, especially immunosuppression) within 5 days of symptom onset, this includes inpatients with recently diagnosed nosocomial SARS-CoV-2 infection; whether later administration is appropriate in highly immunosuppressed patients must be decided on a case-by-case basis.
Indicated in high-risk patients (lack of immune protection, especially immunosuppression) within 5 days of symptom onset, this includes inpatients with recently diagnosed nosocomial SARS-CoV-2 infection; whether later administration is appropriate in highly immunosuppressed patients must be decided on a case-by-case basis.
Indicated in high-risk patients (lack of immune protection, especially immunosuppression) within 5 days of symptom onset, this includes inpatients with recently diagnosed nosocomial SARS-CoV-2 infection; whether later administration is appropriate in highly immunosuppressed patients must be decided on a case-by-case basis.
Indicated in high-risk patients when symptom onset was ≤7 days ago or when SARS-CoV-2 detection was ≤3 days ago and when there are no or only mild symptoms. This includes inpatients with recently diagnosed nosocomial SARS-CoV-2 infection. The use of mAbs requires a negative antibody test, which, however, can be omitted in highly immunosuppressed patients.
Indicated (weak recommendation)
Indicated in high-risk patients when symptom onset was ≤7 days ago or when SARS-CoV-2 detection was ≤3 days ago and when there are no or only mild symptoms. This includes inpatients with recently diagnosed nosocomial SARS-CoV-2 infection. The use of mAbs requires a negative antibody test, which, however, can be omitted in highly immunosuppressed patients.
Indicated (strong recommendation)
Indicated in high-risk patients when symptom onset was ≤7 days ago or when SARS-CoV-2 detection was ≤3 days ago and when there are no or only mild symptoms. This includes inpatients with recently diagnosed nosocomial SARS-CoV-2 infection. The use of mAbs requires a negative antibody test, which, however, can be omitted in highly immunosuppressed patients.
∗ Indicated in high-risk patients (lack of immune protection, especially immunosuppression) within 5 days of symptom onset, this includes inpatients with recently diagnosed nosocomial SARS-CoV-2 infection; whether later administration is appropriate in highly immunosuppressed patients must be decided on a case-by-case basis.
∗∗ Indicated in high-risk patients when symptom onset was ≤7 days ago or when SARS-CoV-2 detection was ≤3 days ago and when there are no or only mild symptoms. This includes inpatients with recently diagnosed nosocomial SARS-CoV-2 infection. The use of mAbs requires a negative antibody test, which, however, can be omitted in highly immunosuppressed patients.
Table 3Overview of recommended therapies for SARS-CoV-2 infection.
Medication and dose
Antiviral therapy
Indication
Important comments and considerations for CLD and LT recipients
Remdesivir (Veklury) 200 mg on day 1 followed by 100 mg on days 2 and 3 (intravenous).
Prevention of severe COVID-19 in at-risk patients (within 7 days of symptom onset).
Monitoring liver parameters, eGFR. Usage in patients with an eGFR of <30 only if the potential benefits outweigh the risks. No significant DDI is expected.
Nirmatrelvir/ritonavir (Paxlovid) 300 mg (2 tablets)/100 mg (1 tablet) twice daily for 5 days (per os)
Prevention of severe COVID-19 in at-risk patients (within 5 days of symptom onset).
Because of limited experience outside clinical trials.
, not recommended in advanced cirrhosis, caution in LT because of DDI.
Molnupiravir (Lagevrio) 800 mg (4 tablets) twice daily for 5 days (per os)
Prevention of severe COVID-19 in at-risk patients (within 5 days of symptom onset).
Contraindicated in pregnancy and in women of childbearing potential not using effective contraception, no significant DDIs are expected. Monitoring liver parameters, eGFR
Because of limited experience outside clinical trials.
.
mAbs Sotrovimab (Xevudy) 500 mg (intravenous) Bebtelovimab 175 mg (intravenous) Tixagevimab/cilgavimab (Evusheld) 150 mg/150 mg or 300 mg/300 mg (intramuscular) – only approved for pre-exposure prophylaxis
Prevention of severe COVID-19 in at-risk patients (unvaccinated individuals or individuals without detectable serological response to vaccination. Treatment within 72 hours but no longer than 7 days after symptom onset (post exposure prophylaxis). Recommendations are based on the current knowledge of the in vitro activities of available mAbs against the circulating SARS-CoV-2 variants and subvariants.
Monitoring for hypersensitivity reactions.Consider SARS-CoV-2 variants (e.g. sotrovimab is not recommended if omicron BA.2 is dominant). Serology (antibody) assessment is not essential in immunocompromised patients.
Immunomodulatory therapies
Dexamethasone 6 mg for 10 days (per os or intravenous)
Treatment of COVID-19 WHO ≥5 (oxygen demand)
Monitoring liver parameters. HBsAg/anti-HBc test, prophylactic NAs in HBsAg-positive patients, adjust immunosuppression in LT.
Janus kinase 1/2 inhibitor Baricitinib (Olumiant) 4 mg per day for 14 days (per os)
COVID-19 WHO ≥5 (oxygen demand) in addition to dexamethasone
Dose adjustment if eGFR <60, not recommended if eGFR is <15. Monitoring of eGFR, liver parameters. HBsAg/anti-HBc test, prophylactic NAs in HBsAg-positive patients, adjust immunosuppression in LT, no combination with anti-IL-6.
IL-6 receptor antagonist tocilizumab (Actemra) 8 mg/kg (<65 kg = 400 mg, up to 90 kg = 600 mg, >90 kg = 800 mg) as a single dose (intravenous).
COVID-19 WHO 6-9 (High-flow oxygen demand, NIV) in addition to dexamethasone
Monitoring liver parameters. HBsAg/anti-HBc test, prophylactic NAs in HBsAg-positive patients, adjust immunosuppression in LT, no combination with JAKI, contraindicated in patients with absolute neutrophil count <2,000/μl; active tuberculosis.
Direct antiviral approaches aim to inhibit viral replication by interacting with key proteins or other structures necessary for viral replication, whereas viral neutralising monoclonal antibodies (mAbs) can inhibit viral replication by interacting with the SARS-CoV-2 spike protein to prevent cell entry. Due to the dynamics of acute respiratory tract infections, in which viral replication is known to be greatest during the first few days after infection, the therapeutic window for antiviral approaches is narrow compared to immunomodulatory therapies which can be employed later in the disease course (Fig. 1).
Remdesivir
Remdesivir, an adenosine analogue, inhibits the RNA-dependent RNA polymerase of coronaviruses and has demonstrated potent activity against SARS-CoV-2 in vitro and in animal models.
In the ACTT-1 study, which included 1,062 hospitalised patients with COVID-19 and evidence of lower respiratory tract infection, those randomised to receive 10 days of remdesivir recovered more rapidly than those receiving placebo (median recovery time 10 vs. 15 days). All-cause mortality estimates by day 29 were 11.4% in the remdesivir group and 15.2% in the placebo group.
Despite improved recovery times in ACTT-1, the clinical benefit of remdesivir in hospitalised patients with COVID-19 remains controversial. The Solidarity trial, which assessed multiple repurposed antiviral drugs using data across 405 institutions in 30 countries, showed no clinical benefit of remdesivir vs. standard of care.
Remdesivir treatment in hospitalized patients with COVID-19: a comparative analysis of in-hospital all-cause mortality in a large multi-center observational cohort.
These conflicting results are most likely explained by variability in the timing of remdesivir treatment initiation. Antiviral therapies must be administered in the early phase of infection when patients are asymptomatic or have mild symptoms (Fig. 1). Large-scale electronic health record data have suggested that remdesivir is unlikely to be of benefit in more severely ill patients with well-established disease.
This is corroborated by the DisCoVeRy study which showed no clinical benefit of remdesivir in hospitalised patients who required oxygen support and had been symptomatic for >7 days.
Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial.
Conversely, the PINETREE study showed that early introduction of 3-days treatment with remdesivir in high-risk non-hospitalised patients with symptoms <7 days appeared safe and resulted in an 87% lower risk of hospitalisation or death compared to placebo.
However, use of remdesivir as a pre-emptive treatment in an outpatient setting is limited by the need for intravenous administration. Despite preclinical investigations demonstrating reversible ALT elevations with remdesivir, its use in controlled trials has not been associated with significant ALT elevations compared with placebo (4% vs. 5.9%)
although most trials have excluded patients with baseline ALT >5 ULN. There are no specific drug interaction concerns with the use of remdesivir.
EASL position
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Remdesivir should not be used in symptomatic patients requiring invasive ventilation.
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For hospitalised patients with COVID-19 pneumonia who require oxygen therapy or non-invasive ventilation, no recommendation can be made at present for or against therapy with remdesivir. Treatment may be considered in this setting based on experience and the availability of alternative options.
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Remdesivir can be given pre-emptively within 7 days of symptom onset to patients with SARS-CoV-2 infection who are at increased risk of a severe COVID-19 course.
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Patients with CLD, transplant recipients and patients with hepatobiliary cancer can be treated with remdesivir in the condition listed above.
Nirmatrelvir/ritonavir
Nirmatrelvir is an oral inhibitor of viral 3CL protease which can be boosted with both ritonavir (r), a potent inhibitor of cytochrome P450 (CYP) and P-glycoprotein that enables peroral use with good bioavailability.
In a phase II/III study including 2,246 patients, nirmatrelvir/r given as early as possible and within 5 days of symptom onset, significantly reduced hospitalisation and/or death rates compared with placebo in non-hospitalised patients with mild/moderate COVID-19 (without supplemental oxygen requirements) and at least 1 risk factor for a severe disease course (7.0% vs. 0.8%) This equates to a relative risk reduction of 88.9% if given within 3 days of symptom onset, and 87.8% if given within 5 days.
Numerous clinically relevant drug-drug interactions (DDIs) must be considered with the use of nirmatrelvir/r due to the inhibition of CYP450 enzymes by ritonavir.
Websites to check the DDIs are available (https://www.covid19-druginteractions.org/checker, https://www.fda.gov/media/155050/download). This is particularly important for SOT recipients as ritonavir will lead to changes in drug levels of immunosuppressive medications. As yet, there are no data reporting on the clinical impact of nirmatrelvir/r in patients infected with the omicron variant. However, in vitro data suggest that nirmatrelvir/r should be effective against most COVID-19 variants currently circulating.
There are also no data specifically for patients with CLD, transplant recipients or patients with hepatobiliary cancer. To date, reported ALT elevations are uncommon, typically mild, and are not more frequently observed with nirmatrelvir/r than with placebo.
However, as both nirmatrelvir and ritonavir are metabolised in the liver by the cytochrome P450 system (largely via CYP 3A4), caution is needed in patients with advanced cirrhosis. This is consistent with well-established concerns regarding the use of similar protease inhibitors in patients with decompensated HCV-cirrhosis.
European Association for the Study of the Liver Electronic address: [email protected], Clinical Practice Guidelines Panel: Chair:, EASL Governing Board representative:, Panel members: EASL recommendations on treatment of hepatitis C: final update of the series.
Nirmatrelvir/r can be given within 5 days of symptom onset to adults with SARS-CoV-2 infection who are at increased risk for severe COVID-19.
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Clinicians managing liver transplant recipients with SARS-CoV-2 infection who begin treatment with nirmatrelvir/r must cautiously approach calcineurin inhibitor and mTOR inhibitor dose-adjustments and drug level monitoring.
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Based on the experience with protease inhibitors in the treatment of chronic hepatitis C, nirmatrelvir/r should not be administered to patients with decompensated liver cirrhosis (CP-C) and only with caution to patients with CP-B cirrhosis if no other options exist.
Molnupiravir
Molnupiravir is an orally available antiviral agent that increases the frequency of viral RNA mutations by the viral RNA-dependent RNA polymerase and impairs SARS-CoV-2 replication in preclinical models.
Molnupiravir has been shown to significantly reduce hospitalisation and/or mortality compared with placebo in non-hospitalised patients with mild/moderate COVID-19 (without supplemental oxygen requirements) and at least 1 risk factor for a severe disease course (6.8% vs. 9.7%). This equates to a relative risk reduction of 30%, absolute risk reduction of 3%, and a number needed to treat of approximately 33.
In this study, therapy was initiated as early as possible and within 5 days of the onset of symptoms. The most commonly reported adverse reactions to treatment were diarrhoea (3%), nausea (2%), dizziness (1%), and headache (1%). Particular consideration should be given to the mutagenic and teratogenic potential of molnupiravir, which makes its use contraindicated during pregnancy or in women of childbearing potential not using effective contraception. No specific data have been reported on the use of molnupiravir for patients infected with the omicron variant and for patients with CLD, hepatobiliary cancer or LT recipients. As molnupiravir is a polymerase inhibitor, variants with mutations in the spike protein (e.g. omicron) should not impact its efficacy and this has been demonstrated in vitro.
To date, there are no concerns regarding the administration of molnupiravir to patients with cirrhosis and no relevant DDIs have been reported. However, there are concerns about the potential for molnupiravir to influence the rate of SARS-CoV-2 mutation. Therefore, manufacturers are required by the FDA to establish a monitoring process using genomic databases in order to detect the emergence of treatment-related SARS-CoV-2 variants.
EASL position
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Molnupiravir can be given within 5 days of symptom onset to adults with SARS-CoV-2 infection who are at increased risk for severe COVID-19.
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Patients with CLD, including cirrhosis (including CP-B and CP-C), transplant recipients, and patients with hepatobiliary cancer can be treated with molnupiravir.
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Pregnancy is a contraindication to molnupiravir therapy.
Monoclonal antibodies
Several mAbs are approved for passive immunisation of SARS-CoV-2-infected patients who are at increased risk of severe disease and are either unvaccinated or have mounted a suboptimal immune response to COVID-19 vaccination. In randomised placebo-controlled trials including non-hospitalised patients with mild-to-moderate COVID-19 and risk factors for disease progression, the use of anti-SARS-CoV-2 mAbs (e.g. casirivimab plus imdevimab,
) has been shown to reduce the risk of hospitalisation and death. For example, hospitalisation or all-cause mortality at 28 days occurred in only 1% of patients treated with sotrovimab compared with 7% receiving placebo (6% absolute reduction and 85% relative risk reduction).
However, pooled analysis of all available randomised-controlled trials indicates a low level of certainty about mAb efficacy, particularly in hospitalised individuals.
This is likely due to multiple agents being included in trials and because several studies did not account for SARS-CoV-2 antibody status. The importance of this is demonstrated in the RECOVERY trial, which included 9,785 patients randomised to casirivimab and imdevimab vs. placebo. In this study, mAb use was not associated with significant differences in clinical outcomes when all patients were considered together (including those with unknown antibody status), however 28-day mortality was improved in patients who were seronegative at baseline.
RECOVERY Collaborative Group Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
Whilst cell culture studies show that the omicron variant (BA.1) is resistant to several therapeutic antibodies, the virus appears to remain sensitive to tixagevimab plus cilgavimab, or sotrovimab.
This is corroborated by some preliminary human data, i.e. sotrovimab effectively prevented disease progression in omicron-infected, predominantly severely immunocompromised patients with mild-to-moderate COVID-19.
For example, the omicron subvariants BA.1 and BA.2 have many differences in their mutations in the spike protein, and the difference between BA.1 and BA.2 is even greater than the difference between the original variant and, for example, the alpha variant. Therefore, it is comprehensible that in vitro data show that sotrovimab is not as effective against the BA.2 compared to earlier variants. Tixagevimab plus cilgavimab does appear to remain active against BA.2
However, within a trial setting, the TACKLE study assessed the efficacy of tixagevimab plus cilgavimab vs. placebo given within 7 days of symptom onset in >900 outpatients with symptomatic COVID-19 and showed that active treatment reduced progression to severe COVID-19 or death (relative risk reduction 50.5%).
Efficacy and safety of intramuscular administration of tixagevimab-cilgavimab for early outpatient treatment of COVID-19 (TACKLE): a phase 3, randomised, double-blind, placebo-controlled trial.
but at present there are no efficacy data from placebo-controlled clinical trials. Knowledge of the predominant circulating viral variants and the immunological serostatus of the patients is therefore important when considering the use of mAbs.
Limitations associated with mAb use include the need for parenteral administration, clinical monitoring during and for ≥1-hour post-infusion, and potential hypersensitivity reactions. In addition, genetic mutations in the spike protein, which are associated with high-level resistance in vitro have been shown to occur in SARS-CoV-2-infected patients treated with mAbs (e.g. bamlanivimab
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