News from the 2021 International Liver Congress

This month's infohep bulletin highlights the key news from the 2021 International Liver Congress, the annual meeting of the European Association for the Study of the Liver (EASL), which took place from 23 to 26 June.

Professor Rifaat Safadi speaking at an International Liver Congress 2021 press briefing.

Among people with non-alcoholic fatty liver disease (NAFLD), those with more advanced liver fibrosis did not respond as well to the Pfizer-BioNTech COVID-19 vaccine, according to study results presented at the 2021 International Liver Congress. These and other findings from liver transplant recipients raise the question of whether a third booster dose could improve immune response.

Prior studies have shown that people with liver disease, including advanced cirrhosis and alcoholic liver disease, are more likely to develop severe COVID-19 and die from it. Another study found that fatty liver disease may help explain the greater likelihood of severe COVID-19 among people with obesity.

Professor Rifaat Safadi of Hadassah University Medical Centre, Jerusalem, and colleagues analysed vaccine responses in two cohorts. One cohort consisted of 511 vaccinated people with blood test data available to calculate FIB-4 scores. In this cohort, ten people failed to develop adequate antibody responses after vaccination. Strong antibody responses were less common in people with a FIB-4 score above 2.

The second cohort consisted of 140 people with NAFLD who underwent liver biopsies. People with more advanced fibrosis did not respond as well to vaccination, Safadi reported. Among those with mild fibrosis (stage F1), 39% had an excellent response while 28% had a weaker response. However, among those with advanced fibrosis (stage F3), just 14% had an excellent response and 17% had a weaker response. For those with cirrhosis (stage F4), the corresponding figures were 8% and 23%, respectively.

"Older age, advanced fibrosis with decreased steatosis are risk factors for lower vaccine response for Pfizer’s BNT162b2 vaccine," the researchers concluded. "A third dose vaccine booster in those risk factor populations should be evaluated in future trials."

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Liver transplant recipients in Israel were less likely to develop antibodies after a second dose of the Pfizer SARS-CoV-2 vaccine than healthy volunteers, transplant specialists from Tel Aviv’s Sourasky Medical Center report in the Journal of Hepatology.

The findings mirror those discussed by an Israeli transplant specialist from Jerusalem during a recent International Liver Congress press briefing (see section above). Professor Rifaat Safadi reported that 41% of a group of 90 liver transplant recipients failed to produce an adequate antibody response after a second dose of the Pfizer vaccine.

Dr Liane Rabinowich and colleagues tested antibody responses in 80 people who had received a liver transplant at Sourasky Medical Center and now receive outpatient care through the clinic. Recipients had undergone a liver transplant a median of five years prior to vaccination and had an average age of 60 years.

They compared vaccine responses in transplant recipients to those in 25 healthy volunteers who also received the Pfizer vaccine. All volunteers in the control group showed protective levels of antibodies after vaccination but 42 out of 80 transplant recipients failed to develop positive antibody responses. Furthermore, antibody titres were significantly lower than the control group in the 38 transplant recipients who had positive antibody responses to vaccination.

Multivariate analysis showed that a negative antibody response to vaccination was associated with older age, use of high dose prednisone in the past year, treatment with mycophenolate mofetil or triple immunosuppressive treatment. Better kidney function was associated with a reduced risk of a negative antibody response.

Image by Francisco Àvia. Creative Commons licence.

People with advanced cirrhosis or alcohol use disorder were significantly more likely to die from COVID-19 in France during 2020 compared to the rest of the population, a study of the French national hospital database has found.

The findings, presented to the conference by Dr Vincent Mallet of Cochin Hospital, Paris, and published in the Journal of Hepatology, showed that people with advanced liver disease had an increased risk of death, but people with less advanced liver disease or transplant recipients did not.

However, the French researchers say that their findings may be explained by triage decisions, described by Dr Mallet as “therapeutic effort limitations”, by which scarce mechanical ventilation resources were allocated to patients judged to have a better prognosis. The study found that people with decompensated cirrhosis, alcohol use disorders or primary liver cancer admitted to hospital with COVID-19 were at higher risk of dying but were less likely to receive mechanical ventilation.

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People taking tenofovir (Viread) as treatment for hepatitis B were significantly less likely to suffer severe COVID-19 or to need mechanical ventilation after admission to hospital than people taking the alternative hepatitis B treatment entecavir (Baraclude), a review of COVID-19 patients in 28 Spanish hospitals has revealed.

The findings were presented at the conference by Dr Beatriz Mateos Muñoz of Universidad de Alcalá, Madrid.

A second study presented at the conference, of people tested for SARS-CoV-2 in South Korea, found that chronic hepatitis B and antiviral treatment with either tenofovir or entecavir for hepatitis B were each associated with a lower risk of testing positive for SARS-CoV-2. However, antiviral treatment did not reduce the risk of severe COVID-19 or death.

The two studies investigated whether the antiviral drug tenofovir protects against severe COVID-19 illness in people with hepatitis B, following the observation in a Spanish study that people with HIV taking tenofovir as part of an antiretroviral regimen had a lower risk of severe COVID-19 outcomes.

Heiner Wedemeyer at the International Liver Congress 2021.

The entry inhibitor bulevirtide (Hepcludex) suppressed hepatitis delta viral load and improved liver enzyme levels in a phase III clinical trial, according to late-breaking study results presented at the conference.

Hepatitis delta virus (HDV) is a defective virus that can only replicate in the presence of hepatitis B virus (HBV). Over years or decades, chronic hepatitis B can lead to advanced liver disease including cirrhosis and liver cancer. People with HBV/HDV co-infection have more aggressive liver disease progression than those with HBV alone. It is estimated that 12 million people worldwide have both HBV and HDV.

The MYR301 study randomised 150 adults with chronic hepatitis delta in Europe, Russia and the US to receive either immediate treatment with daily subcutaneous injections of 2mg or 10mg bulevirtide or delayed treatment. They could also use antivirals for hepatitis B. The trial's primary endpoint is efficacy and safety at 48 weeks.

The interim results showed that after 24 weeks of treatment, 55% of people in the 2mg bulevirtide arm and 68% in the 10mg arm either reached an undetectable HDV viral load or experienced at least a 2-log decrease in HDV RNA from baseline, compared with just 4% in the delayed treatment arm. However, the magnitude of the decline was similar in both bulevirtide arms.

ALT normalisation was more frequent in the 2mg arm compared with the 10mg or delayed treatment groups (53%, 38% and 6%, respectively). The combined primary endpoint of virological and biochemical response was achieved by 37% and 28% of people in the 2mg and 10mg arms, respectively, but no one in the delayed treatment group.

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Peer support increased hepatitis C treatment initiation and completion in England between 2017 and 2020, an evaluation of a national peer support scheme run by the Hepatitis C Trust has found. It also increased the likelihood that people who started treatment would do so in a drugs service, highlighting the value of providing hepatitis C treatment in non-clinical settings.

Peer support with lived experience of hepatitis C treatment may encourage people to access treatment, especially those in marginalised groups such as people who inject drugs, prisoners and migrants.

Peer support has been shown to have a positive impact on the uptake of mental health, HIV and cancer services but previous studies of its impact in hepatitis C elimination have been inconclusive.

Hepatitis C elimination efforts in England have included a national peer support programme, partially funded by the pharmaceutical companies AbbVie, Gilead and Merck as part of the competitive procurement agreement between the National Health Service and manufacturers of direct-acting antivirals.

Comparing outcomes between regions that established peer support schemes and those that established peer support schemes later or not at all, the investigators found that peer support increased the odds of starting treatment and completing treatment. After two months of peer support activity, there was also a significant increase in referrals for treatment from drugs services and in the likelihood that people who started treatment would do so in a drugs service.

“We believe that peers are effective in engaging at-risk groups and peers could accelerate attainment of elimination targets,” Davina Jugnarain of Bart’s Health Liver Centre concluded.

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Automatic viral hepatitis testing of blood samples from patients with abnormal liver function has the potential to identify “hard to reach” people with hepatitis B or C who have no known risk factors, an analysis of testing outcomes in the Tayside region of Scotland shows.

The procedure is an example of 'reflex' testing, in which blood samples automatically undergo other tests if they test positive for a condition or show results above a certain threshold.

The findings were presented to the conference by Dr Callum Livingstone, a recent graduate of the University of Dundee School of Medicine.

In Tayside, any patient ALT result above 30 results in reflex testing of the sample for hepatitis B and C by the regional laboratory. The Intelligent Liver Function Test (iLFT) algorithm then uses laboratory test data and patient body mass index (BMI) and other medical history data to propose a diagnosis to the clinician who referred the patient for blood tests.

During the study period, 6791 patients were referred for iLFT, of which 49 tested positive for hepatitis C antibodies. Twenty-nine had detectable hepatitis C virus RNA levels and were invited for treatment.

The cases detected were untypical of Scottish hepatitis cases. Whereas the majority of people diagnosed with hepatitis C in Scotland are aged 30-39 years, the average age of people diagnosed through the iLFT screening system was 53 years. And although the majority of people diagnosed with hepatitis C in Scotland have a history of injecting drug use, 75% of those diagnosed as a result of iLFT said they had never injected drugs.

Finally, whereas half of people diagnosed with hepatitis C live in the most deprived neighbourhoods in Scotland, less than 15% of those diagnosed through iLFT lived in the most deprived neighbourhoods.

“iLFT identifies patients who do not have overt risk factors: those who do not inject drugs, are of an older age and live in more affluent areas,” said Dr Livingstone.

Professor Li Xu speaking at the International Liver Congress 2021.

An experimental immune checkpoint inhibitor plus chemotherapy delivered directly into the hepatic artery in the liver led to good outcomes in people with locally advanced hepatocellular carcinoma (HCC), the most common type of liver cancer, according to a report at the conference.

This treatment "offers a chance for advanced HCC to be cured," Professor Li Xu of Sun Yat-sen University Cancer Centre in Guangzhou, China, said during a conference press briefing. She added that outcomes among this group of people with advanced liver cancer were "almost equal" to outcomes among people with early and middle-stage HCC in other studies.

The participants received FOLFOX hepatic arterial infusion chemotherapy (HAIC) plus IV infusions of sintilimab every three weeks. They were assessed after two cycles, and if their tumours shrank, they were considered for surgery. Those who underwent surgery continued to received sintilimab every three weeks until they experienced disease progression or unacceptable toxicity or completed 16 cycles. Those who were not eligible for surgery received another two cycles of FOLFOX HAIC plus sintilimab and were reassessed.

Thirteen patients experienced partial tumour shrinkage, for an overall response rate of 44.8%. Another eleven had stable disease, yielding a disease control rate of 82.7%.

Twenty-one of the 29 treated patients (72.4%) became eligible for surgery, mostly after the first two treatment cycles. Of these, 19 underwent hepatectomy (removal of part of the liver) and two received radiofrequency ablation (a procedure that uses radio waves to destroy tumours). Four patients went on to achieve a pathological complete response, or full remission.

Among all treated patients, the median progression-free survival (PFS) time was 15.7 months and the 12-month PFS rate, meaning they were still alive without disease progression, was 57.9%. The median PFS was just 5.5 months for patients who did not undergo surgery but was not reached in the surgery group because a majority were still responding. The 12-month overall survival rate was 82.3%.

World Hepatitis Day takes places every year on 28 July, bringing the world together under a single theme to raise awareness of the global burden of viral hepatitis and to influence real change. In 2021 the theme is ‘Hepatitis Can’t Wait’.

On World Hepatitis Day, we call on people from across the world to take action and raise awareness of hepatitis because Hepatitis Can’t Wait.

To get involved, visit the World Hepatitis Day website to view a range of one-minute, ten-minute and longer actions you can take to make sure that the world knows that hepatitis can’t wait.

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