The 30th Asia-Pacific Society for the Study of Liver Diseases (APASL) Annual Meeting was held online from February 4 to 6, 2021. The purpose of this conference is to promote the progress and basic education of liver disease, exchange ideas and reach consensus, encourage the development of medical practice in the field of liver disease, and coordinate scientific research among different regions in different liver disease-related disciplines.Professor Raymond Chung, president-elect of the American Society for the Study of Liver Diseases (AASLD) and director of the Center for Liver Diseases and Liver at Massachusetts General Hospital, was invited to deliver a presentation entitled "Should We Stop HCC Surveillance After the Eradication of viral hepatitis?" on February 6. "Hepatology Digest" was honored to invite Professor Chung for an interview to give an update on the risk factors, surveillance and prevention of viral hepatitis associated hepatocellular carcinoma (HCC).
Hepatology Digest: Due to covid last year, many areas of medicine were affected to varying degrees and the field of liver disease has seen great challenges. Could you talk to us about what are the important advances in the field of liver disease last year and how to manage patients with liver disease under the impact of covid?
Dr Chung: 2020 saw a great deal of change as a result of COVID-19. COVID-19 dominated the headlines of course, and in terms of the pandemic, we know that this is not just a respiratory pneumonia, but also a multisystem disorder that causes a great deal of morbidity and mortality. The liver is no exception in this regard. What we saw is that COVID-19 does very much affect the liver. We know that the virus that causes COVID-19 can infect the two cell types within the liver, including the hepatocytes and the bile duct cells. We know that elevated liver enzyme tests are very frequent in patients with COVID-19. In hospitalized patients, we see elevations in liver tests occur in half of the patients, and some studies have suggested that increases in liver tests may signal poor prognoses for these patients. We have also seen that patients with chronic liver disease, particularly those with cirrhosis, appear to be at higher risk for adverse COVID-19 outcomes in general, but including a risk for acute-on-chronic liver failure. Particularly at risk are those patients with decompensated cirrhosis (liver disease that has already demonstrated organ dysfunction). Alcoholic liver disease appears to be specifically at increased risk compared to other etiologies of liver disease. And patients with hepatocellular carcinoma are also at increased risk for adverse outcomes. Additionally, fatty liver may be associated with adverse outcomes, but this is a difficult entity to separate from the very frequently associated conditions of diabetes and obesity, which themselves are independent risk factors for severe COVID outcomes. So ongoing studies are going to be important for us to understand who gets sicker with COVID-19, and we will also need to understand exactly what impact COVID-19 will have on patients with chronic liver disease. For those who survive COVID-19, will their liver disease be on a worse trajectory? Either way, the existence and availability of vaccines will be incredibly important with regard to this group of patients as a whole, because of their specific increased risk.
2020 saw improvements on other fronts. We saw improvements in the treatment of hepatitis B virus. We know of course that there have been significant improvements with hepatitis C in terms of developing curative strategies. The field as a whole has asked itself, if we can cure hepatitis C, what about a strategy for curing hepatitis B? Hepatitis B virus is a very different virus, but as we understand the virus lifecycle better, we understand there are steps that have historically not yet been targeted, but are now essentially known to be targets for new small molecule antiviral agents that could theoretically increase the likelihood of HBV cure (a functional cure with the loss of HBsAg). In this regard, we have seen advances across several different fronts in terms of specific inhibitors of specific lifecycle steps, including: inhibitors of virus entry, which have shown real promise in helping to prevent viral infection of liver cells in the first place; the development of RNA inhibitors (RNAi) that knock down viral protein production, with the advantage of not only suppressing viral replication, but decreasing viral protein production, which itself may be associated with suppression of the host immune response against hepatitis B. We have seen a number of different RNAi compounds developed, all producing promising reductions in HBsAg levels, and doing so, in some cases, in a sustained manner. There is promise for this class of compounds. There is a related class of compounds called antisense oligonucleotides, which again accomplish reduction in viral protein production. There is another class of inhibitors called capsid assembly modulators, which block virus assembly. We have seen several candidates in this class knock down viral replication as well as potentially improving modulation of other steps in the virus lifecycle. Capsid protein is involved in several discrete aspects of the virus lifecycle, and is therefore an attractive target for inhibition. A fifth class is the so-called nucleic acid polymers, which block surface antigen secretion and their release into the circulation, and in so doing may rejuvenate immune responses that would otherwise be suppressed by the excess quantities of sAg that would be in the circulation. So in 2020, we have seen significant promise for several classes of therapy against hepatitis B, which could potentially be combined with one another to improve the likelihood of functional cure. Yet another approach that was tested in 2020 and in prior years and showing potential for promise, was taking patients who had been on suppressive antiviral therapy with currently FDA-approved compounds known as HBV polymerase inhibitors, which produce excellent rates of suppression but do not accomplish a HBV cure, or at least only in a small minority of patients, and in selected cases, withdrawing these nucleoside analogs or polymerase inhibitors after a long period of suppression and looking for cases of spontaneous control of the viral infection off the drug. In a subset of patients who have had low sAg levels this may be possible and lead to sAg loss in that patient subset. So this withdrawal strategy might be applied successfully in certain chronically well-suppressed patients.
I mentioned hepatitis C virus and the breathtaking cures that have been developed over the last several years. These have continued to advance in terms of their application in infected patients all over the world. We are hoping to achieve the elimination of new hepatitis C cases by 2030. One way to help accomplish that is to really simplify therapy – to get therapy to as many people and across more resource-limited settings as possible. 2020 saw a study showing that we could essentially accomplish successful rates of cure using a minimal monitoring strategy where patients were given their antiviral therapy upfront for 12 weeks and not monitored with study visits and not monitored with blood draws, but completing the treatment course before coming in to document a cure. So this simplification of therapy is possible with very high rates of success and excellent tolerability compared to other approaches of monitoring patients during treatment. In resource-limited settings, this may be a strategy that allows many more patients to be treated successfully. We have also seen that in active injection drug users, who are in many ways the spreaders of the hepatitis C virus today by transmitting the virus from one person to another through shared injection paraphernalia, treatment is not only possible, but can be done with very high rates of success. This can be accomplished either using directly observed therapy or potentially using what we call a patient navigator, who is someone who helps guide these patients through their treatment, in some instances remotely. It is quite possible then that those even at greatest risk of spreading HCV can be successfully treated thus diminishing the rate of spread - a very important concept moving forward.
In the area of fatty liver disease, which of course is the world’s most common chronic liver condition, 2020 saw promising data for a number of different classes of therapy, giving hope that we will soon see approvable agents for the management of non-alcoholic steatohepatitis (NASH). We saw several agents that worked on metabolism to result in decreased fatty acid and triglyceride production within the liver cells themselves. These work across a variety of different mechanisms. One of these is the glucagon-like peptide-1 (GLP-1) agonists, which are historically approved for diabetes. It turns out this group of agents, particularly in diabetics with NASH, may be promising in bringing about improvements in fatty liver, improve inflammation, improve scarring, and even weight loss. There have also been developments with fibroblast growth factor-19 analogs, which again are associated with encouraging rates of resolution of NASH, and improvements of scarring/fibrosis in those patients. The FGF-20 agonists are yet another mechanism by which steatosis can be reduced and consequent resolution of NASH. An agonist of a pathway called PPAR has been successfully used in NASH in early clinical trials showing improved rates of NASH resolution and potential improvements in fibrosis and scarring as well. So there is much encouragement in terms of classes of agents that may improve the state of affairs for patients with NASH. We have a lot to look forward to in terms of successful treatments in that setting.
Finally, in hepatocellular carcinoma, historically we have had a great deal of difficulty in terms of improving survival, largely because HCC develops in patients who already have cirrhosis (>80% of cases). But we have seen extraordinarily encouraging results using advances in combination therapy in patients with unresectable liver cancer. These combinations used two classes of therapy – inhibitors of checkpoints, in this case anti-PD-L1, using atezolizumab, and a second agent that blocks a growth factor, VEGF, called bevacizumab. This combination in a randomized trial compared to the prior standard-of-care for the treatment of unresectable HCC, sorafenib, resulted in a 42% improved survival. This approach has emerged as a go-to therapeutic strategy for patients with unresectable HCC. This is really a significant advance for all of our patients who develop HCC as a major complication of their chronic liver disease. So that is a little bit of a roundup of some of the encouraging advances we saw in 2020 in liver disease.
Hepatology Digest: Is there any difference in the incidence of hepatocellular carcinoma after virus eradication amongst patients trialed with different therapies?
Dr Chung: It is absolutely clear that both curing the virus (for hepatitis C) and suppressing the virus (most often the case for hepatitis B) are associated with real clinical benefits. That is not just improvements in the rate of cirrhosis and the rate of decompensated liver disease, but also the rates of HCC. For instance, with HBV, we know that patients who suppress the virus with nucleoside analogs/polymerase inhibitors and who are non-cirrhotic, that risk reduction is around 80% for HCC. Moreover, patients with cirrhosis who are at greater risk for liver cancer, their risk reduction, if successfully suppressed, is around 30%. Clearly, there are benefits to suppressing the virus. If you can succeed with loss of HBsAg and achieve a functional cure, which doesn’t happen for the vast majority of patients currently but we hope to be able to do with newer therapies, there may be an even greater benefit in terms of the future incidence of hepatocellular carcinoma. So we should still endeavor to achieve functional cure in hepatitis B to reduce that future risk for HCC. For hepatitis C, we can cure these patients. However, for patients with advanced fibrosis or cirrhosis with the highest risk for subsequent HCC, we know that even curing their HCV does not fully eliminate that risk moving forward. They need to continue to be monitored for this subsequent risk for HCC if they have advanced fibrosis. We do know the risk reduction for HCC is still significant. Most studies suggest a risk reduction of around 75% in patients with cirrhosis for their subsequent development of HCC. Put another way, we are reducing that risk by three-quarters. It’s not a 100% reduction, but it is pretty close. We can say to patients that we can reduce their risk dramatically, but they will still require monitoring for HCC moving forward.
Hepatology Digest: What are the risk factors for HCC development in patients after eradication of viral hepatitis?
Dr Chung: The most important risk factor for the subsequent development of HCC after the elimination of viral hepatitis is the state of cirrhosis. If there is cirrhosis, particularly advanced cirrhosis, which can be assessed using elastography or clinically based on the appearance of the liver or through the existence of decompensation, then this is associated with the highest risk for subsequent HCC, even after cure. There are other factors like age and diabetes that are important risks for the subsequent development of liver cancer. The co-existence of fatty liver or heavy alcohol use are important cofactors for subsequent HCC risk. Ultimately, it is hoped that markers will be developed to help prognosticate that risk in patients who have cleared their virus. We don’t have those yet. These may be related to specific gene expression signatures or defects that persist in these patients after virus elimination.
Hepatology Digest: How do we improve HCC surveillance to optimize outcomes in clinical practice?
Dr Chung: I think the main thing is going to be intensifying surveillance by selecting those patients who we view to be at particularly high risk – separating the high-risk patients from the low-risk patients. We take those high-risk patients and subject them to more intensive surveillance. That is the best way for us to arrive at early detection and therefore treatment in those who subsequently develop HCC. The other possibility, and something we are hoping to test in prospective controlled trials, would be the use of chemopreventive strategies. Even after eliminating the virus and by stratifying those patients at increased risk, we could apply additional treatment to further reduce the risk of that patient developing subsequent hepatocellular carcinoma. There may be some promising approaches in that regard using common agents, such as statins, for example.
Hepatology Digest: How should we manage patients with abnormal alpha-fetoprotein or other biomarkers in the absence of scans and other imaging modalities?
Dr Chung: We can’t really diagnose HCC without an imaging modality. That is critically important. I think we are eventually going to need to find a way to get any patient who is at risk access to imaging. It is very hard to arrive at a diagnosis of HCC without imaging because you need to know the extent of the tumor. What I would say is that if someone has abnormal biomarkers, it will be very important to get that patient some form of imaging, the more sensitive the better. I do believe all of this rests on an important imaging approach. Even in those patients where we check circulating tumor cells and use other sophisticated biomarkers, at the end of the day, we are still going to need to understand the extent of the tumor in order to manage it optimally. Imaging will be critical at the end of the day.
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