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The American Association for the Study of Liver Diseases (AASLD) has issued preliminary guidance for liver specialists on managing COVID-19 in patients with liver disease, based on data published up to late March.

COVID-19 is the disease caused by SARS-CoV-2, the new coronavirus identified in China in January 2020. SARS-CoV-2 causes a spectrum of clinical illness ranging from mild symptoms (cough, fever) to severe pneumonia, lung damage and death.

People with pre-existing health conditions including chronic kidney disease, cardiovascular disease and chronic obstructive pulmonary disease are at higher risk of developing serious illness that requires hospital admission and ventilation.

AASLD convened an expert panel to review the available evidence and compile clinical insights that can guide healthcare workers.

Liver enzyme elevations and liver injury

People with pre-existing liver disease were more vulnerable to liver damage if infected with SARS, a related virus. Although it is plausible that the same might hold true for the new coronavirus, there is little evidence about its effects in people with liver disease, AASLD concludes.

The AASLD briefing notes that liver injury occurs more often in severe COVID-19 cases and that liver enzyme elevations in mild COVID-19 cases have usually been transient. Elevated liver enzymes in people with COVID-19 should prompt testing for hepatitis B and C, AASLD suggests.

Experimental agents that are being tested as treatments for COVID-19 may have liver toxicities. Although raised liver enzymes should not be a bar to experimental use of these drugs, regular monitoring of liver enzymes should form part of any experimental protocol for COVID-19 treatment.

Hepatocellular carcinoma

In cases of suspected hepatocellular carcinoma (HCC) or ongoing treatment, specialists should try to minimise clinic visits for patients and carry out virtual consultations. However, imaging should not be delayed too long; two months might be reasonable, depending on the patient and facility. Treatment for HCC should not be delayed.

People awaiting transplant

Limit the number of people coming into clinics for transplant evaluation and prioritise visits by those with HCC or those with high MELD scores who are likely to benefit from immediate listing. Try to move as much management of pre-transplant patients as possible online.

Consider RNA testing of recipient and donor when organs become available. Try to test specimens from multiple sites to overcome lower sensitivity of nasal and pharyngeal specimen testing. People who test positive for SARS-CoV-2 are medically ineligible for organ donation.

Transplant

Liver transplantation during the COVID-19 crisis will be challenged by a shortage of ICU beds. Nevertheless, liver transplants should still go ahead, and services may need to prioritise the patients most likely to die on the waitlist. It is not clear if immunosuppressed people are at higher risk for severe COVID-19. However, immunosuppressed people are known to be more likely to acquire SARS-CoV-2 and are more infectious and have higher viral titres than immunocompetent people once infected with SARS-CoV-2. These factors need to be considered when making decisions about immediate or deferred transplantation.

Post-transplant and immunosuppression

It is not clear if immunosuppressed patients are at higher risk for severe COVID-19. Evidence from outbreaks of SARS and MERS shows that post-transplant immunosuppression was not a risk factor for death. Immunosuppressive medication should not be halted in COVID-19 patients. Post-transplant patients should minimise contacts and continue to practice all hygiene measures recommended for post-transplant patients.

If post-transplant patients acquire SARS-CoV-2, prednisone dosage reduction should be considered, as well as dose reductions for other immunosuppressants such as azathioprine, mycophenolate or calcineurin inhibitors. Any dose reduction however must be decided by the treating doctors and certain doses will usually be vital for patients. The European Reference Network recently warned liver patients on immunosuppressants to not reduce or stop their immunosuppressants without seeking advice by their specialist, as this may cause complications such as hepatitis flares or even organ failure.

There is speculation that immune reactions may play a role in severe and worsening COVID-19 lung disease. However, it is unknown at this time if immunosuppressants have any impact on COVID-19, and if the impact would be positive or negative. Therefore, the World Health Organization recommends avoiding the use of corticosteroids for treatment of COVID-19 unless indicated for another purpose.

AASLD advises to consider drug-drug interactions with immunosuppressive drugs if using experimental agents to treat COVID-19. Lopinavir/ritonavir is not proven as an effective treatment for COVID-19 to date but is being tested in several large randomised clinical trials. Lopinavir/ritonavir is a potent inhibitor of CYP3A4, which is involved in the metabolism of calcineurin inhibitors, sirolimus and everolimus. AASLD also recommends to consider a dosage reduction of tacrolimus to 2-5% of baseline dose due to this drug-drug interaction.

It is still unclear if people with chronic liver disease are also at higher risk of severe illness.

A meta-analysis of the first 53,000 cases of COVID-19 reported in China, published in 30 studies since late January, looked at the prevalence of a range of co-morbidities in people admitted to hospital with COVID-19, as well as demographic factors and laboratory markers such as liver enzymes.

The meta-analysis confirmed that chronic kidney disease, cardiovascular disease and chronic obstructive pulmonary disease were each associated with an increased risk of severe illness.

The meta-analysis found that chronic liver disease was not associated with a higher risk of severe COVID-19 (see Table 3, page 39). 0.8% of severe cases and 1.6% of non-severe cases in China had chronic liver disease, a non-significant statistical difference.

The meta-analysis also found that elevated liver enzymes (AST or ALT) were more common in severe cases at the time of diagnosis.

These are preliminary findings and more data are being gathered through registries of COVID-19 cases in liver disease patients that have been established in Europe and North America.

Writing in the The BMJ, researchers from the University of Birmingham have urged caution in interpreting early results of studies looking at risk factors for severe illness. They warn that chronic health conditions are underdiagnosed in China, health records are incomplete, and analyses of risk factors have not controlled for age, sex and smoking status.

Chinese researchers from the National Clinical Research Center for Infectious Diseases, Beijing, also draw attention to imprecise information about pre-existing liver conditions in case studies of COVID-19. They say that chronic liver disease affects around 300 million people in China but has many causes, and the impact of different underlying causes of liver injury in COVID-19 needs to be “meticulously evaluated”.

Hepatitis Australia published guidance for people with viral hepatitis in consultation with the Doherty Institute, University of New South Wales on 20 March 2020, suggesting that people with viral hepatitis are not at increased risk of illness unless they have advanced liver disease or underlying health conditions.

“At this stage there is no evidence to suggest people living with hepatitis B or hepatitis C, who are well are at greater risk of infection with COVID-19. However, current information suggests some people living with hepatitis B and hepatitis C who also have other conditions such as hypertension, cardiovascular disease and diabetes will likely have an increased risk of serious illness if they get COVID-19.

People who have developed advanced liver diseases (including cirrhosis) and deteriorating health as a result of hepatitis B or C should be vigilant in protecting themselves from contracting COVID-19 as they are at risk of more serious illness. This includes people who have ongoing health conditions as a result of a previous hepatitis C infection which has been cured.

People living with hepatitis B or C should use the same protective measures recommended for the general population.”

NHS England advises people with chronic liver disease to be particularly stringent in following social distancing measures. NHS England published a list of groups of people at increased risk of illness due to underlying health conditions on 23 March 2020. The NHS England list of conditions is more detailed than those published by some other countries (e.g. US Centers for Disease Control and Prevention).

• aged 70 or older (regardless of medical conditions)
• under 70 with an underlying health condition listed below (ie anyone instructed to get a flu jab as an adult each year on medical grounds)
• chronic (long-term) respiratory diseases, such as asthma, chronic obstructive pulmonary disease (COPD), emphysema or bronchitis
• chronic heart disease, such as heart failure
• chronic kidney disease
• chronic liver disease, such as hepatitis
• chronic neurological conditions, such as Parkinson’s disease, motor neurone disease, multiple sclerosis (MS), a learning disability or cerebral palsy
• diabetes
• problems with your spleen – for example, sickle cell disease or if you have had your spleen removed
• a weakened immune system as the result of conditions such as HIV and AIDS, or medicines such as steroid tablets or chemotherapy
• being seriously overweight (a body mass index (BMI) of 40 or above)
• those who are pregnant.

NHS England has identified several groups (24 March) receiving immunosuppressive treatments as at high risk of serious illness from coronavirus infection. These groups include the following potential liver disease patients:

• Solid organ transplant recipients
• People having immunotherapy or other continuing antibody treatments for cancer
• People having other targeted cancer treatments which can affect the immune system, such as protein kinase inhibitors or PARP inhibitors
• People on immunosuppression therapies sufficient to significantly increase risk of infection.

NHS England is contacting all patients at highest risk to advise strict social isolation for at least 12 weeks.

Shielding is a measure to protect extremely vulnerable people by minimising interaction between those who are extremely vulnerable and others. This means that those who are extremely vulnerable should not leave their homes, and within their homes should minimise all non-essential contact with other members of their household.

The US Preventive Services Task Force (USPSTF) now recommends screening for hepatitis C infection in all adults ages 18 to 79 without known liver disease, regardless of their risk.

This recommendation incorporates new evidence and replaces the 2013 USPSTF recommendation, which recommended screening for hepatitis C infection in persons at high risk for infection and one-time screening in adults born between 1945 and 1965.

Healthcare professionals, local government and community organisations have launched a London route map for hepatitis C elimination, setting out five 'opportunity' areas for an intensified focus on reaching undiagnosed people and vulnerable populations in the capital.

A third of new hepatitis C diagnoses in England occur in London. Over 2600 people were diagnosed in London in 2018.

The estimated number of people living with hepatitis C in London has been reduced recently, from 40,000 to 14,200, due to efforts to test and treat people in the capital. Reaching the remaining people with hepatitis C in London will be challenging as most are undiagnosed.

People living with HIV who have non-alcoholic fatty liver disease (NAFLD) often have liver fibrosis and are at risk for fibrosis worsening, researchers reported earlier this month at the Conference on Retroviruses and Opportunistic Infections (CROI 2020). The research was presented virtually after the in-person meeting in Boston was cancelled due to the coronavirus crisis.

Dr Lindsay Fourman of Massachusetts General Hospital in Boston presented findings from a study of liver fibrosis among HIV-positive people with NAFLD in a clinical trial of tesamorelin (Egrifta). Fibrosis severity is the strongest predictor of mortality in people with HIV-associated NAFLD, the researchers noted as background.

In this study, the presence of fibrosis was associated with more visceral fat, but not with subcutaneous fat or body mass index (BMI). Looking at the placebo group – reflecting the natural course of liver disease progression when not treated with tesamorelin – 38% experienced fibrosis progression over 12 months, 13% showed regression and 50% remained stable. More than half of those with fibrosis progression had no evidence of fibrosis at baseline. People with worse fibrosis at baseline were most likely to see improvement.

Higher visceral fat content at baseline was the only significant predictor of fibrosis progression.

EASL has postponed the International Liver Congress (ILC 2020) that was scheduled for 15-19 April. It will now be held from 25-28 August 2020 at the same venue.

Delegate registrations will remain valid. But if individuals cannot or do not wish to attend, EASL will provide a refund of registration fees, minus the handling management fee required by their agencies.

Gilead has announced that the US Food and Drug Administration (FDA) has approved a supplemental New Drug Application (sNDA) for Epclusa (sofosbuvir 400mg/velpatasvir 100mg; sofosbuvir 200mg/velpatasvir 50mg) for patients as young as six for the treatment of chronic hepatitis C.

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