The Changing Practice of Hepatology with speakers, Dr. Scott Friedman, Elliot Tapper, Victor Navarro, Michael Volk, and Sanjeev Arora. Welcome everyone. And I'll start with a question for you, Scott. You spoke so eloquently about personalization of medicine. What infrastructure do you think is required for an institution to develop a personalized medicine program? That's a great question, Ray, and thanks again for including me on the panel and as part of this great course. You know, I think there needs to be an institutional commitment, certainly well beyond hepatology. At Mount Sinai, we invested in a human biobank over 10 years ago, developed institution-wide IRB processes, and also developed the big data and informatics expertise, as well as our own computing power. So most or all of those components are required. Now, they don't all need to depend on localization within a single institution. One can look to partner with other institutions or even commercial partners. But there needs to be a serious and long-term investment in these technologies, which to me is as meaningful as investing in a clinical laboratory, which now, of course, is part, or radiology department, which is part of our standard of care. And so for those in institutions who haven't made those investments yet, they are coming, or at least the need for them is coming, because this is gonna be part of our practice of medicine. So, thank you, Scott. What do you think the current barriers are to implementing personalized medicine in clinical practice? Well, part of it we've already just addressed in so far as that there needs to be good infrastructure. There also needs to be education of clinicians. And I think that's obviously what this course is starting to address. As well, there needs to be infrastructure that will allow personalized medicine or clinical genomics data to be integrated into the electronic medical record. I mean, after all, if we're busy seeing patients, we can't start looking up the meaning of genetic polymorphisms. We need information to be translated to us that immediately impacts on clinical decision-making at the point of care. And there's a lot of effort underway by both the US government and also international bodies in Europe to develop software that takes genetic information and seamlessly integrates it into the clinical record in a way that advice is provided that can influence decision-making. We'll write that in there. Do you think payers will move in lockstep with these developments? Well, payers never move in lockstep with anything. But that aside, I think that anytime we as providers or provider organizations can show that it improves outcomes, reduces the cost of care through better diagnosis, better treatments, decreased length of stay in hospitals, then payers will sign on for sure. Thanks very much, Scott. I'll ask of Dr. Tapper, who covered non-invasive approaches to staging and assessment of liver disease. What do you think, Dr. Tapper, about screening the population for cirrhosis, given all of its morbidity and mortality? Well, thank you for the great question. And it was a privilege to be a part of a great postgraduate course. I think that we are starting to see emerging evidence that if we are able to effectively link patients with cirrhosis to care, screening is cost-effective in high-risk groups. So you at least have to establish a group of patients who have a group of people with a high pretest probability. So we're not talking about the whole population, but at least people with a known risk factor like diabetes. And because early care does reduce the risk of costly complications of things like advanced liver cancer, it is repaid in the future. You've talked a lot about several of the etiologies of liver disease in terms of the performance of non-invasive tools. What do you think the best non-invasive tool for alcohol-associated liver disease might be? So another great question, and I think that this is a relatively understudied facet, even though it is one of the most common diseases that we see. In general, the alcohol is going to confound serologic markers of fibrosis by increasing ASD, decreasing the platelet count. And we are going to rely primarily on the elastographic test. And we do have pretty good data, particularly from the group in Denmark that shows that the performance of something like Fibroscan is going to be good, albeit with a slightly higher cutoff than you'd get for non-alcoholic steatohepatitis. And this is from the audience. How do we educate our PCP and other colleagues on screening for liver disease? Yeah, so this is the hard work that we all have to do, and there is no easy way to do it. Because as it stands right now, there's a lot of education that has to be done about the importance of the diagnosis of something like non-alcoholic steatohepatitis. And so there is more awareness in the community that's not going to be there widespread for a very long time. And so we each have to do our part in educating the people who refer our patients. And that's going to be an ongoing part of our practice, and we should view it as such. Ray, can I just make a comment on that? Of course. Yeah, there's a study showing that if your average primary care doctor followed all the screening guidelines, it would take them eight hours a day, thus leaving no time for actual care of sick patients. And for this reason, as Dr. Tapper and I have discussed multiple times, the focus will need to be more on population medicine. Right. Dr. Navarro, thank you for your talk on the team sport that Management of End-Stage Liver Disease represents. What are the cost implications of team-based care in liver disease? Does it actually save costs? Really good question. Thanks, Ray and Larry and Kim. Wonderful participating, it's been an honor. Thank you. Team-based care is clearly associated with better outcomes and decreased healthcare utilization. We know that, we've seen it a bit in liver disease, but it's been shown in other medically complex diseases. We haven't really seen a lot of this in liver disease and cirrhosis, but no matter what the disease paradigm, there's a real fundamental issue that we have to worry about here and deal with, and that is when we develop teams, there's a cost associated with that. There's direct costs because we're paying for people's time. There's opportunity costs because people who come to the clinic so that a patient, when we were seeing patients face-to-face, most of us are again, you know, there's travel time and that's time that they could be doing something else within their own field, maybe, you know, that might be even more efficient at generating revenue. There's indirect costs, but the bottom line is that the healthcare system bears the cost to a great extent and the payer often enjoys the savings. So team-based care, although there is great evidence and it's intuitive that this is better for everybody, nobody has really shown that in liver disease, there's a great cost savings. Now, in order really to get to the point where we can demonstrate that, you know, we really have to take advantage of some of the new payment models. And, you know, these have been launched by CMS. We're all familiar with these. They really haven't hit hard in cirrhosis, but the sustainability of team-based care in any disease, let alone in liver disease is gonna require us to live under some sort of an advanced payment model. And it really is gonna depend upon the ability and willingness of us as providers of our healthcare systems and the payers to share risk and to understand those costs and to allocate them so that as we deliver team-based care, the costs of that are actually not, you know, don't hit us at the end of the day when we're looking at our expenses. So, you know, I think it's gonna come down to really careful cost accounting. And then we hopefully will see that we in fact are enjoying reduced cost savings because of decreased healthcare utilization, which is one of the most important things we see coming out of team-based care. Thanks very much, Victor. Mike, I'll come back to you around cirrhosis quality care and the measurements of that. You described a wonderful initiative that's Cirrhosis Quality Collaborative. Members of the audience wanna know how they could join the CQC. Yeah, so there's certainly things that you can do at your own institution right now, which is start setting up a mechanism to figure out which are your cirrhosis patients at your institution. You know, hence not all of them come to your liver clinic, but we hope to release a request for application in early 2021 for additional sites to join the CQC. Great, fantastic. And I'll close with you, Dr. Arora. You know, you've made a very compelling argument for forced multiplication of echo. Do you see a role, and you've described it elegantly for hepatitis C and many other diseases. What about potentially extending that to hepatitis B or fatty liver disease for that matter? Hey, I think the bigger, yes, absolutely. Those would be excellent examples of using the echo model for forced multiplication. The real issue that I see, Ray, is that almost 6 billion people in the world, vast majority, don't have access to the services of a hepatologist. And as has been shown in studies, having access to a specialist actually improves outcomes here. So I think we need to force multiply all the expertise of a hepatologist, and not just for hepatitis C, for management of cirrhosis. The VA system showed that the mortality was half when a primary care doctor was participating for cirrhosis with them. And then there is, of course, chronic cirrhosis management. There is this issue of preventing disease, liver disease, NASH, hepatitis B. And so my pitch is that I'm inviting all our listeners today to reach out to us because we can provide them the technology platform at no cost to them and the training to set up an echo project within their own organization. And for example, we would give them the Zoom platform at no cost to them for more than five, six years to democratize. But of course, what we need is a person who has a desire to democratize their knowledge and have much bigger impact on liver disease in their community, in their country, et cetera. Well, that's a wonderful lesson, Ajit. I wanna thank session one speakers, Drs. Friedman, Tamper, Volk, Aurora, and Navarro for their wonderful presentations. Thank you all very much. And we'll move on to session two. Okay, very good, everyone. Thank you. We are ready to bring in Kathleen Corey, Mack Mitchell, and Anna Mae Deal. And just a reminder, so I see everyone's here. Just a reminder, please leave your camera on until you hear from me when he introduces session three. Okay, let's see. Do I have an extra person here? Dr. Aurora, you can turn off your camera. Okay, everyone ready? Yes. Okay. Drs. Kathleen Corey and Dr. Mitchell, we have a question from the audience. In patients with acute alcoholic hepatitis who appeared to candidates for steroid therapy, is there any proven benefit to prednisolone over prednisone? So that's a question that's been kicking around for a long, long period of time. Initially, prednisolone was favored over prednisone because there was concern that since prednisone requires conversion to prednisolone in the liver, that the injured liver in patients with alcoholic hepatitis might not be able to conduct that conversion properly. But a lot of other evidence has suggested that it takes place relatively unimpaired. So I think you could use whichever compound you're most comfortable with from a dosing perspective. So it's 40 milligrams of prednisone, 32 milligrams of methyl prednisolone, or 40 milligrams of prednisolone. That's the only thing to just keep in mind. Another one for you, Mac. Is there any evidence that the genotype of PMPLA3, or any other genetic marker for that matter, influences the outcome of treatment for alcohol-associated liver disease? Right, that's a question that's a very good one, and probably we will have to answer in the future. I do think as we learn more and more about the genetic markers that are involved in risk for both alcohol-related liver disease and non-alcohol-related liver disease, that we will need to subdivide these patients into those who have PMPLA3GG, which is the risk genotype versus those who do not. And I believe that the genetics here are going to guide us in treatment of this disease in the future, even though to date we don't have any evidence for that. In patients with severe alcohol-associated hepatitis who are treated with steroids, what's the value of the LEAL score? And does it hurt to continue steroids even when the LEAL continues to exceed 0.45? That's an important question from the standpoint of management, Ray. I think that the LEAL score is a useful guide because we know that if the LEAL score is less than 0.45, the chances that someone is responding to the anti-inflammatory corticosteroid medications is there, and therefore we should continue treatment. In those who have a LEAL score above 0.45, I personally don't recommend continuing steroids because I think that that would increase the risk of infection without necessarily increasing any potential benefit. So based on risk-benefit, I would stop steroids in those patients with LEALs over 0.45. Matt, given the data you presented from the STOPPING-H trial, do you feel that treating with steroids has benefit, certainly we don't see any long-term benefit, but even is that short-term benefit real, and how do you feel about treating patients with steroids based on those data? What's interesting is there's some additional new evidence from the STOPPING-H trial that's been published by Mark Thurs and the other investigators that I think could guide us in that. What they found is that the majority of those patients who responded to steroids in the STOPPING-H trial actually had MELD scores between 20 and 25, and those who had MELD scores above 25 were less likely to respond. So I think for a selected group of patients with what I would consider to be the more moderate end of the severe alcoholic hepatitis spectrum, steroids probably are beneficial. And again, if we use the LEAL score, we can avoid any potential risks of continuing steroids that might increase the risk of infections. Thanks very much, Matt. Kathleen, thank you for your presentation on really other aspects outside of obesity for Fernaphalde. So here's a question from the audience. What do you counsel patients with simple steatosis regarding cardiovascular disease risk? Should we refer each of these patients to a cardiologist to assess and stratify their cardiac risk? That's a great question. I mean, I think that there is conflicting data about whether simple steatosis versus NASH versus NASH fibrosis are the real drivers of increased cardiovascular risk overall in NAPHLD, but we do know that steatosis is associated with other important metabolic risk factors associated with cardiovascular disease. And so what I encourage primary care doctors to do as I'm communicating back with them is making sure that we're looking at the LDL for these patients and considering statin use, making sure we're carefully watching blood pressure and using antihypertensives at the newer guidelines at the lower levels, thinking about tobacco cessation, and then thinking about aspirin. I don't necessarily recommend referring forward to a cardiologist unless a patient clearly has symptoms of stable or unstable angina, and then of course referring them, or if someone has a lot of metabolic risk factors that I feel like they could benefit from more comprehensive care, then I do refer them. Do you work closely with cardiologists in this regard? Do you have a kind of working or multidisciplinary type of relationship in the management of your patients who cross those boundaries? Absolutely, I think having a good or several good cardiologists who can help you decide how to risk stratify patients is really helpful. You know, a lot of us can use, and I'll be talking about tomorrow at the expert session on NAPHLD and cardiovascular disease, but we can use the ASCVD risk score, which you can calculate online, and that gives you a lot of good advice about how to manage patients, but things are becoming increasingly complex. So I think having a close cardiologist to talk to when do you do a CTA? When are you looking for coronary artery calcium? How do you further risk stratify some complex patients I think is really helpful. And we're also really fortunate to have great endocrinologists that we work with. So they help manage not only the diabetes, but also we have a number of lipidologists who can help with those who have refractory triglycerides that we can't get down with standard therapies or LDLs that don't respond and need things like PSK9. Thank you. Do you think, speaking of endocrinologists, do you think diabetics should all be screened for fatty liver disease? That's a, it's a great question. I think that based on our study, which was using ultrasound, screening high-risk patients, those with diabetes and obesity, did not change life-year expectancy, did not change quality adjusted life years. I do think if that were redone now with FibroScan, we'd see very different results, fairly low cost, low risk exam. So I do think more data needs to be out before we do population-based screening because it does have unintended consequences, but I think that testing is needed, that study is needed. Thanks very much, Kathleen. Anna Mae, among the approaches to manipulate the microbiome, which you described to us so wonderfully earlier, what do you think, where would you put your chip as to what will be the most productive or effective? Yeah, Ray, that's a great question. I think we're probably gonna try to come up with the best soup, if you will, rather than a particular cocktail of microbes because that will likely be highly variable among individuals. So I guess I'd put my money on trying to figure out what they're making that is helping us or hurting us and try to design soups of things that could substitute for the bacteria. We may get good enough, I guess, that we could modify the whole community to configure itself so that it produces that. But I suspect that that will be quite challenging. So you think it'd be more bang for the buck in terms of targeting the products of the bacteria rather than the bacteria themselves? I do, I do. Great, well, great, that's terrific. Thank you very much. And I guess, do you think there's any realistic shot for treatment approaches like we heard earlier about phage and knocking out specific pathogenic species like the yellow you described? Yeah, I think that's very exciting. And again, could be feasible, but I'm so impressed by the malleability of our microbiome and how responsive they are. We know that they change in all of us according to time of the day and whether we ate. I guess if we ever fly on a plane again, they'll be changing. So I don't know how you hit a moving target consistently, but perhaps somebody will figure that out. Well, I'd like to thank our speakers from session two, Dr. Mitchell, Dr. Corey, and Dr. Diehl for your wonderful presentations. And we'll move on to session three. Thank you very much. Thanks so much, thanks for having us. Bye. Welcome back. We're now. Doctors Marlon Mayo, Mike Dugan and Paul Watkins. Welcome to all of you. And why don't we go ahead and start with you, Marlon. You describe wonderfully and comprehensively the armamentarium of approaches to autoimmune and cholestatic liver disease, several classes of therapy. And I wondered about the possible approach to combining some of these treatment approaches. You spoke elegantly to fibrates, for instance, as well as FXR agonism. What do you think about a possible combination of approaches being additive or even synergistic? Your mute's on. Can you hear me? All right. Sorry about that. Thank you for the question. So I kind of alluded to that a little bit in my last slide, but I didn't actually provide any data to say that that is a good approach. However, what I believe is that probably that's where the future is going to be in treating particularly cholestatic liver diseases. I think that's true whenever you have a medication that works well, but not completely. And then you have another medication that works well, but not completely, but through a different mechanism. So it just makes logical sense to combine those. With respect to combining FXR agonists and fibrates, we have no trials on this, but there was at the European liver meetings, not this past time, but the time before that, I believe an abstract that was presented on triple therapy. So patients who were treated with ursodiol didn't have an adequate response, had a beta-cholic acid added, still had an elevated alkaline phosphatase, and then had bezafibrate added on top of that. It was really small series, like 10 people, but they did show that it looks like using those two different approaches is additive, that they got further reduction in alkaline phosphatase. And even people who were itching on the ursodiol, a beta-cholic acid combination when the fibrate was added, for half of them, their itching got better. And with the incremental reduction alkaline phosphatase with triple therapy, I think they had about 50% of the patients that normalized ALK-FOS. So that was just a little snippet of data, but I think it's provocative. And I think that's what we need to see over the next five to 10 years, is a lot more clinical trials telling us how do we combine all these different kinds of drugs? Do we start off with triple therapy? To borrow some terminology from the IBD people, do we do a top-down or a bottom-up approach? Or how do we best serve our patients with so many different drugs? Well, thank you, Marlene, it's great to have options. Another question from the audience, what is the highest dose of mycophenolate that can be used in autoimmune hepatitis? Well, I don't know that there is a milligram limit. I think you're limited by toxicity, usually. In the case series and clinical trials that have been done, nobody's ever gone above 1,000 BID. But I don't think there's a hard and fast rule that you couldn't if your patient was tolerating it and getting incremental response to slightly higher doses. Wow, great. So a question, this is directed to you, Mike, and this is regarding concerns about aggressive immunosuppression recommended for checkpoint inhibitor hepatitis patients. Some of them are frail, emaciated, and might have an unfavorable risk-benefit ratio. The question really, I think, refers more to, is there an active collection of this real-world experience in a national database to understand just exactly what outcomes are in these patients might be? That's a very interesting question. Unfortunately, the answer is no, that we do not have a national database collecting these outcomes right now. There's a lot of work. I guess the first step in this field has actually been to build internal groups that are collaborating oncology with hepatitis subspecialists to try to look at all of these toxicities, including hepatitis, and that those cancer centers and hospitals that have built those groups are now starting to collaborate together and starting to build the collaborative processes that are gonna be necessary to study outcomes in what's always a subset of a subset of patients. People who get a toxicity like hepatitis on immunotherapy are always some subset of the people on immunotherapy, and a subset of the people who have that kind of cancer. So we really do need these collaborative groups to get answers to questions like, do we really have to use such high doses of steroids? I think the answer to that is almost certainly no. In my own practice, I've been dialing back the dose over time and seeing similar outcomes for the hepatitis. I think we do need to control the hepatitis. I don't think we can just let it go in most cases. I think it does tend to escalate and get worse and worse with time, as do most of the other toxicities from immunotherapy if they're untreated. To get at that minimization of anti-tumor or minimization against anti-tumor effects, do you see any role for agents such as budesonide, which may be more selectively taken up, of course, in the liver? I think that's another really good idea and something that needs to be studied. And yes, one of the issues even with budesonide is that many of these patients do have tumors in the liver still. And whether checkpoint hepatitis is actually more common in patients who have some liver lesion is another question that is being actively looked at. But I do think localized therapies as much as possible are the right way to go. In somebody who's checkpoint inhibitor has been stopped because of a severe episode of hepatitis, do you see any scenarios under which that inhibitor or another inhibitor could be reintroduced to that patient? Absolutely. So first of all, if you change class of inhibitor, so for example, if you were on a CTLA-4 inhibitor and switched to PD-1 inhibitor, there's really no evidence that that sort of switching is going to lead to the same toxicity. So the switching seems like it's a pretty safe thing to do. In many cases, hepatitis is coming in the context of a multi-drug cocktail. Hepatitis is actually not particularly common in patients who are on single agent treatment. So if you can, for example, take someone off of the tyrosine kinase inhibitor that they were on, they often can be retreated with immunotherapy. And then when people have no other option, we certainly have retreated them. I mean, the cancer is a lethal disease. And so it's often worth the risk for re-challenge. And some people do not get the hepatitis recurring. We don't really know what the risk factors for recurrence are at this point. We don't really have good numbers on how likely it is to recur. But I certainly have had patients re-challenged when they have no other treatment options. Thank you. Question for you, Paul. Do you envision in the future, and this is from the audience, a time when we'll have a printout for an individual patient that will guide us to the potential risk for DILI for any given medication or prescription? Yes, that would be a very tall order, I think, because what we hoped in the DILIN network was that we would, in looking at the genetics, find sort of a common set of variants, genetic variants that could be on a chip that would be useful in screening for general susceptibility to drug-induced liver injury. And what we've discovered is the susceptibilities tend to be quite drug-specific. So from a genetic standpoint, I don't think there's going to be a simple genetic test that will be broadly useful. And of course, it isn't just genetics. What we heard in the hepatotoxicity SIG yesterday from Jack Utrecht is the whole concept of T-cell receptors, which are created by random recombination, so are not reflected in genomic DNA being a critical factor. So genetics will have inherent limitations in what they can predict. And of course, there's also age, concomitant medications, disease, and other factors. But I do think, I am seeing drugs in development now where there's continued development with the hope of a genetic test or other patient-specific risk factors that will improve management of that risk. And very quick question, Paul. If someone sees DILI cases in their practice, how can they be enrolled in the DILIN registry? Right now, DILIN is only for the U.S., but there are, of course, registries now in China, the Spanish, South American, the idyllic network in Europe. I would just go to the DILIN website and contact the nearest principal investigator that's in the network. And there's a way to enroll subjects even at a distance. Terrific. Well, I wanna thank each of you, Dr. Mayo, Watkins, and Dugan for a wonderful session. Thanks again. Thanks for the opportunity. Thank you. Session four, Rethinking Complications of Liver Disease. And I'm pleased to be joined by the five speakers in that session, Drs. Jackie O'Leary, Guadalupe Garcia-Sal, Steve Caldwell, Julie Heimbach, and Jorge Morero. Let's start with you, Dr. O'Leary. You wonderfully covered acute and chronic liver failure. Are there different clinical scenarios where the different definitions of ACLF are more pertinent? Well, thank you so much, Ray. I do think that they are more pertinent in certain areas. Naxalde and ezoclif only deal with cirrhosis patients and ezoclif has a greater sensitivity. So if you're looking to be more broadly inclusive and cover a greater range of severity, ezoclif, but naxalde is more specific for negative outcomes, specifically short-term negative outcomes like transplant and in-hospital mortality. For the APOSL definition, it's really most useful in patients who either have cirrhosis or are non-cirrhotic with chronic liver disease who then develop a hepatitic viral infection, specifically like a reactivation of hepatitis B or a new infection of hepatitis C. Great, thank you very much. Lupe, speaking of portal hypertension, what should we do if a patient does not tolerate even the minimal dose of non-selective beta blockers? Can I make a comment about ACLF a little bit before I answer that question, which is a very important question? I just want the audience to understand that acute on chronic liver failure is not a diagnosis. In the case that Jackie presented, if you go to someone and say, oh, I just admitted a patient with ACLF, it's like, whatever, right? So it's a patient that has SVP, that got AKI, she meets criteria for ACLF, whatever, with a mortality that is so much. Because the most important, perhaps, ACLF that we are seeing currently is alcoholic hepatitis, which is your typical acute on chronic. It's an acute alcohol injury on top of a mostly a liver that has cirrhosis. So I think that it's important that the audience understands that it's not a diagnosis, it's more of a prognostic entity. And Jackie, you can correct me if you think I'm wrong, but I just think that it's incredibly important. And maybe in all of this, I want you to say, is it a direct liver damage, which is an infection leading to inflammation, or is the alcoholic hepatitis that leads to inflammation? So, but at the end of the day, we are clinicians, and we need to know what is leading to this acute on chronic liver failure. Well, so I somewhat agree with you, but I certainly think that the future of ACLF is gonna be more about determining patients who have a high risk, such as the metabolomic signature that we've found with Naxold, or the microbiome signature that we found with Naxold, and then being able to implement strategies that may have been educational in those patients to then change the microbiome or replete the endopropionic acid, or change certain things that then improve the intestinal barrier function so that we can prevent ACLF in those patients in the future. So it just would have to be in addition to what is the main precipitant of ACLF, right? If it's SVP, you're gonna have to give antibodies, if it's alcoholic, if not, why are we talking about one of the therapies for alcohol-induced hepatitis, right? Sure, but certainly, as you pointed out, we need to make sure that we're not having the, so much of it is probably from leaky gut, right? So when you have that translocation, how do we prevent translocation? How do we prevent translocation so that that really results in so many infections? So maybe we need to be thinking about doing a better job of that in certain ways. Zinc, even simple things like tube feeds that improve intestinal barrier function, and zinc in those zinc-deficient patients that promote the tight junctions, and maybe tips earlier, things like that that may help to prevent ACLF. So it is something that is a unique diagnosis that has prognostic indication that we know about, but that I think may educate how we treat people in the future for prevention, mostly. Yeah. All right, so anyhow, so coming back to my question, so these, I talked about how beta blockers can not only prevent variceal hemorrhage, that the shift in paradigm is that we're gonna use beta blockers to actually prevent decompensation, which is a much more lofty goal than just preventing variceal hemorrhage. And that we would do this in patients who we determine have clinically significant and poor hypertension. Now, if the patient cannot tolerate even the minimum dose of beta blockers or has contraindications for beta blockers, then we go back to the old paradigm. So then in these patients, what you're trying to prevent would be variceal hemorrhage. So then the patient will need to have an endoscopy. If they have high-risk varices, meaning medium to large varices, then they would have to be ligated, they would not be candidates for beta blockers, right? That is in primary prophylaxis. If it's in secondary prophylaxis, where like I said, the combination of ligation and beta blockers is essential. If the patient cannot tolerate beta blockers, and I showed you how the mortality is much higher if you leave the patient on ligation alone, I think that in this case, one should think of tips earlier rather than later for preventing recurrent hemorrhage. So I guess it depends on what the scenario is. Got it, thank you. Julie, can liver patients who died from COVID-19 be transplanted? This is from the audience. Oh, wow, that's a great question. Actually, I did just exactly that recently. So obviously it's not a known answer about this, but I did have an offer that was that story. The patient then swabbed negative and our infectious disease team felt it was safe to proceed. So yeah, there's a lot to be learned about it. Obviously, I'm not gonna tell you that I'm an expert on COVID-19, but I think you need to work with your infectious disease people and the clinical scenario, but it's not detected in the blood as far as I understand it. So if the patient has now swabbed negative after having that injury before, there's potentially it's a possibility. Great, thank you. Steve, this is a question from the audience as well. There's a patient with poor vein thrombosis and large varices and was treated for, and is being treated for the poor vein thrombosis. Is a beta blocker enough to bridge them to successful anticoagulation? There are concerns about waiting to ban the varices and losing months before starting anticoagulation. Yeah, thanks. Thanks to you and other organizers for inviting me too. I think it's been a really cool session or cool course. Yeah, it's controversial whether beta blockers may actually by reducing portal blood flow increase the risk of portal vein thrombosis. And I think John Stein who's now at Hershey and used to be with us has published one paper suggesting that, I know it remains controversial, but we use the two together. I really think the biggest risk in anticoagulation therapy, I think we can deal with the bleeding risk in general, whether by beta blocker with those reservations or by banding. I think the bigger risk though is the fall risk and getting a subdural or subarachnoid hemorrhage. And we don't have a good measure for assessing that risk. My suspicion is that something like the frailty index would serve that purpose, but it's really not been tested. We've definitely had patients who had propagation of thrombus. We felt kind of compelled to treat them and we've seen a fall. And I used one of those cases in my discussion with a subarachnoid. So I think the fall risk is what really scares me about treating them. I think we can handle the bleeding risk in general. We just have to be real cautious about, who's gonna wake up in the middle of the night having to urinate, stumble and fall. Thanks very much, Steve. And Jorge, this from the audience, you showed some game-changing data on Atezo and Beva for the management of advanced HCC. Should we be using those agents for patients awaiting liver transplantation for free? Is there a scenario where you would see that ever being used? Thank you, Ray. And thank you for not allowing me to mention all these big words for Atezolizumab and Bevacizumab. Anyway, so I think there has to be a washout period. The experience with the use of checkpoint inhibitors prior to bone marrow transplant and other tumors, once they get the actual transplant, it leads to a significant GVHD rejection. So there has to be a washout period. What is that a specific time? It's unclear, but at least three to six months and before they can be actually transplanted because a lot of, we're gonna see more combination therapies with checkpoints and local regional therapies coming down the pipeline. Great. And I think you've already answered the question about whether we should ever use it in our post-transplant patients in terms of rejection. Yeah, the data is tough. There can lead to mortality. So for now, I wouldn't use it. Great. Thank you so much. And thank you to all the presenters in this session for really wonderful talks. And thanks again. Thank you. Thank you, Ray. We'll move on to session five. And welcome back for our Q&A for the fifth session, Revising Our Goals in Viral Hepatitis. I'm delighted to have our three speakers from that session, Drs. David Thomas, Anna Locke, and Jordan Feld joining us. And why don't we start with you, Dr. Locke on Hepatitis B. Is Hepatitis B surface antigen loss an appropriate measure of HPV functional cure for all classes of therapy? Because there are some classes you've described that actually knock down surface antigen and what do we follow there? Yeah, this is a very good question. This is the best measure that we have right now. But as you indicated, there's some drugs that specifically just knock down S-antigen production or S-antigen secretion. In those some cases, when we see that S-antigen drops or become undetectable, does it really mean that HPV DNA replications shut down? Does it mean that some CCC DNA transcription is really suppressed? Those are really great questions. And I think time would tell that so far, most of these trials have involved combination therapy. So they're not really used in isolation, they're used in combination with news. But there are a lot of issues whether S-antigen undetectable truly means that the virus is suppressed, CCC DNA is suppressed. There are also other questions as to when S-antigen remains detectable, does it mean that the CCC DNA is produced S-antigen? Or is it coming through and integrate to HPV DNA? And those are all complex issues which calls for new markets, new assays to allow us to differentiate where's the source of the S-antigen. But I think this is the best that we have right now. Here's a question about Hepatitis Delta from one of the audience members. Would you recommend extended use of PEG interferon for Delta patients after reducing their viral load by say three logs and normalizing their liver tests? Would you put them on a kind of extended course of interferon thereafter? Well, this is a great question. In fact, there are some of these reports, one of which came from the NIH where the patients have been on interferon for up to eight, nine years. And I also showed a data from the Turkish group where they look at patients who receive multiple causes of interferon. And it looked like either intermittent causes of interfering over time or very prolonged cost does benefit some of these patients. And some of these patients even go on to S-antigen clearance. But you and I know that not all patients can tolerate interferon. And I think we need to be able to select for patients in whom there's a chance that this is gonna work. They can tolerate and we see some initial response and maybe retreating them would be a good idea. And a quick one. Can we stop antiviral therapy after surface antigen becomes undetected with or without surface antibody production? What's your view on that? And we're talking about new therapy here. Well, it looks like, I mean, even with new therapy, if in those few lucky patients we managed to get S-antigen loss. And I think that several studies have now shown that you do want to repeat the surface antigen on another occasion, at least six months apart to confirm that this is real. And if that's the case, a majority of these studies show that you can stop treatment and you don't need to worry about biological relapse. Great. Let's turn to you, Dave, regarding Hepatitis C. Given the COVID-19 pandemic, how has COVID-19 interrupted or even derailed efforts at HCV elimination? Thanks, Ray. Yeah, that's a really important issue because, of course, COVID-19's affected virtually all parts of our healthcare system and none more have been more affected than plans to try to eliminate Hep C because, you know, and there are a number of reports that have come out of ways in which there have been disruptions to testing, disruptions to linkage to care, and even difficulties with appropriating treatment. So the COVID epidemic has definitely set back efforts to eliminate global hepatitis. Flipping it around, do you see any potential benefits of COVID-19 in terms of assisting efforts at a preventive HCV vaccine, for instance? Well, I think, first of all, COVID-19 taught us what can happen if you don't have public health systems. And it's made that point crystal clear to the whole world, even places where they have excellent individual health programs, like in the United States. And so I think that will help us eliminate hepatitis because, of course, we need public health infrastructure to be able to make testing and treatment available to those that don't readily access individual clinics. But I think it's also possible that it's set the stage for beyond that sort of broad paradigm that it's also will be helpful, but it's hard to know, it's hard to predict what's going to happen. Dr. Feld, let's talk about some of the other forms of hepatitis affecting the liver. You mentioned that severe hepatitis from SARS-CoV-2 is relatively uncommon, but there's some interesting reports from this meeting and other scattered reports of bile duct injury and even a secondary sclerosing cholangitis type of a picture following COVID-19. Do you have any thoughts regarding these observations? Thanks, Ray. It's an important question. And of course, this field is changing so quickly that between me recording this talk a few weeks ago and now, obviously, so much has changed. So it's hard to keep track of it all, but there have been some reports and there's a really nice, I would refer to a nice poster, like breaking poster from Ira Jacobson's group in New York, where they reported on 13 people that had what looked like a pretty severe secondary sclerosing cholangitis. And it's interesting because as I mentioned in my talk, the ACE2 receptor for the virus is actually expressed on cholangiocytes. So it sort of makes sense that you might see this. Now, why we see it only in certain people, and it seems to be pretty rare, what they found was interestingly, all 13 were men. The people that they saw it in all had severe COVID. So these were all people in the ICU, either intubated or on ECMO. And this bile duct injury really lasted a long time. So they had biopsies in a few of them and it looked more like a sclerosing cholangitis. So it wasn't really bile duct loss, but a large duct injury that seemed to persist for a long time. And at least what they mentioned in the poster is that a couple of these people are actually being evaluated for possible liver transplantation. So really a persistent injury. And that, so just to reference it, it's a late written poster 28. Yeah. Well, one wonders even if there's a sort of component of ischemia kind of built into that as well. There's been a lot of interest in repurposing drugs from other diseases, other viruses and disease areas for that matter to treat COVID-19. Has there been any work repurposing antivirals in the hepatitis space for SARS-CoV-2? Yeah, it's an interesting question because actually there's been, a lot of people have looked at this. I think it was a natural first reaction to say, we've got a lot of antivirals. Let's see if they work for this virus. And most of them focused on things that inhibited SARS-CoV-1. But people have actually looked at how well do some of our polymerase inhibitors inhibit the SARS-CoV-2 polymerase. People have looked at the protease, but from the hepatitis world, actually tenofovir at least binds to the polymerase and may inhibit it in cell culture. It doesn't really look like it works in people with the infection. There were some interesting reports early on that patients on sofosbuvir and daclatasvir might have slightly better outcomes. Not really well-controlled data. And to be honest, I'm not sure that's so convincing, but we're really familiar with interferon and that's a pretty good drug for using for targeting a new viral pathogen because it's not specific. Turns on our very broad antiviral response. And so there's been a lot of interest in using type one interferons, interferon alpha and mostly beta. And we've been looking at using interferon lambda as I think you have and some others have. We've seen some promising results with that with very good antiviral activity, at least in outpatients. And we're now looking in a sicker hospitalized population. Got it. And the last question for you, Dave, what effect do you think the recommendation of a one-time test as recommended by USPSTF for all patients with hep C will have on our ability to identify that sort of remaining group of patients who we need to clear out? Well, I'm certainly all in favor of that. I think that recommendation is excellent. I fear that for many people who currently haven't been tested and need to be treated that I'm not sure that that recommendation will be pivotal to the outcome of their hepatitis because for many of them, they're not in care actively or there are other reasons that they're not linked because they're either young and part of the opioid epidemic and newly infected or they're in the baby boom generation. And so they should have been tested already, right? And so why there's probably more than just a recommendation that's going to be necessary to bring them into care. So I'm all in favor of it. I think it's terrific. I'm just, I don't think it will be the panacea that solves the elimination problem in the United States. Great, great. And with that, I want to thank each of you for, again, a terrific final session at this year's postgraduate course. So thank you again very much. I'd like to turn the podium over to my co-chair, Kim Brown, for some closing comments. Kim? Thanks, Ray. To everyone out there who's watching, on behalf of Drs. Chung, Friedman, and myself, we really would like to thank you all for joining us in this live audience Q&A session and really for your participation in the first ever virtual postgraduate course for AASLD. We'd also like to thank all of our speakers for the outstanding presentations that they were able to record and their heroic efforts really in recording their own talks. Each of their talks was very exciting and illustrated, I think, the tremendous paradigm shifts in our diagnosis and management of patients with liver disease. One reminder, if you have not had a chance to view the presentations, or if you missed some of the live Q&A session, all of the content will be available on the Liver Meeting Digital Experience On Demand until February 21st, 2021. And for continuing education credits at the conclusion of the Liver Meeting Digital Experience, attendees will receive information on how to obtain a Certificate of Attendance, CME Certificate, or even claim the ABIM MOC points. So with that, I thank you all and have a great rest of the meeting.

virtual postgraduate course

AASLD

liver disease

COVID-19 pandemic

hepatology

complications

viral hepatitis

personalized medicine

continuing education credits