News from the 2020 Digital International Liver Congress

This month's infohep bulletin highlights the key news from the 2020 Digital International Liver Congress, the annual meeting of the European Association for the Study of the Liver (EASL), which took place from 27 to 29 August. It was held virtually this year due to coronavirus.

Visit the official website where you can find more information about the conference and download the abstract book. You can watch highlights videos from the conference here.

Predicting liver cancer after hepatitis C is cured

Gamal Shiha of the Egyptian Liver Research Institute and Hospital presenting to EASL 2020.

Three new methods using readily available clinical parameters can help predict who will develop hepatocellular carcinoma (HCC) after achieving sustained virological response to hepatitis C treatment, according to studies presented at the recent 2020 Digital International Liver Congress.

An analysis of the French ANRS C022 HEPATHER cohort identified eleven variables associated with development of HCC, including male sex, age greater than 64 years, hepatitis C virus genotype 3, prolonged prothrombin time (a measure of blood clotting ability), alpha-fetoprotein (AFP) level, and FIB-4 score. The researchers assigned a point for each variable and calculated a composite HCC risk score. Scores below 6 were considered low risk, scores of 6 to 11 were medium risk and scores of 11 or above were high risk.

After three years of follow-up, just 2% of people with lower-risk scores developed HCC, rising to 7% for those with medium-risk scores and 23% for those with high-risk scores. Those with high scores began to see a steep increase in liver cancer incidence even during the first year of follow-up, while those with low or medium scores saw a more gradual rise.

Two other studies, one in France, one in Egypt, also found that scoring systems based on fibrosis stage and laboratory markers before and after treatment were able to distinguish who was at highest risk of developing HCC.

Immunotherapy for advanced liver cancer

Bruno Sangro presenting findings from the CheckMate 040 trial to EASL 2020.

Three checkpoint inhibitor immunotherapy regimens show promise for people with hepatocellular carcinoma (HCC), the most common type of liver cancer, according to a set of late-breaking presentations at the conference.

Checkpoint inhibitors are monoclonal antibodies that help the immune system fight cancer. Atezolizumab (Tecentriq), nivolumab (Opdivo) and pembrolizumab (Keytruda) interfere with PD-1, an immune checkpoint on T-cells that regulates immune function, thereby restoring T-cell activity against tumours. Ipilimumab (Yervoy) targets CTLA-4, a different immune checkpoint that suppresses T-cell multiplication.

Primary results recently published in The New England Journal of Medicine showed that atezolizumab plus bevacizumab reduced the risk of death compared with sorafenib. After a year on treatment, overall survival rates were 67% and 55%, respectively, and the median progression-free survival time was 6.8 versus 4.3 months, respectively. 

Safety results from a phase 3 study of atezolizumab plus bevacizumab showed that the combination did not result in a higher rate of adverse events when compared to sorafenib. The most common treatment-related events in the atezolizumab plus bevacizumab group were hypertension, protein in the urine, fatigue and AST liver enzyme elevation. Although immune-mediated adverse events were more common in the atezolizumab plus bevacizumab group, these were largely managed by corticosteroid treatment.

Based on the strong efficacy results and patient-reported outcomes, as well as the in-depth safety evaluation presented at the International Liver Congress, the researchers concluded that atezolizumab plus bevacizumab "should be considered a new standard of care" for people with advanced liver cancer.

Results from early-stage studies of combinations of nivolumab plus ipilimumab, or of pembrolizumab plus lenvatinib, were also presented, showing promising activity against advanced HCC.

Liver disease risk in people with HIV

Mathieu Chalouni, University of Bordeaux presenting to EASL 2020.

People living with HIV do not have a higher risk of liver-related complications or death from liver disease after hepatitis C treatment with direct-acting antivirals, researchers from the French HEPAVIH cohort reported at the conference.

They matched people with HIV who had been co-infected with hepatitis C with people who had hepatitis C alone and looked at mortality from liver and non-liver related causes after treatment with direct-acting antivirals. A total of 2049 people with previous hepatitis C infection and 592 people with HIV and previous hepatitis C infection were included in the study. Participants were followed for a median of 2.8 years after treatment.

There was no significant difference in the incidence of liver-related events or liver-related mortality between the two groups. There was a trend towards higher non-liver-related mortality in people living with HIV. Study presenter Mathieu Chalouni said that the higher risk of non-liver-related mortality may be explained by HIV-related inflammation and immunodeficiency or higher alcohol and tobacco consumption. As reported in an article published this month in the Journal of Hepatology, this cohort had a higher risk of non-liver cancer and non-AIDS-defining cancers and these were the chief causes of death in people with HIV during the follow-up period.

COVID-19 and liver disease

Dr Thomas Marjot of the University of Oxford presenting to EASL 2020.

People with advanced liver cirrhosis are more likely to develop severe COVID-19 complications and to die from it, but those who have received liver transplants do not appear to be at greater risk, researchers reported at the conference.

Dr Thomas Marjot of the University of Oxford and colleagues analysed data from two international registries of people with liver disease and COVID-19. The SECURE-Cirrhosis registry collects case reports from North and South America and parts of Asia, while EASL's COVID-HEP registry includes reports from the rest of the world. Dr Marjot reported on outcomes in 745 patients with chronic liver disease and COVID-19, of whom 386 had progressed to cirrhosis, registered up to 8 July 2020.

The analysis compared people without cirrhosis and those with three levels of cirrhosis severity: Child-Pugh (CP) class A, B and C, with C being most severe.

For each higher level of liver disease severity, the risk of adverse outcomes, including intensive care unit admission, mechanical ventilation and death, increased in a stepwise fashion.

Most people without cirrhosis survived, with mortality rates of 8% for those who were hospitalised and 21% for those on ventilators. Among those with CP class A, mortality rates were 22% once hospitalised and 52% once put on a ventilator. Among those with CP class B, the respective rates were 39% and 74%. Among those with CP class C, more than half of hospitalised patients (54%), and most of those on ventilators (90%) died.

The most common cause of death for people with cirrhosis and COVID-19 was respiratory disease (71%), far exceeding liver-related deaths (19%) and cardiac deaths (5%). Nearly half of people with cirrhosis (46%) experienced liver decompensation, but even in this subgroup lung disease led to higher mortality than liver-related complications (64% versus 24%, respectively).

Prof. Marina Berenguer Haym of the University of Valencia in Spain presented an analysis of outcomes among liver transplant recipients with COVID-19 in the same two registries. The findings were published in The Lancet Gastroenterology and Hepatology.

This analysis included 181 liver transplant recipients with COVID-19 in 18 countries. The control group included 627 COVID-19 patients who had not received transplants.

Transplant recipients and non-transplant patients with COVID-19 were hospitalised at similar rates (82% vs 76%, respectively). However, the transplant patients were more likely to be admitted to intensive care (28% vs 8%) and to be put on ventilators (20% vs 5%). Nonetheless, the transplant group had a somewhat lower mortality rate than those who did not receive transplants (19% vs 27%).

"We should be reassured that clinicians and health policy makers should be aware liver transplantation does not confer major additional susceptibility to adverse outcomes," Prof. Thomas Berg of the University of Leipzig in Germany said at a press briefing in advance of the conference. He suggested that a bigger concern is that people with liver disease may avoid medical care due to fear of COVID-19, which could lead to subsequent waves of advanced liver complications in the future.

Experimental treatments for hepatitis B

Experimental treatments for hepatitis B had a high profile at the conference.

Hepatitis B is a chronic infection. Current treatments can suppress viral replication and reduce liver damage but cannot cure the infection.

Nucleoside or nucleotide analogues (NRTIs) block hepatitis B virus (HBV) replication but do not block the production of hepatitis B surface antigen (HBsAg) nor prevent the replenishment of the pool of cccDNA in hepatocytes which supports viral replication if NRTI therapy is stopped. NRTI treatment must continue indefinitely to control hepatitis B replication.

Combining NRTIs with antivirals which directly block viral entry into hepatocytes, or prevent the production of viral proteins, is judged more likely to deliver a functional cure for hepatitis B infection – viral suppression without the need for treatment.

Achieving a functional cure is likely to require a combination of drugs. 'Functional cure' means that all antigens (e.g. HBsAg, HBeAg) and the HBV DNA of the virus disappear from the blood, and only antibodies remain. The cccDNA of the hepatitis B virus however remains in the liver cells. So far, it is not possible to also eliminate hepatitis B cccDNA from liver cells, which would be closer to a 'sterilising cure'. This DNA forms the reservoir which supports ongoing viral replication.

JNJ-3989, a small interfering RNA agent, is being developed by Arrowhead and Janssen, a Johnson & Johnson company. The small interfering RNA (siRNA) binds to messenger RNA (mRNA), preventing transcription of mRNA involved in the production of viral proteins, including HBV polymerase and HBsAg.

Professor Edward Gane presented 48-week follow-up from the phase 2 study at the Digital International Liver Congress. Forty-eight weeks after the final injection of JNJ-3989, 34% of participants maintained a reduction in HBsAg of at least 1 log10 IU/ml. Future studies will test 48 weeks of JNJ-3989 and NRTIs, with or without JNJ-6379, a capsid assembly modulator.

GSK-3228836 is an antisense oligonucleotide, a chain of nucleic acid designed to cut hepatitis B RNA, preventing the transcription of viral proteins. GSK-3228836 is being developed by GlaxoSmithKline. Phase 2a study results presented at the conference showed a mean reduction in HBsAg of -1.55 log10 IU/ml at day 29 compared to no change in the placebo group in people with no prior history of NRTI treatment. GSK-3228836 is moving forward to phase 2b trials comparing longer dosing periods.

However, selgantolimod, a toll-like receptor agonist designed to enhance immune responses to hepatitis B virus, showed only modest effects on HBsAg levels in a phase 2 safety and efficacy study.

Selgantolimod is an immune-modulating treatment that can enhance immune responses against hepatitis B virus. Toll-like receptor agonists are compounds that can trigger toll-like receptors in the liver to produce interferons and activate natural killer cells and T-cells against the hepatitis B virus. Several companies are developing toll-like receptor agonists as potential immune-modulating treatments for hepatitis B.

The phase 2 study showed that only one person out of 36 who received selgantolimod experienced an HBsAg reduction of greater than 1 log10 IU/ml.

Hepatitis D treatment

Professor Heiner Wedemeyer of Essen University Hospital.

High-dose bulevirtide (Hepcludex) combined with pegylated interferon alfa-2a (Pegasys) or tenofovir disoproxil fumarate (TDF; Viread) led to suppression of hepatitis delta virus (HDV), according to a presentation at the conference. What's more, a third of people taking bulevirtide with TDF maintained an undetectable HDV viral load after stopping the drug. Bulevirtide was approved in the EU for treatment of hepatitis D on 31 July 2020.

Hepatitis C elimination

Only one in four high-income countries is on track to eliminate hepatitis C by 2030 and nearly two-thirds will miss the targets by more than 20 years at current rates of progress, according to an analysis of 45 countries presented to the conference by Homie Razavi of the Center for Disease Analysis.

In 2016, World Health Organization member states agreed to work towards elimination of hepatitis B and C by 2030. They set targets of reducing deaths from hepatitis B and C by 65%, by diagnosing 90% of infections and treating 80% of eligible people, as well as reducing new infections by 90% (the previous incidence target was 80%).

The Center for Disease Analysis used the most up-to-date data on rates of diagnosis and treatment to model reductions in mortality and hepatitis C incidence for 45 high-income countries.

Updating an analysis presented in 2019, this year’s progress report shows that eleven countries are on target to achieve elimination by 2030, up from nine in 2019.

Australia, Canada, France, Germany, Iceland, Italy, Japan, Spain, Switzerland, Sweden and the United Kingdom should reach the targets by 2030.

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