Hepatitis B virus and hepatitis C virus are the main types of viral hepatitis. Most liver diseases progress from hepatitis B to cirrhosis to liver cancer. The occurrence and development of diseases are accompanied by different action mechanisms, corresponding to different treatment methods. What are the current hot topics of hepatitis B and hepatitis C? What is the mechanism of progression from hepatitis C to liver cancer? How to choose new hepatitis B drugs for treatment? Around these questions, during this year's annual meeting of American Association for the Study of Liver Diseases (AASLD2021), Hepatology Digest media specially invited Dr. Raymond Chung - the chairman of the conference, the director of the Center for Liver Diseases and Liver of Massachusetts General Hospital and the professor of medicine at Harvard Medical School, to answer them one by one.
Hepatology Digest：Cure of hepatitis B is still a mission impossible at present. The ideal endpoint of treatment for now is socalled “functional cure”. In your opinion, which aspects of hepatitis B should be the focus at present? How should we make choice among the new hepatitis B drugs?
Dr Chung：These are all very good questions. As you have already pointed out, chronic hepatitis B is a real challenge to think about the notion of cure, in a large measure, because it is a highly latent virus with a very stable form in the nucleus of the infected cell - the covalently closed circular or cccDNA - that is extremely difficult to eliminate once established. In persons with chronic hepatitis B, our goals, at least to this point, have really been more modest. These include suppression with nucleoside analog treatments that block the HBV DNA polymerase, which of course is the engine of HBV nucleic acid replication. There are new classes of therapy as you implied that I think give us hope that we will be able to enhance the rates of functional cure, namely the loss of HBsAg in chronically infected patients, which is a highly elusive endpoint on NUC therapy alone. These other classes of therapy include inhibitors of other life cycle steps, the most prominent of which would be the assembly of the virus aided and abetted by a protein known as the HBV capsid protein. There are a number of inhibitors of these capsids, called capsid assembly modulators, which have an antiviral effect, and whose antiviral effect is actually additive to the effects of nucleoside analog therapy. It is quite possible that these capsid assembly modulators may also work on other steps in the life cycle, including replenishment of the HBV cccDNA in the nucleus. So, there is excitement around that class, and another class of therapies that block viral protein production by specifically targeting HBV nucleic acids as they emerge from the nucleus. For instance, there is an HBV transcribed RNA that emerges from the nucleus to be translated into viral proteins, and this so-called pregenomic RNA (pgRNA) can be the target of therapies known as either RNAi (interfering RNAs) or oligonucleotide antisense molecules that can again bring about the degradation of these mRNAs and prevention of the translation of the products. The attractiveness of this class of therapies is that this can actually knock down levels of proteins including HBsAg as well as other key proteins that are responsible or necessary for viral replication in the viral life cycle in virion production. Then another class of therapy is immunotherapy. These, of course, are therapies directed against the immune responses or enhancing immune responses that have become much more feeble during infection. These approaches range from therapeutic vaccines, to antibodies, to exhaustion molecules such as PD-1, that would potentially be unregulated during chronic infection. The premise here is that by restoring these responses, we may be able to enhance functional cure rates by allowing T-cells to recognize chronically infected cells that they don’t recognize during chronic infection. I think the promise really lies in the fact that therapies that are targeted against that immune response that is weakened during chronic infection, are likely to have a disproportionate impact on our likelihood of obtaining functional cure. The reason I say that is because when we talk about achieving a functional cure, the best example of that is actually the spontaneous clearance of hepatitis B during natural acute infection. In persons with mature immune responses (namely adults) who experience acute infection, clearance and functional cure is the rule, rather than the exception. These individuals eventually lose HBsAg and develop strong neutralizing antibody responses in the form of anti-HBs. What is clear in those patients is that they have excellent and broad T-cell responses against hepatitis B. What we are looking to try to do in chronic infection is really to reinvigorate those responses, and essentially pave the way for a clearing or curative response that might be seen in acute resolving infection in persons who are chronically infected. So can we emulate that roadmap that we see in acute infection? I am excited about approaches that would tweak that immune response pathway, potentially in conjunction with some of the other classes of therapy that I described earlier that work on specific viral life cycle steps, including the RNAi pathway, which is responsible for HBsAg production itself. The attractiveness of including RNAi with, for instance, immunotherapy, is the notion that HBsAg secretion (which we see in excess in chronic infection) may actually contribute to the subversion of those host immune responses. Knocking down HBsAg may have the net effect of liberating some of those immune responses, in addition to the immune therapy strategies we talked about. So, it is possible that combination approaches may result in even more impressive responses in terms of recovery of immune response against hepatitis B.
Hepatology Digest：You are among the internationally acknowledged leaders in the field of HCV virology, pathogenesis and liver cancer. What do you think about the development of liver cancer in some HCV patients who have achieved SVR? What is the mechanism of HCV related liver cancer?
Dr Chung：This is a really excellent question. We certainly have made revolutionary advances with the introduction of curative direct-acting antiviral therapy for hepatitis C. It has really been an extraordinary marvel to see the cure rates approaching 98-100% in our patients with chronic hepatitis C. And yet, in those patients with more established fibrosis (i.e. advanced fibrosis and cirrhosis) who have achieved sustained responses (and that is the great majority of those patients), there is a reduction, but not an elimination of the risk of those patients for progression to hepatocellular carcinoma. An important practical element of this is that in patients who do have advanced fibrosis, we are not completely done with managing these patients, because they still have residual liver disease that puts them at risk for HCC. Now that risk goes down by about 70~75%, but still there is a remnant risk for HCC progression. Those patients need to be surveyed for HCC moving forward. You get at the mechanisms of that persistent risk, and when we think about HCC, we have to state that it is different from hepatitis B virus, another well-known virus that causes and contributes to liver cancer,? but it’s mechanisms are going to be different, because HBV is a DNA virus that integrates genetic material into the host. So there is the very real possibility of an insertional mutagenesis event occurring in hepatitis B infection. In contrast, in hepatitis C, there is no integration or latency of this virus. So that cure is in fact achievable, because this virus must continue to replicate for its viability. That is the reason we are able to achieve cure in so many instances of chronic hepatitis C infection. So what goes on there in terms of persistent risk? Well, it is known that HCV affects multiple signaling pathways, including the epidermal growth factor signaling pathway and other growth related pathways. The Hippo signaling pathway is another example, and the LCA (lysophosphatidic acid) pathway. All are potentially deranged in the context of hepatitis C infection. Those growth pathways may then in turn contribute to the risk of hepatocarcinogenesis. Interestingly, one would expect those pathways to calm down after cure of infection, but in reality, transcriptional studies of mRNAs in the livers of patients who have been cured of hepatitis C have shown that these pathways may remain switched on or only partially suppressed despite clearance of the virus. So this raises questions as to what in the hepatic or liver environment persists now that the virus is gone to explain these persistent alterations. Studies have demonstrated perhaps a number of persistent alterations, including the persistence of oxidative stress, which in turn can contribute to hepatocarcinogenesis, as well as so-called epigenetic changes - changes not so much in the DNA sequences themselves, but in the chromatin that surrounds the DNA that lead to its access to transcription of the genetic material. These epigenetic alterations may be permissive for more transcription of certain growth related genes as I described earlier. So these epigenetic changes may actually be more persistent after chronic hepatitis C infection, and even after clearance of hepatitis C infection as early studies have demonstrated. We think there are probably some other mechanisms at work that differ from those we have historically attributed to hepatitis B, for instance, and that these may remain. So I think it is important for us to understand which among those patients are going to be at risk for persistent hepatocarcinogenesis risk moving forward. These prognostic tools are going to be very important and interesting to develop based on some of these alterations that appear to persist.
Hepatology Digest：HBV and HCV infection are the main causes of liver cancer. Could you please share the current hot-spots in the research of these fields??Are you interested in other aspects? Could you please show us some new findings from Massachusetts General Hospital?
Dr Chung：Thank you for the question. I think for hepatitis B virus, it is really trying to understand how important it is to try to restore those immune responses that have otherwise become exhausted. This is particularly true for T-cells, which are really the main engine of clearance of virally-infected hepatocytes, but there are other cell types, both innate and adaptive cells, that have been shown to be involved in both viral control and pathogenesis. So I think it is really trying to understand what chronic hepatitis B infection does to those cell types and their disarming of those functional responses over time, as well, of course, understanding how reversible those responses are with proper and appropriate manipulations. I think the answer to that question is really going to go a long way towards describing how reversible chronic infection is in terms of restoring those T-cell and other immune responses. That is going to be the exciting line of work in hepatitis B, and of course, other studies of hepatocarcinogenesis, as well as those I have alluded to in my answer to the previous question. That is going to be very important. These can be done using cell-based models, animal models of hepatitis B infection, and even so-called organoid models, which in vitro are really more representative of examples of multiple cells in three-dimensions with one another to more accurately replicate the in vivo situation. I think these models are really going to be most informative in terms of telling us about mechanisms of hepatocarcinogenesis, as well as the immune response and the reshaping of that immune response and the contribution to functional cure, and even biological cure. From the vantage point of other research on hepatocarcinogenesis, fibrogenesis and disease progression in general, we have been very interested in looking at chemopreventive approaches. It is well-known, as I said earlier, that there is still persistent risk for patients with advanced liver disease, not only for hepatocarcinogenesis, but also for continued fibrosis and disease progression. We can’t transplant all patients. Transplantation is just not a widespread enough resource. It is also labor and capital intensive. So for those with advanced liver disease, we need to talk about strategies that would keep them from developing the serious complications of that liver disease, even if we can’t cure the underlying driver of that disease. That is particularly true in hepatitis B, and also true in other causes, like non-alcoholic fatty liver disease as a good example. Based on the persistence of these gene signatures that I referred to earlier, and the persistence of risk for disease progression and liver cancer, we are examining the role of possible chemopreventive compounds that might work to block those pathways that I described earlier that may persist in patients, even in those patients cured of hepatitis C for example. Is there a role for agents such as statins or aspirin, or even other more specific pathway inhibitors, to help prevent disease progression to the feared clinical complications of cirrhosis and liver cancer? This is an active area of investigation that we have been pursuing. We have also been very interested in investigating the interaction of hepatitis B as an example with other cofactors such as fatty liver disease, as well as HIV coinfection, both of which accelerate the course of HBV-related disease, and vice versa. We have investigated and are exploring new pathways that may contribute to disease progression for not just HBV disease, but also HIV and fatty liver disease. We are quite excited about some of our findings in that regard in terms of the contribution of factors such as hypoxia-inducible factor, just as one example. We are exploring many of these interactions, and are excited about the idea of elucidating new pathways that can be specifically targeted to prevent further progression of these important forms of liver disease.
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