Saving lives - World Hepatitis Day 2022

Around 350 million people around the world are living with viral hepatitis – an infection that causes liver inflammation and damage.

Autoimmune hepatitis (AIH) is a rare cause of long-term hepatitis, in which the body’s immune system attacks and damages the liver.

Due to inherent problems with existing treatments for both viral and autoimmune hepatitis, new approaches are urgently needed.

Within the last decade, we've invested £3.8 million into hepatitis research, all thanks to generous donations from the giving public. This includes HCV Research UK, one of the largest hepatitis C virus (HCV) research cohorts in the world, and six research fellowships, for scientists tackling both viral and autoimmune hepatitis.

Read on to find out more.

Finding the right treatments for hepatitis C

HCV Research UK is a clinical research database and biobank, which was established to address critical gaps in our understanding of HCV.

Thanks to clinical data from 12,000 patients, and a repository of 150,000 samples, HCV Research UK has provided vital information about the longer-term impact of the virus to researchers, patients, the NHS, and the pharmaceutical industry.

Professor John McLauchlan at the Medical Research Council (MRC) University of Glasgow Centre for Virus Research, who co-leads HCV Research UK, says it has offered the research community a “unique opportunity to ask the most pertinent and challenging questions, powered by integrated biological, epidemiological and clinical data, at a national level.”

HCV Research UK began its patient recruitment just ahead of revolutionary new antiviral treatments being tested in the clinic. Following a decision by NHS England to make these new treatments available through an early access programme to very ill HCV patients – on the condition that their data and samples were provided to HCV Research UK – clinicians could now access invaluable insights into the performance of these new therapies in the real world and outside the confines of a clinical trial.

“We discovered that these treatments were capable of curing HCV in these very sick patients, and without this early access programme, they wouldn’t have received the therapies that they desperately needed,” says Professor McLauchlan.

Read the full story in our Impact Report.

Controlling liver damage in autoimmune hepatitis

“There is evidence that in people with autoimmune hepatitis (AIH), the body’s protective mechanisms are duped and do not work properly,” says Dr Palak Trivedi from the University of Birmingham.

“We think there’s a reduced function of potentially protective immune cell types (called regulatory T cells, or ‘Treg’) and an increased number and function of cells that drive inflammation (effector T cells). The key question is: how do we restore the balance between protective cell types and the ones that drive inflammation?”

Thanks to fellowship funding from the Foundation, Dr Trivedi is investigating whether injections of Treg can control liver damage caused by the body’s immune system. Previous work from the Birmingham research group has shown that Treg can be taken from patients, enhanced in the lab, and safely returned by injection, with a quarter of the injected cells travelling back to the inflamed liver.

“We want to take a targeted treatment approach, which homes in on the liver and gives the body the type of immune cells it needs to keep the fine balance of protective and inflammatory cells in check.”

Dr Trivedi’s work could be used to identify and treat AIH patients much earlier.

Investigating a new biological phenomenon in viral and autoimmune hepatitis

Dr Zania Stamataki from the University of Birmingham is also looking at the role of Treg cells, but for both viral and autoimmune hepatitis. Specifically, she is looking at how the liver regulates Treg cells.

“We recently discovered that the main cells that make up 80 per cent of the liver, hepatocytes, actively engulf Treg cells and destroy them,” says Dr Stamataki.

“We called this new phenomenon enclysis, from the Greek word for enclosure, confinement and captivity. Indeed, we found increased enclysis in AIH compared to hepatitis B livers donated to research after transplantation. It is therefore possible that toggling enclysis may help improve both disease outcomes.”

Dr Stamataki is running a series of experiments to test this hypothesis, using human liver tissues. The broader aim is to improve and prolong the effectiveness of immunotherapies for patients with viral and AIH.

Estimating the benefits of liver cancer screening

Dr Hamish Innes from Glasgow Caledonian University is developing a new clinical prediction model which estimates the benefit of liver cancer screening for patients with liver cirrhosis, who have been cured of hepatitis C.

With this model, clinicians will be able to identify those patients who will gain the most from screening in terms of increased life expectancy (and vice versa, those who are likely to benefit minimally or not at all). This is something that existing prediction models are not able to do.

“We hope this project will improve survival rates, following a diagnosis of liver cancer, in patients with cirrhosis and a hepatitis C cure,” says Dr Innes. “The modelling framework we develop could also be adapted to liver cancer screening for patients with other forms of chronic liver disease, such as alcohol-related liver disease and non-alcoholic fatty liver disease.”

Investigating hepatitis B immune and viral outcomes

Dr Upkar Gill from Queen Mary University of London is investigating the immune and viral outcomes of treatment in patients with chronic hepatitis B, using a minimally invasive liver sampling technique.

Dr Gill’s previous research has shown that a subset of immune T and natural killer (NK) cells are only based in the liver and cannot be sampled in the blood. To solve this problem, they optimised the fine needle aspirates (FNA) method, allowing them to sample the liver in a relatively pain-free manner.

“Using this method, we can study liver immune cells and viral markers over time during therapy,” says Dr Gill. “We will assess the function of these cells, along with their ‘energy’ demands, to see if they are more ‘exhausted’ compared to non-infected patients. We’re aiming to establish a ‘favourable’ NK cell subset and harness it to facilitate viral control, linking this with the level of virus in liver cells during treatment.”

Dr Gill’s research will advance our understanding of immune cells and their interaction with the hepatitis B virus in liver cells during therapy. This work will also be vital for drug development in the search for a hepatitis B cure.

Tailoring treatments for hepatitis B

Dr Leo Swadling from UCL is looking at ways of selecting specialised immune cells (known as T cells) from people who have cleared a hepatitis infection, and using the receptors from these T cells to develop ways to control and cure hepatitis B infection.

Each T cell has a unique receptor on its surface which defines what infection it recognises and within the millions of T cells in your body, only a small subset will recognise the hepatitis B virus (HBV). In patients that are chronically infected with HBV, persistent exposure to the virus leads to exhaustion of these HBV-specific T cells, meaning they can no longer fight the infection, and cannot be expanded by vaccination.

Instead of rejuvenating the existing exhausted T cells within chronically infected patients, emerging technologies allow researchers to redirect healthy T cells to recognise HBV, by transplanting into each T cell a receptor that recognises HBV (receptor gene therapy). These redirected T cells are in turn transferred into patients.

Dr Swadling is looking to improve on the initial success of this technology, by pinpointing protective T cells in the liver. “We're studying the gold-standard immune responses in patients that can control infection, and using these as a blueprint to tailor novel immunotherapies,” says Dr Swadling.

Understanding how the hepatitis A virus hijacks and infects cells

Dr Elisabetta Groppelli from St George’s University of London is investigating how the hepatitis A virus (HAV) infects cells in the body, to help develop anti-viral strategies that will block the infection. Using a combination of molecular and state-of-the-art structural biology approaches, Dr Groppelli is trying to understand how RNA viruses deliver their genes to cells.

HAV causes more serious disease burden in developed countries, as their improved economic and sanitary conditions reduces childhood infections, resulting in accumulation of more vulnerable adults. Although the World Health Organization encourages all its member states to vaccinate against HAV, low availability and high costs of the current vaccine have made it harder to develop large-scale vaccination strategies.

Dr Groppelli’s research will lay the foundation for developing anti-viral strategies that block the HAV infection.

“I’m isolating and manipulating the hepatitis A virus in the lab, to understand how it hijacks and infects cells. This will help us understand how the infection then spreads through the body,” says Dr Groppelli.

Revealing how the hepatitis B virus replicates

Dr Nikesh Patel from the University of Leeds is visualising the replication of the hepatitis B virus (HBV), using a combination of techniques, to understand what is happening at the molecular level. Understanding the key steps involved in the virus’s replication will help identify new drug targets.

"HBV is a worldwide health concern,” says Dr Patel. “Chronic infections kill around 800,000 people per year, mainly through a combination of liver cirrhosis and cancer.

"Current treatments focus on stopping the replication of the virus, however, drug resistance eventually occurs. My research aims to use Cryo Electron Microscopy and X-Ray Footprinting to look at the molecular mechanisms involved in viral replication, in order to identify novel drug targets."

All of the research detailed here is funded by gifts in Wills, with the exception of Dr Zania Stamataki's autoimmune hepatitis research - which is funded by Robert Colvile and his supporters.