AASLD 2020 |Prof. Raymond Chung: Development of new drugs for hepatitis B and NASH, and chronic disease management in epidemic situation in 2020

With the possibility of a cure for hepatitis C, our expectations for a cure for hepatitis B have only increased.At the end of 2020, "Hepatology Digest" special invitation to the American society for the study of liver diseases (AASLD) incoming chairman, Massachusetts general hospital, director of the center for liver disease and liver and professor of medicine at harvard medical school,  Dr Raymond Chung, introduce new drugs and nonalcoholic fatty hepatitis b hepatitis (NASH) new drug research and development progress and future prospect, at the same time share the slow COVID - 19 pandemic disease management experience.

Hepatology Digest: Most patients with hepatitis C can be cured with currently available DAAs, however, ‘functional cure’ is only rarely achieved in patients with chronic HBV infection with current antivirals and there are currently no approved therapies for NASH. How about the latest progresses in the research of treatment of HBV infection and NASH presented at this meeting?

Prof. Raymond Chung: This is a wonderful question. There was a great deal of activity in both of those areas presented at the recently concluded TLMdX (the Liver Meeting Digital Experience). Let's start with hepatitis B infection, where the whole idea, as you've suggested, is that if we can accomplish cure for hepatitis C, what's to keep us from doing the same for hepatitis B? They are two very different viruses. They do infect the same organ, the liver, of course, but they have very different life cycles and very different behaviors. Hepatitis B, in particular, is a much more persistent infection because of its ability to reside in the infected nucleus as a very stable form, so cure of hepatitis B infection is much more challenging to accomplish.

Having seen the success we have had with DAAs for hepatitis C has really stimulated all of us in the field to evaluate new approaches to treating hepatitis B and in this regard, there has been lots of activity in the development of agents that work against multiple targets of the hepatitis B. A classical target to which currently approved agents are directed is an enzyme known as the HBV polymerase. Given the complex life cycle of hepatitis B, we’ve now seen several agents developed targeted at additional steps in the virus life cycle. Examples of this include the so-called capsid assembly modifiers, which block both replication and assembly of the virus. Data was presented on several of these agents at this meeting, which demonstrate that they each have an anti-viral effect against hepatitis B replication. They also appear to diminish a formation of assembly of the virus as well and may have impact on the ability of that highly stable form of HBV in the nucleus of the infected cell to be transcribed and translated. In this regard, they provide additional activity against hepatitis B that polymerase inhibitors don't offer.

With currently available treatments, there was also excitement around other mechanisms targeting the RNA that comes out of the nucleus that becomes transcribed and ultimately translated into viral proteins. This RNA can now be bound to and blocked by a number of different strategies, one of which is called RNA interference, or RNAi, and another is called antisense oligonucleotides. Both of these rely on specific sequences that recognize and bind to hepatitis B virus RNA coming out of the nucleus. They are delivered to the cell using highly efficient, targeted approaches. They knock down production of the viral proteins. We saw exciting data that supported the idea that RNAi can not only engage their targets, but do so in a very prolonged manner and knock down synthesis of hepatitis B virus for a very long period of time. This class of treatment offers encouragement for us to believe that combined with other strategies, we may be able to see enhanced rates of functional cure, defined as the loss of hepatitis B surface antigen in patients who are chronically infected.

Similarly, for nonalcoholic steatohepatitis (NASH), there has been a great deal of activity evaluating inhibitors of different targets that contribute to the development of fatty liver, liver inflammation and scarring (fibrosis) that are characteristic of NASH. We're excited to see that several of them show considerable promise for their ability to reduce liver fat, reduce liver inflammation, resolve NASH itself, and improve fibrosis. Moreover, we observe additional benefits for some of these agents in their ability to reduce weight in many patients, an important finding in a population that is so frequently obese or overweight. We've also seen some agents improve even serum lipids and blood sugars in a favorable direction, an important finding in patients who have a high frequency of diabetes or hyperlipidemia. There are reasons to believe that some of these compounds will emerge as successful strategies for a condition that affects such a large portion of the population and for which there are currently no approved therapies. These include treatments that would work on a variety of different mechanisms.

Among the classes of compounds with promise are agonists of fibroblast growth factor 19 and fibroblast growth factor 21, and agonists of PPAR, all important regulators of liver fat production. In addition, encouraging data were also presented for a fatty acid synthase inhibitor, an enzyme involved in the generation of fatty acids in the liver. There have been improvements as well in agents that work on blood sugar or glucose handling; some of these also introduce weight loss, which is such a problem for most of our patients with NASH who are overweight or obese. These include agonists of glucagon like peptide-1 (GLP-1), which have shown their ability to improve NASH and bring about significant weight loss. There are also inhibitors of the SGLT-2, which is involved in the transport of glucose. These can be seen or have been used in diabetic patients and have been shown to also produce beneficial effects on fatty liver. So collectively speaking, with several classes of treatment having had data presented at this meeting, we're very excited about the idea of these agents targeting host metabolism, bringing about improvements in the key features of fatty liver disease. We anticipate that many of these will move deeper into clinical trials and we hope that several of them will be ultimately approved for treatment of our patients.

Hepatology Digest: In COVID period, it is difficult for patients with chronic liver disease receiving regular follow-up, how to solve the problem?

Prof. Raymond Chung: This has been a huge issue for care providers all over the world. In many ways, the pandemic has effectively dramatically accelerated the integration of tele-medicine into practice.

I think what we've all come to learn is that there is a subset of our patients who may very well benefit from continuing telemedicine care long after COVID is solved or has an effective vaccine, and after it's safe for patients to be coming back to the hospital or to the clinic. Many of these will have stable conditions and several may face logistical challenges getting into the medical center for care. So, we've already seen, I think, some important changes occur that will affect our delivery of care are moving forward.

Other ways of coping with COVID has been to have patients in more remote areas use local less crowded resources such as local laboratories and radiology, for instance, to minimize need to make it in to a larger medical center. This approach will decongest traffic to the medical center but allow patients to have enhanced convenience.

I think another important aspect of COVID and tele-medicine that will impact care moving forward is delivering advice to other providers. So here again, the academic medical center, which may be the hub of knowledge about specific conditions can be used as a resource to train other specialists or primary care physicians who are seeing those patients on the front lines help them learn the tenets of care of conditions like hepatitis C, hepatitis B or nonalcoholic fatty liver disease. So in this regard, we can multiply the effectiveness of the workforce that does exist. This could be particularly effective in more rural areas where those patients may not be able to make it to the academic center and for whom they may be seeking care much more locally.

Of course, I do not mean to suggest that we will completely replace the need for face to face visits for our most sick patients, many of whom have advanced liver disease. They will need and continue to require, at a minimum, periodic face to face visits and in many cases continued direct care.

 

Hepatology Digest:  A large US multi-center cohort study showed that patients with chronic liver disease and COVID-19 experienced high morbidity and mortality, so whether patients with chronic liver disease, especially patients with cirrhosis are more susceptible to COVID-19?

Prof. Raymond Chung: This is another really important question. Are patients with advanced liver disease more susceptible to COVID-19 disease and to its mortality? There are number of studies that have looked at this. And certainly, again, several presentations at this meeting did address that. The one presentation I think that you're referring to was very provocative in that there were three major risk factors among patients who had cirrhosis that appeared to put those patients at higher risk for mortality when contracting COVID-19.

The first was the presence of decompensated liver diseases, in other words, cirrhosis that is no longer stable with regard to the preservation of hepatic function or has been complicated by the development of significant portal hypertension, such as bleeding esophageal varices, ascites, or encephalopathy.

A second independent risk was for patients having hepatocellular carcinoma (HCC) or liver cancer. And it appeared that this risk was independent of the first risk of having decompensated cirrhosis, so that even if you had HCC but not have decompensated liver disease, there still appeared to be an increased risk. Whether this was related to the cancer itself or to its treatment remains to be seen and deserves further analysis.

A third independent risk factor appears to be the existence of alcoholic liver cirrhosis. In particular, among all the causes of cirrhosis, alcoholic cirrhosis appears to be at increased risk for worse outcomes with contraction of COVID-19. The specific basis or explanation for why this condition actually confers a higher mortality was not clear from the analysis of these data. But I think it was reasonable to speculate, as the authors did, that alcoholic liver disease is accompanied by enhanced inflammatory profiles that are stirred up further by the contraction of COVID-19. Again, further work will be necessary to try to tease out this connection.

So, these are, all in all, highly provocative findings that merit confirmation and follow up in other groups of patients.  Until then, I think that for those patients who have advanced liver disease in the form of decompensated cirrhosis, we will need to take great care to minimize their exposure to COVID-19 wherever possible.