Welcome to session four, Rethinking Complications of Liver Disease. I'm Dr. Kimberly Brown, and we have five exciting lectures in this session that will look at some of the common complications of liver disease, and our speakers will utilize emerging data to help us reformulate how we approach these patients, and very importantly, how we look toward treating these individuals. Our first presentation, entitled Acute and Chronic Liver Failure, Evolving Concepts, will be given by Dr. Jacqueline O'Leary, Associate Professor of Medicine at the Baylor University Medical Center. Our second presentation, Portal Hypertension, Revisiting Our Principles, will be given by Dr. Guadalupe Garcia-Sau. She is past president of the ASLD, professor of medicine, chief of digestive diseases, director of the Clinical Translational Research Corps, and director of the Hepatitis C Resource Center at Yale University. Our next presentation, Hemostasis and Thrombosis in Chronic Liver Disease, New Concepts in Management, will be given by Dr. Stephen Caldwell, professor of medicine at the University of Virginia. Following that, we will hear Evolving Strategies to Optimize the Outcomes in Liver Transplantation, and this lecture will be given by Dr. Julie Heimbach, professor of surgery and chair of the Division of Transplantation Surgery at the Mayo Clinic in Rochester. And then finally, our final talk, Transformation of the HCC Management Paradigm, will be given by Dr. Jorge Marrero, professor of medicine and director of the Liver Transplant Program at the University of Texas Southwestern Medical Center. It is my distinct honor and privilege to present to you today on acute on chronic liver failure, or ACLF, evolving concepts. My name is Jacqueline O'Leary, and I'm chief of hepatology at the Dallas VA, and I'd like to thank the organizers, Drs. Friedman, Chung, and Brown, for the opportunity to present to you today. These are my disclosures. We're going to start with a case and then discuss diagnosis and prevalence of ACLF, pathophysiology and prediction of ACLF, prevention and improving prognosis of ACLF, and finish off with liver transplantation in ACLF. Our case is a 50-year-old Hispanic female with decompensated NASH cirrhosis and well-controlled ascites who was admitted with new onset grade three hepatic encephalopathy after her PCP parts are on zolpidem and simvastatin at 40 milligrams per day. On day three of hospitalization, she suddenly develops worsening ascites and hypotension and is diagnosed with SBP, AKI, worsening encephalopathy back to grade three, a serum bilirubin that climbs to four, an INR of 1.4, and she goes to the ICU for low-dose pressers. And we're going to answer the questions today. Does she have ACLF and how do we best manage this patient? Starting with diagnosis and prevalence of ACLF, three definitions of ACLF remain. All focus on organ failures. Naxal is the simplest where brain failure is defined as Westhaven grade three or four encephalopathy, circulatory failure is the need for pressers, renal failure is the need for dialysis, and respiratory failure is the need for intubation or bypass. Azole cliff defines brain failure the same as Westhaven grade three or four encephalopathy, and circulatory failure is the need for pressers or turlipressin. Renal failure is defined as a serum creatinine greater than or equal to two, and respiratory failure is defined by the PaO2 to FiO2 ratio or the SpO2 to FiO2 ratio. Liver failure is defined as a serum bilirubin greater than or equal to 12, and coagulation failure is defined as an INR greater than or equal to two and a half, or platelets less than or equal to 20. By the Naxal criteria, if you have two or more organ failures, you meet the binary definition of ACLF. But azole cliff grades ACLF one through three. Apozzle does not require a diagnosis of cirrhosis, unlike Naxal and azole cliff, but it does require an acute hepatic insult with a serum bilirubin climb over five or equal to five, coagulopathy with an INR greater than or equal to one and a half, complicated within four weeks by ascites and or encephalopathy. So does our patient have ACLF? By Naxal criteria, she has brain failure and circulatory failure, and because she has two organ failures, she does meet the definition for ACLF. By the azole cliff definition, she has brain failure, circulatory failure, and renal failure, and therefore she has grade three ACLF. But by apozzle, she does not meet their criteria for ACLF. How common is ACLF? In the VA data set from 2008 to 2016, in approximately 80,000 outpatients with compensated cirrhosis followed for a little over three years. The incidence of a modified azole cliff ACLF definition occurred in approximately 2% per year. Apozzle ACLF occurred in approximately 0.6% per year. In a slightly sicker patient population, in a prospective study of 466 outpatients with a mean meld of 12, azole cliff ACLF incidence was 14% one year, and risk factors included baseline ascites, a higher baseline meld score, a lower baseline mean arterial pressure, and a lower baseline hemoglobin. In an even sicker patient population of decompensated admitted cirrhosis patients, in the VA data set over 10 years, approximately a quarter of admitted patients met the definition for azole cliff ACLF. In the national inpatient sample during a similar time period, evaluating about 2 million admissions for cirrhosis and defining ACLF by ICD-9 codes of two or more organ failures, approximately 6% of patients met the definition for ACLF. NASH is the most rapidly growing etiology of liver disease in patients with ACLF, and unfortunately the in-hospital mortality has decreased over the study period, but the number of admitted patients with ACLF continues to rise every year. In the VA data set in 80,000 outpatients with compensated cirrhosis, there was marked discordance between who met the criteria for azole cliff and apposal definitions of ACLF. If we looked at the cohort that met either definition, only 14% met both. However, in follow-up, the 90-day mortality was similar between the groups. Comparing NAXL to azole cliff in a subset of the NAXL study cohort of approximately 1,000 patients with a mean meld of 20, azole cliff diagnosed more cases of ACLF, most of which had grade one. NAXL identified a sicker patient population who more often needed ICU care and experienced in-hospital mortality. In a prospective single center study of 486 non-electively admitted cirrhotic patients, almost a third met the criteria for azole cliff ACLF versus 7.4% who met the NAXL criteria for ACLF. The NAXL criteria was demonstrated to have a higher specificity, a higher positive predictive value, but a lower sensitivity, and NAXL was able to better identify patients at higher risk for the need for transplant and who experienced in-hospital mortality, leading me to conclude that azole cliff is more sensitive to diagnose ACLF, but NAXL is more specific to identify patients at higher risk for short-term negative outcomes. Now turning our attention to pathophysiology and prediction of ACLF. In 181 patients with ACLF compared to patients with acute decompensation, compensated cirrhosis, and healthy subjects, the serum metabolome was analyzed and unsupervised hierarchical cluster analysis was utilized to identify the pentose phosphate pathway and the glucuronate aid pathway as being upregulated in ACLF, and mitochondrial function was identified as being markedly impaired, leading to the conclusion that bioenergetic failure and systemic inflammation underlies ACLF, but ultimately can we predict who will get ACLF so that hopefully in the future we could intervene and prevent it. In 118 patients from NAXL without ACLF on admission, who had their admission microbiome stool analyzed, 8% of this cohort later developed ACLF and 21% later died. There were marked differences in admission microbiota found between the patients who later developed ACLF and died versus those who did not. The highlights from this study include cirrhosis dysbiosis ratio being lower in patients who developed ACLF, and negative outcomes were more associated with a higher percentage of the bacteria from phylum proteobacteria and a higher percentage of Firmicutes members Enterococciaceae and Streptococciaceae. There were better outcomes that were associated with a higher percentage of Firmicutes members Lactospiraceae and Clostridialis. In a separate 602 patient cohort from NAXL without ACLF on admission, that had their admission serum metabolome analyzed, 15% of this cohort later developed ACLF. Independent predictors of ACLF development and death were found after controlling for age, gender, alcohol etiology, admission meld, admission white blood cell count, and admission serum sodium and albumin. The highlights from this study include marked increases in bile acid intermediates indicative of cholestasis and failure of good microbiota function to sulfate metabolize and eliminate these bile acid intermediates. There were also higher levels of estrogen metabolites, which in prior studies have been found in association with worsening liver disease, but this was independent of meld. There were marked lowering levels in the endopropionic acid, which stabilizes the intestinal barrier and therefore indicates an increased risk for translocation. Marked decreased microbial metabolites of phenylalanine and tyrosine, which promote local immunity, once again highlighting that these patients were at increased risk for infections from being immunocompromised. And decreased phospholipid moieties associated with cell membrane integrity, indicating less cell membrane integrity in our patients at highest risk for ACLF. Machine learning was subsequently employed using admission variables and metabolomic analysis to predict ACLF development during that admission. And the final model had an area under the curve of 0.84. Of note, a very strong link between gut microbial composition and function, or really failure, and the metabolomic analysis was identified. Now turning to prevention and improving prognosis in ACLF, it is imperative to review medications on our in and out patients with cirrhosis. Proton pump inhibitors increase the risk for infection in patients with cirrhosis because they block the oxidative burst of the neutrophil and therefore further immunocompromise our patients. And many patients with cirrhosis don't even have an indication for PPI use. In one of our quality studies with Naxal, medications were found to be the most common precipitant of hepatic encephalopathy, specifically lactulose overuse or underuse, benzodiazepine use and opioid use. Statins have a dichotomous effect in ACLF. In a seminal paper by Tripathi and colleagues, they utilized a decompensated cirrhotic model in a mouse and injected LPS to mimic infection. And they developed ACLF, which was characterized by a decrease in their main arterial pressure, an inflammatory burst seen as the PMN infiltration of the liver, and increased portal pressures. However, this could be mitigated to some extent by pretreatment with simvastatin. Leading to the conclusion, statin pretreatment may decrease the initial injurious effects of infection in patients with decompensated cirrhosis. But the dose of the statin likely matters. And in the liver hope safety trial of 50 patients, a double-blind, randomized, placebo-controlled trial of simvastatin rifaximin in our child's BNC cirrhotics, there was a statistically significant increase in ALT and CPK in patients randomized to the 40 milligram arm, unlike those randomized to either the 20 milligram arm or the placebo arm. Of note, all patients with ALT elevations also had CPK elevations, but there was one patient that had a significant increase in their INR, indicating true liver dysfunction. To hear more about this, NAXL data has been utilized to show inferior outcomes in admitted patients with cirrhosis on versus not on a statin, being presented at this meeting by Dr. Guadalupe Garcia-Tao in Abstract 1852. Leading to the conclusion, statins may help to prevent ACLF. But once acute decompensation or ACLF occurs, please consider holding or decreasing the dose of the statin. Appropriate and early antibiotics are imperative to treat infections. Consistent data has shown one-third of non-electively admitted cirrhotic patients are infected. All admitted cirrhotic patients need to have infection ruled out. And when choosing antibiotics, think of four things. First, the etiology. Second, the severity of the infection. Third, your local resistance patterns. And fourth, how the infection was acquired. Was it community acquired, healthcare associated, or nosocomial? Early administration of antibiotics in sepsis decreases in-hospital mortality, and every hour counts. For our case patient who has nosocomial SVP, because it was diagnosed greater than 48 hours after admission, there's actually a randomized controlled trial to help educate our antibiotic choice. And in this randomized controlled trial of patients with nosocomial SVP, they were randomized to receive ceftazidine, which is a third-generation cephalosporin, and would be the treatment of choice for community acquired SVP, versus meropenem and daptomycin. The response rate to the third-generation cephalosporin was 25%, versus 87% in the meropenem and daptomycin group. After SVP therapy, secondary SVP prophylaxis is always required. In meta-analysis, no definite treatment is preferred over another, but daily treatment is needed in order to decrease breeding resistance. In two separate randomized controlled trials evaluating terlipresin versus norepinephrine for the treatment of AKI-HRS, they found no difference in HRS-1 or HRS-2. In countries where terlipresin is available, this would be the treatment of choice for simple AKI-HRS because of the robustness of the data. However, in patients with hypotension who need pressor support, norepinephrine is the pressor of choice in patients with cirrhosis because of its renal protective effects. IV albumin is the standard of care for renal protection in patients with SVP and is an integral part of treatment for AKI. In a multicenter open-label trial of IV albumin for non-SVP infections, the treatment group that received IV albumin was sicker because more patients had ACLF and AKI, but there was no overall difference in hospital mortality. There was, however, a higher rate of resolution of ACLF and a decreased rate of nosocomial infections. And now we turn to liver transplantation and ACLF. Almost a quarter of patients in the United States are transplanted with or having had ACLF, and ACLF grade 3 has a higher expected mortality on the wait list compared to status 1. Post-transplant survival can be impaired in those going to transplant who are mechanically ventilated and those who are receiving inferior quality organs, as defined by the donor risk index being greater than or equal to 1.7. In order to improve outcomes post-transplant, we evaluated this in Naxold and found that a negative delta MELD from admission to transplant, indicating improvement, pretended a better prognosis post-transplant. This was similarly highlighted in another study where ACLF without improvement was the single biggest risk factor for death or retransplantation. And now we return to our case. So does she have ACLF? Yes, by the Naxold criteria. Yes, ACLF 3 by the Easel-Cliff criteria. And no, by APOSL. How do we best manage this patient? Well, zolpidem clearly precipitated her new onset encephalopathy and so therefore must be discontinued. Oral lactulose was started and her simvastatin was held. She had nosocomial SVP because it was diagnosed greater than 48 hours after admission. And she should immediately receive her first dose of antibiotics. We chose meropenem and daptomycin because of the severity of the infection and because of our local resistance patterns, but those two factors must educate your antibiotic choice as well. IV albumin was given because of her SVP, but also because of her AKI. And because she needed pressor support, she received norepinephrine. At discharge, she had made a recovery and daily secondary SVP prophylaxis was started. And simvastatin was restarted at a lower dose of 20 milligrams per day. Our key takeaway points from today include ACLF is a distinct entity in patients with chronic liver disease defined by organ failures and pathophysiologically characterized by bioenergetic failure and systemic inflammation. Simvastatin is the presser of choice in patients with ACLF, and it is always important to check medications and try to minimize PPI use. Do diagnose and treat infections early as every hour delay increases the risk for death. And statins can have a dichotomous effect. So consider holding them in inpatients and checking the dose in both in and outpatients. In stool microbiome and serum metabolomics can help predict who will get ACLF. Liver transplantation in patients with ACLF is often needed, and inferior outcomes can occur in those patients who are ventilated, and the best outcomes are seen when the MELD is improving prior to transplant. I want to thank all of my collaborators at Naxled and the patients and their families, and thank you so much for your attention. Hi everybody. First of all, I want to thank the course organizer for having invited me to give this lecture on portal hypertension, revisiting our principles. That being, I have no disclosures. As you know, cirrhosis consists of two main stages, compensated and decompensated, with the decompensated stage being defined by the presence of overt complications, variceal hemorrhage, ascites, or encephalopathy, and they're entirely different diseases prognostically. The compensated patient will have immediate survival that exceeds 12 years while the patient remains compensated, while the patient, once he or she develops one of these complication events, will have immediate survival that goes down to around two years. The main driver of decompensation is something that we call clinically significant portal hypertension, which is defined as an hepatic venous pressure gradient, or HVPG, more or equal to 10. So this is what happens. In cirrhosis, you first have regenerative nodules, fibrous tissue that increase the resistance inside the liver, increase resistance to portal flow, and this leads to mild portal hypertension. So normally it's 3 to 5, and while the HPG goes to 6 to 10, this increase in pressure is enough to make the splenic arterioles to secrete more nitric oxide. They get vasodilated. This leads to more flow into the gut, more flow out of the gut and into the portal venous system, and this leads to clinically significant portal hypertension. And it's only then when varices and other collaterals form. Now there's not only splenic, but also systemic vasodilatation, and this leads to effective hypervolemia, that is, the bowel receptors feel like there's underfilling, and they secrete neurohumeral systems, renning, angiotensin, aldosterone, the sympathetic nervous system that gets activated, and this leads to sodium and water retention, hypervolemia, and leads to increased cardiac output. You have a hyperdynamic state that increases the flow even further. Furthermore, these neurohumeral systems are vasoconstrictive, cause vasoconstriction inside the liver, and this increases the resistance even further, so it's like a vicious cycle. In the presence of increased pressure in the sinusoid, and with sodium and water retention, you will have ascites formation. If the flow increases to varices, they will grow, and they will rupture, leading to variceal hemorrhage. And in the presence of portal systemic shunting, encephalopathy will ensue. So the three complications that define decompensation are due to clinically significant portal hypertension. So what is our main goal in patients with compensated cirrhosis? It's actually to prevent decompensation, but we now know how to stratify these patients. Those with mild portal hypertension are very unlikely to decompensate, so in these patients, we have to concentrate our efforts in eliminating the challenge, for example, hepatitis C therapy. In patients with clinically significant portal hypertension, they are at high risk of decompensating, and these are the patients that we have to target to prevent decompensation, and we're going to do this by decreasing portal pressure. How are we going to decrease portal pressure? We're going to use non-selective beta blockers, that's the medication that we have been using for over 30 years, and they act by decreasing the flow. They do this through their beta-1 adrenergic blocking effect that decreases cardiac output, but the most important effect is actually the beta-2 adrenergic blockade that causes splastic vasoconstriction, and in this way, decreases the flow into the gut, out of the gut, and decreases portal pressure. Now carvetilol is a special type of non-selective beta blocker that, in addition to having the beta-1 and beta-2 blocking effect, also have an alpha-1 adrenergic blockade effect that acts in the intrafatic circulation, we think, and causes vasodilation at this lever, and therefore, there's a dual effect. What we do know, in fact, is that the AGPG reduction with carvetilol is greater always than the one that you get with propranolol and needle. Can we use these drugs to prevent decompensation by decreasing portal pressure? The answer is yes, and this is the result of the PRADESIC trial, a multicenter Spanish trial that looked at patients with compensated cirrhosis and CSPH. They actually measured the AGPG to enroll the patients in this study, and these patients had no or small virus, so they excluded patients with large viruses because it would have been unethical to randomize them to a placebo. In this group of patients, they could show that the primary outcome was the probability of developing any decompensating event, that is, not only variceal hemorrhage, but also ascites and encephalopathy, and preventing death. As you can see, this is the main result of this study. There was a significant reduction in these primary outcomes with the use of beta blockers compared to placebo, and this was significant. There was a reduction in 49% of decompensation. When one looked at the specific decompensating event that was significantly reduced by the beta blocker, ascites was the one that was solely lower in the beta blocker group, 20% in placebo versus 9% in beta blocker, and Y-based ascites is the most common decompensating event. Now, they used Carvedil in one-third of the patients at these doses, and in post hoc analysis, they seemed to show that it was more effective than propranolol at these doses, titrated to a heart rate of more than 55 beats per minute, and a systolic blood pressure more than 90. So, can clinically significant portal hypertension be determined non-invasive? We're going to be treating these patients now with beta blockers, do we have to measure the HPT? There's an invasive method by which you can see that you have to catheterize the jugular vein, go through the heart and into the hepatic vein, you wedge it, and then you get a free patient that's the HPT. However, we do have now non-invasive ways of determining whether there is CSPH, and the joint effort of all these studies, actually mostly the anticipated studies, have shown that non-invasive assessment in these guidelines that I'm going to give you apply to alcoholic liver disease, hep C, hep D, and non-obese NASH. In this last paper, they show that in obesity, obesity over predicts the risk of CSPH. Obesity sort of makes everything so much more difficult. But in non-obese NASH, these are the rules. If you have a liver stiffness, LS is out, liver stiffness more than or equal to 25, or a liver stiffness from 15 to 24, and a platelet count less than 150, that rules in clinically significant poor hypertension. On the other hand, if you have a liver stiffness that's less than 15 and a platelet count more than 150, that rules out CSPH. Now in the obese patients and in the patient with NASH, if you look at this PONS paper, you will see that a nomogram that includes BMI, liver stiffness, and platelet count can estimate the probability of CSPH. The other way of non-invasively assessing CSPH is that if the patient has varices or on cross-sectional imaging has obvious portosystemic collaterals, this is indicative that the patient has also CSPH. So there are ways of looking at this non-invasively, and then these patients want to start on non-selective beta blockers. Now how else can we reduce portal pressure? And we've been looking at increase in flow, but we can also act on increase in resistance because not all of it is structural, not all of it is fibrous tissue. There's a 30% that is function, that is vasoconstriction inside the liver. This is due to a decrease in nitric oxide in the vessels, in the intra-hepatic vessels that causes vasoconstriction. Statins have been shown in experimental studies to increase the bioavailability of nitric oxide inside the liver, and therefore causes vasodilation and reduction in pressure. I'll show you the best proof-of-concept study of simvastatin in patients with clinically significant portal hypertension. This was a proof-of-concept randomized trial that randomized patients to placebo or simvastatin, starting at 20 and going on to 40. They measured the HPV. There were no changes on placebo. There was a modest reduction in the simvastatin group that was nevertheless significant. There were no changes in blood flow, which indicates that this decrease in pressure was due to a decrease in resistance. Now, if you think about it, when you're looking at beta-bloggers, you're decreasing the flow that goes into the portal system, and therefore into the liver as well, so you're decreasing flow into the liver. With statins or anything that vasodilates the intra-hepatic circulation, you're going to increase flow into the liver, which in a way would improve function. In fact, in this study, they looked at the clearance of indocytin in green, which is the indirect method of intra-hepatic flow and function, and it was improved in the patients that were on simvastatin. What we have dealt with with other vasodilators is that they vasodilate the peripheral circulation, and then you get hypotension, and this does not happen with the simvastatin. It has no effect on the arterial pressure. There are now observational studies, this is a propensity-matched study that we did in patients with HCV-compensated cirrhosis in the VA cohort, and you can see here that in terms of these were all patients that were propensity-matched at the outset, they were all having the same probability of being prescribed statins, that is, they had the same cardiovascular risk, the same degree of hyperlipidemia, and actually also the same severity of cirrhosis, and you can see how the statin user was more likely to be free of decompensation than the non-user, and this was significant. Not only that, there was also an effect on mortality with the statin user being less likely to die than the non-user. Again, observational studies in another VA cohort and another observational study, but this included patients of all etiologies. For every year of statin exposure, there was an 8% to 9% decrease in mortality in child A and B patients, and in fact, these authors, Dr. Kaplan and Dr. Taddei at the VA have now initiated a randomized controlled trial of statin versus placebo in patients with cirrhosis and CSPH. More to come. Now, we've talked about compensated cirrhosis, let's talk about decompensation, and because I do not have a lot of time, we'll just talk about variceal hemorrhage, which is the direct effect of having portal hypertension. Guidelines say that you should cautiously transduce plaque red blood cells, that you should use antibiotics, and that you should use a safe vasoactive drug, and then within 12 hours, do an endoscopy, and if the bleeding is from esophageal varices, to do endoscopic variceal lambdas. Now, normally, what one does is you continue the IV vasoactive drugs anywhere between two and five days. Five days is perhaps the most common. If there's no bleed, then one papers off the IV drug, and most are secondary prophylaxis. Now, if the patient bleeds in this time, then the patient has failed standard of care, has failed standard therapy, and then you need to place a tip then as a rescue. Rescue them from failure. And who are the patients that are more likely to fail? This and several studies have been shown that these are child C patients. So the theory behind the preemptive tips is that in these patients that are most likely to fail standard therapy before waiting for them to re-bleed and then get a tip, you put a tip in before they re-bleed. So you've done the endoscopy, the patient is stable, but the patient's high risk of re-bleeding, you put in a tip. That is preemptive tips. And this is the data. This is a mini-study from Garcia Pagan in the New England Journal of Medicine. They included child C, 10 to 13 points, so they excluded those with 14 and 15 points, and child B with active bleeding and endoscopy, and showed that with preemptive tips, there's a significantly better survival than in drugs plus abandonment survival. And in fact, the one year absolute risk reduction for dying was 25%. There has always been an issue about the child B patient with active bleeding, even though in this study it was 50-50, so half of the patients had this. But then a subsequent randomized controlled trial came along from the Chinese group of Liu et al., and they included more patients than in the Garcia Pagan study, but they included child B patients, all child B patients, with or without active bleeding and endoscopy. And they also found that in fact, preemptive tips, they called them early tips, we're now calling it preemptive tips because it's a better description of what we're doing, you had a significantly better survival, a 50% less mortality than in the patients that got standard therapy, ligation, and medication, and that was significant. Now these patients, if you look at them, most of the patients were child B without active bleeding, so therefore they were less sick patients, and therefore the one year absolute risk reduction was actually lower than in the Garcia Pagan study. Now the Garcia Pagan study included mostly alcoholic and hep C cirrhosis, while the Liu study included mostly hepatitis B cirrhosis patients. And one wonders, would we have the same effect in patients with NASH cirrhosis? Non-clear. Additionally, there's a recent small RCT that included 58 patients, and now they said B8 and C10 to 13, that did not find the same result, but the problem is that they encountered problems regarding feasibility of P tips within the timeframe, they could either not put the tips or they were way beyond this timeframe of 72 hours, which is why it was originally called early tips. You have to place it within 72 hours of admission of the patient. More to come. I think we still need more data about this, and there are two meta-nods that are about to be published that I'll show you in two seconds. Anyhow, so when the patient comes in with a probable variceal hemorrhage, your first question is, is this a P tips candidate, or is it not a P tips candidate? And in the non-P tips candidate, you'll do standard of care, in the P tips candidate, you're going to put in tips within 72 hours of admission, that's early tips. And as far as we know now, the candidate seems to be child C pages, 10 to 13 points, and this was confirmed in an individual metamorphosis EPUB in gastro this month. And also for the child B pages, there's two possibilities, score more than seven with active bleeding and endoscopy, so now we're excluding the seven points, only including eight and nine points, and active bleeding, and this is in the same individual meta-analysis, plus in another meta-analysis by the Chinese group that was presented at ESL, that also showed that this is a high-risk group that benefits from tips, but they also showed another group that had a modified CLIFT-AD score of more than 48. So we're waiting for this one to be published, but they seem to be the potential candidates. It is very clear that the patients that are not P tips candidates are child A, child B, seven, either too healthy, and child C, 14 to 15, either they are too sick. Now what are we going to do with the majority of patients that are not P tips candidates that do not bleed after you start them on standard therapy, and after four to five days you discontinue the Utreta, you discontinue the Cetraxone, and I usually do it at the same time, and now we start secondary prophylaxis with non-selected beta-blockers and ligation. The patient has to be started on non-selected beta-blockers before he or she leaves the hospital. And the data on this, I'm showing you in individual meta-analysis, and I want you to concentrate on the red area. These are the trials that were actually significant, the above or not, that compared ligation alone versus combination therapy. So you're exploring, adding the beta-blocker, right? And you see that overall there was clearly a benefit from combination therapy, but remarkably in child B and C patients, which are the decompensated patients, there was a benefit of combination therapy. And if you look at, because we did an individual meta-analysis, we could look at survival curves, look at this, ligation and beta-blockers, significantly better than ligation. So in a patient who's child B and C, which are the patients that are most likely to have ascites, they need the beta-blocker. The beta-blocker is the key component of combination therapy, particularly in these sick patients. So what is the deal with beta-blockers in patients with cirrhosis? And I'll show you one very important study that was published this year. They looked at two types of patients, diuretically responsive ascites patients and refractory ascites. The data had been on refractory ascites, and you can see here that in diuretically responsive ascites, the systolic function was not different with beta-blockers and the renal perfusion pressure, even though it went down, it did not go below the threshold that is related to a decrease in renal blood flow and renal blood flow autoregulation, whereas in refractory ascites, which are patients that are more vasodilated, then there was a significant decrease in systolic function, and there was a significant decrease in renal perfusion pressure. But it had to do with the fact that these patients are always more hypotensive at the beginning. So diuretically responsive are less hypotensive. And then there's a study by Therges recently that looked at patients with ascites that are now requiring LVP, and they looked at the survival, there's a survival rates on beta-blockers or not on beta-blockers, which is the red lines, and if the MAP was more than 65, there was a significant survival benefit with non-selective beta-blockers. And the same in patients with ascites and SVP, which were the two at risk, as long as the MAP is more than 65, you get actually a benefit in survival with beta-blockers. So bottom line, non-selective beta-blockers are beneficial in patients with refractory ascites and SVP, as long as the MAP is more than 65. Now in patients that have lead-formed varicose veins, the addition of synvastatinin has shown to actually, so these are patients that had re-bled, are now on beta-blockers and ligation. You can see here that there was no effect on re-bleeding, but there was an effect of synvastatinin on mortality, a significant reduction. But the problem in decompensated patients is that they will develop rhabdomyolysis, and in this trial, it occurred in two patients who were, both of them had bilirubin more than 5. So we have to be aware of synvastatin or statins in decompensated patients. Finally, covered TIPS is more effective than non-selective beta-blockers plus ligation, but there's more encephalopathy. So even though they're better, the bane of the existence of TIPS in these patients is their philosophy. So the recommendations continue to say that TIPS is recommended in patients who experience recurrent hemorrhage despite combination therapy and ligation. I, this is my recommendation, if the patient has difficult to treat ascites, has portal vein thrombosis, or had been very compliant to non-slick beta-border when he or she bled, you have to think of TIPS sooner rather than later. So in conclusion, in compensated cirrhosis, rather than screening for viruses, one should be screening for CSPH. Portal pressure-reducing strategies like non-selective beta blockers and statins can prevent cirrhosis decomposition in those with CSPH. In patients with acute variceal hemorrhage, think of preemptive TIPS candidacy at the time of admission. Non-selective beta blockers should not be avoided in patients with refractive ascites or SVP unless the systolic blood pressure is less than 90 or the MAP less than 65. And many of these things we will have to re-evaluate in patients with NASH cirrhosis, they seem to be somewhat different than patients with hep C or alcoholic cirrhosis. Thank you so much for your attention. I want to thank the organizers for inviting me to present on hemostasis and thrombosis and chronic liver disease, new concepts and management. Steve Caldwell from the University of Virginia. These are my disclosures, only Daiichi possibly relevant to this presentation. Well, I want to open with a study illustrating the bleeding in ICU-hospitalized critically ill patients with cirrhosis. And you can see in the dark bars here that bleeding in this group of patients is significantly more frequent than in the non-cirrhotic patients. This is associated with higher mortality. Bleeding risk in the cirrhotic patients were related to levels of fibrinogen and platelets. The procedural bleeding risk was 5% in cirrhosis patients versus 1% in no cirrhosis patients. I think these findings support findings that most of us are familiar with. Well, I want to open with a case of a 43-year-old male with autoimmune hepatitis and cirrhosis by transvenous biopsy. You can see here high risk varices on endoscopy. His HVPG was 22 millimeters mercury, INR 2.2, and platelets were 41,000. He had no history of gum bleeding or other indicators of bleeding risk. Well, is the INR of 2.2 in this case a good measure of bleeding risk in liver disease? The INR, as you recall, was developed for warfarin therapy. It was normalized across centers based on the activity of a reagent called thromboplastin. The thromboplastin activity, or ISI, or International Sensitivity Index, varies markedly in cirrhosis patients. In several studies, 40% of identical samples obtained at the same moment showed an INR to be higher or lower than 1.5, depending on the lab utilized in measuring that. What does plasma actually do for prolonged INR if we encounter this? Well, this is a study in vitro from Armando Trappotti. You recall that thrombin, or factor II, converts fibrinogen, or factor I, to a fibrin clot. This can be measured by the thrombin generation assay, which measures the amount of thrombin generated in a patient's sample. What does plasma administration do to thrombin generation in cirrhosis? In this study, Armando Trappotti added normal plasma to cirrhotic plasma at a dose equivalent to 10 mL per kg. This equals about four units of plasma in an average adult human. It improved INR, but it had no effect on thrombin generation. What about in vivo? This is a study from the University of Sao Paulo looking at thrombin generation before and after FFP, again at the same dose, about four units in an adult patient. They were hospitalized, undergoing a procedure. Notably, after the administration of this much plasma, thrombin generation decreased in one third of the patients due to an anticoagulant effect, probably due to replenishing protein C in these patients, which slows the hemostatic pathway. TGA, or thrombin generation, only improved in a very few patients. What about the volume effects of administering plasma for a prolonged INR? Well, there's a near linear relationship between portal pressure and vascular volume. And each 100 cc's of volume expansion predictably raises portal pressure. So this may be actually adversely affecting bleeding risk. So why not target an INR in cirrhosis patients? As I've shown you, there's poor reproducibility of the INR between reference labs. A cutoff of 1.5 for the INR is physiologically meaningless. Plasma at a dose of 10 ml per kg, or about four units on average in adults, doesn't improve thrombin production, in vitro or in vivo, as we've seen. But it may exacerbate portal hypertension. In the case we opened with, with the high-risk varices, INR of 2.2 in platelets of 41,000, he was banded without sequelae and has now had his varices fairly well controlled without prophylactic intervention. What about his platelets of 41,000? It is known that platelets greater than 50,000 enhance thrombin production. A single dose of pooled platelets, or about the same as what we used to call a six-pack of platelets, raises platelets from a mean of 39,000 to 52,000 in vivo in another study by Armando Trappotti. However, it had limited but positive effects on clotting parameters in vivo by enhancing clot firmness measured by rotem, or rotational thromboelastography. So current recommendations are, depending on the operator's risk perception, aim for platelets of greater than 50,000. We do have available now two approved agents, avatrombopag and lucitrombopag, to raise platelets. Both require 10 to 12 days advanced planning, so they're not really good for the urgent situation. They're not recommended for platelets levels greater than 50,000. Once treatment is administered, you should plan for a procedure between around 12 days on average with either agent. Whether these actually reduce bleeding or not has yet to be established, but they do produce more optimal platelet levels. I want to turn attention now to the liver and portal vein blood flow. This is a 46-year-old male with primary sclerosing cholangitis and ulcerative colitis with a known spontaneous splenorenal shunt and recurring bouts of hepatic encephalopathy. Imaging showed portal vein thrombosis, which you can see here. And you can see the large spontaneous splenorenal shunt here, which probably promoted stasis and thrombosis. He didn't have high-risk varices, however, so we initiated therapy with anticoagulation. In his case, we used warfarin. This was some years ago. And after six months, re-imaging showed partial recanalization of the portal vein. At that time, the portal vein velocity was very slow at 6.9 cm per second. Lower than 15 is usually associated with a thrombotic risk due to stasis. We did a test occlusion of the spontaneous shunt and showed portal velocity increased to 90 centimeters per second. Partial occlusion of the spontaneous shunt was then undertaken. 15 months after his course of anticoagulation started and partial occlusion of the shunt, he underwent re-imaging in the setting of marked clinical improvement. His liver had increased from 873 cc's volume to 1,346 cc's volume. He had clinical recovery. His synthetic indices improved, and he was no longer bothered by encephalopathy. It's now been seven or eight years, and he's continued to do relatively well. So from this, we can understand that restoring portal blood flow can result in clinical recovery. Portal blood flow appears to be trophic for the liver. And as side points, spontaneous splenorenal shunts promote stasis and add to cirrhosis portal vein thrombosis risk. Also, a cautious, stepwise, collaborative medical and interventional approach can obviously be very effective. Well, there's downsides, of course, to trying to treat portal vein thrombosis. This is a 75-year-old female with NASH cirrhosis with worsening of ascites and extension of known portal vein thrombus into the SMV. She had previously controlled endoscopically by primary prophylaxis varices. She was started on apixaban 5 milligrams BID for symptomatic portal vein thrombosis. Three months later, she had a bout of hepatic encephalopathy in a fall and was admitted with mental status changes and subarachnoid hemorrhage. Apixaban was held, and she was given platelets. Because of the time lapse between the fall and the transfer, no prothrombin concentrate was administered or reversing agents or antifibrinolytics. Her mental status slowly improved. And about a year later, her thrombosis and portal vein, superior mesenteric and splenic vein remained stable. So what considerations do we need to take in recommending anticoagulation? Well, we need to look at the extent of thrombus and its progression, the presence or absence of symptoms noted in up to 50% of patients. In my experience, this is mainly ascites exacerbation or hydrothorax, pain or bleeding less frequently. 50% are asymptomatic. We need to assess the transplant status, and I'll show you a little more on that in a minute, and assess the fall risk. And I think that's probably best measured by your assessment of their frailty. We generally will assess bleeding risk by EGD and banned varices prophylactically if present. Also, when considering this, it's good to recall that spontaneous resolution of a partial portal vein thrombosis occurs in 30% to 50% of patients without an intervention. And finally, if it's very chronic and there's already been cavernous transformation, you may also want to treat the patient, but it's very unlikely to recantalize once it's become a cavernoma. There has been a meta-analysis, a study from Francisco Violi's group looked at 353 patients from eight trials treated with either low molecular weight heparin or warfarin or untreated. There was significantly greater repermeation of the portal vein in the treated group, 71% versus 42%, and actually significantly fewer variceal bleeds in the treated group, 2% versus 12% in the treated group. And so this probably results from reopening of the portal vein in a significant number of patients and therefore decreased collateral blood flow into the varices. Well, it's best to remember the reason for all of this concern is portal vein thrombosis and cirrhosis is happening in the setting of Virchow's triad. There's an acquired protein C deficiency, which is made in the liver with high factor VIII and von Willebrand factor, which are endothelial derived factors. The result is a very high thrombin generation potential. There's slow portal vein, as we alluded to earlier, due to increased resistance and endothelial injury related to inherently to the liver disease. And we also made note that spontaneous portosystemic shunts contribute to this risk by slowing flow through a steel phenomenon. Genetic thrombophilic factors are not so important really in this group. Only in 10% to 20%, probably because of the overwhelming effects of the conditions related to cirrhosis itself, such as the protein C deficiency. So what approach do I recommend for portal vein thrombosis? If planning to treat and I don't treat them all, my colleagues can certainly, they've heard me say we're not treating because this patient's too frail. There's not one size fits all here. But if you're going to undertake therapy, if possible, I begin with low molecular weight heparin. And I do look at the antithrombin III in most patients, especially if they're a little more advanced. Antithrombin III or antithrombin as it's known now is heparin cofactor. You'll get resistance to heparin if it's low. So at 4 to 12 weeks, I'll transition to a DOAC if they're tolerating therapy. And then if the treatment period is really indefinite because the conditions leading to the thrombosis are not going to change unless their cirrhosis gets better. We re-image at 1 to 3 months, at least initially, and then depending on the course. Avoid treating child pub B minus, the 8, 9 patients, or C, or patients that are deemed to be highly frail. What about the bleeding disorders in cirrhosis? Most of these are portal hypertensive driven and not related to hemostatic pathways significantly. But there is a condition called hyperfibrinolysis that is related to disordered hemostasis. This is a 56-year-old male undergoing a transplant evaluation. He developed persistent bleeding after prophylactic dental extractions. Pre-procedure, his platelets were 60,000. His fibrinogen was low normal. But this bleeding was significant. You see a large hematoma here. And he was admitted with a significant anemia. And this led to decompensation. The bleeding was treated with amicar or amino caproic acid with control. But by this point, he had evolved to ACLF and eventually passed away. Well, fibrinolysis disorders in cirrhosis are one of the oldest described phenomenon. This is a publication by Dr. Goodpasture at Johns Hopkins in 1914 noting increased fibrinolysis in chronic liver insufficiency. Well, hyperfibrinolysis is a condition of premature clot dissolution. It's a disorder of the clot remodeling system. It's a clinical diagnosis and is characterized by diffuse mucosal and puncture wound bleeding, late procedure bleeding. So the patient has a procedure. They do well for four to six to eight or 12 hours. And then they start having bleeding problems when the clot dissolves prematurely. The mechanism remains uncertain. It clearly involves a disorder of plasmin equilibrium. It resembles DIC except factor VIII, which is endothelial derived, is often increased. It may respond to antifibrinolytics like amicar or aminocaproic acid or tranexamic acid. By our current available testing, it's difficult to confirm by lab. And we often make the clinical diagnosis and we treat with one of these agents if there's no contraindication and assess their response. So the key takeaway messages for this presentation are INR is a very poor measure of bleeding risk in cirrhosis. We recommend individualized risk assessment for a procedure and then with attention to platelets, usually greater than 50,000 if you perceive a high risk, and fibrinogen, usually greater than 120 to 150. Again, if you perceive a higher risk. The hypercoagulability of cirrhosis is best characterized as an acquired protein C deficiency. There's other factors, but this is what's really driving increased thrombin production. The potential benefit of restoring portal blood flow in portal vein thrombosis, I think, is illustrated in the cases that we've shown. but also we illustrated the potential risk of this intervention. And I think we really have to be careful with it, use it with our best judgment, and discuss with the patient in terms of what risk they may be experiencing with it. It's hyperfibrolysis or disordered clot remodeling is, I think, the major form of a truly hemostatic disorder leading to bleeding in liver disease patients. It's also been called AICF or accelerated intravascular coagulation and fibrinolysis. So thank you for your attention. I think we're going to have a question and answer period later, and I'll be glad to try to answer any questions that may arise. Thank you. Hello, I'm Julie Heimbach. Today, I'm going to speak to you about evolving strategies to optimize outcome in liver transplantation. I'm a professor of surgery in the chair, the division of transplant surgery at Mayo Clinic in Rochester. And I have no disclosures except to say that virtual presentations are certainly a challenge. The purpose of talking about optimizing outcomes is illustrated in this slide, which shows the outcome for a patient who is listed at three years. We can see that 59% of those listed within three years had undergone transplant, while unfortunately, 31% have been removed from the waiting list for being too sick or for death on the wait list, which is the outcome we are hoping to improve. So what we're going to review today are the use of hepatitis C-nat positive donors for hepatitis C-negative recipients, as well as the use of novel mercine perfusion devices. And we're also going to cover recent allocation changes and how they may impact waitlisted candidates. So first, hepatitis C-positive allografts for hepatitis C-negative recipients. And we're going to start with a case that can highlight this. This is a 42-year-old female with decompensated cirrhosis due to alcohol and alpha-1 antitrypsin, who is awaiting liver transplantation, currently admitted with a mouth of 39, with a height of 158 centimeters and a weight of 58 kilos. And I'm highlighting that because it's important to note that this patient's size will impact the potential grafts that you are able to accept for her. The donor we received an offer for was a 32-year-old male, brain-dead donor, hepatitis C-nat positive with normal enzymes, as you can see. A height of 160 and a weight of 69 kilograms, so excellent size match for our recipient. We do not have a pre-procurement biopsy available despite the nat positivity. So would you accept this donor? I will now provide to you the picture of the liver, which you can see appears to be an excellent allograft, and an intraoperative biopsy, which shows 0% steatosis, no fibrosis, and no inflammation. We're going to review the data behind this scenario, which is recently published, a single-center series by Kwong et al from Stanford in 2019, providing information on 10 patients transplanted from 2017 to 2018, including actually seven with a prior treatment of hepatitis C virus. With a median follow-up of 380 days, they can demonstrate, of course, that patients, as expected, would have viremia, and that they, after receiving DAA-based therapy, 100% are able to achieve SVR at 12 weeks, demonstrating no growth loss or death in this report. Now, of course, we have been using nat positive donors for a long time, limiting their use to nat negative or nat positive recipients. But now, with the efficacy of DAA therapy, we essentially don't have very many nat positive recipients. So really, this looks at the concept of using these for patients who don't have hepatitis C, rather than not using them at all. We can see that more and more often, this is actually happening. When we examine SRTR data from 2008 to 2018, we can see the combination of nat positive donor to nat negative recipient went from just 7 cases in 2008 up to 107 cases in 2017. We do also know from this report, because I looked at it, showing that nat positive donors tend to be younger and have a lower BMI than nat negative donors. And when we look at the outcomes for these livers, we can see that there is essentially no difference in graft survival based on whether the donor was nat positive or nat negative. Importantly, nat positive donor to a HCB negative recipient was a worse outcome when using a DCD graft. This is true even in the absence of hepatitis C. And importantly, in this scenario, using a DCD nat positive, we would have a limited opportunity to obtain a biopsy, which can guide your decision and your selection of these grafts and should be used to help in most cases. This is an elegant study, a modeling study, actually, that looked at whether there would or would not be anticipated to be benefit for patients who are waiting for a transplant. And what they were able to show, in fact, is, indeed, there is a benefit, a survival benefit, anticipated for essentially all patients with a mild greater than 20. And they also walk through how there is quite a difference in the frequency of hepatitis C positivity among organ donors, with it being over 10%, as you can see in region 1 and in region 2, shown in the bar graph, whereas in other regions, such as region 7, with the lowest percentage of hepatitis C positive donors being less than 4% of the donors. So the benefit for the individual recipient increases when the hepatitis C frequency is increased within the organ donor population, because if you're not willing to accept a hepatitis C positive donor, you have less other donors to choose from. However, this recent case report does highlight an important consideration. This is a patient who had NASH, not hepatitis C. They accepted a hepatitis C positive donor, and their initial application to start the DAA therapy was denied by the insurance company. Post-operative day 18, the patient developed acute renal injury and had to start hemodialysis. And biopsy of the kidney showed an immune complex mediated glomerulonephritis, which was associated with hepatitis C infection. The patient was then able to start DAA therapy in a delayed fashion on post-operative day 24, with clearance of hepatitis C by three weeks, and a current creatinine of 1.7 off dialysis, but with continued proteinuria. So the important word of caution is that it is essential to ensure access to DAA therapy if using hepatitis C, not positive. We can also see the recommendation for that treatment from the ASLD IDSA guidance website, which is continuously updated and essentially highlighting the need to use a pan genotypic DAA regimen and starting that on an early basis, which means within the first month after transplant, but preferably within the first week if and when the patient is clinically stable. And just speaking about the different regimens and the doses, you can see here with the two different pan genotypic regimens being recommended for a duration of 12 weeks. And also notably, they're recommending no additional dose adjustment for CNI therapy, but recommending that levels are followed closely and adjusted. Moving on to machine perfusion. This is an elegant review from seminars on liver disease in 2020, walking through the different strategies demonstrating a hypothermic machine perfusion, which would have a low amount of liver metabolism, as you can see indicated on the figure over in the blue section with just 10% to 20% of the metabolism. And interestingly, hypothermic can be either dual perfusion through both the artery and the portal vein, or perfusion only through the portal vein. These devices can be with or without oxygen, and they can be utilized either at the donor hospital or at the transplant center. Whereas the review nicely contrasts this with normal thermic perfusion, which is obviously at a higher temperature, body temperature, 37 degrees. It is generally always with dual perfusion with an oxygen carrier. This is usually initiated on site at the donor hospital, and the normal thermic devices allow the assessment of organ function through the bile production and various other liver metabolites, which can be measured. They also walk through another strategy of hypothermic machine perfusion followed by normal thermic machine perfusion, which is also being studied. So looking at all of the different reports, I've chosen to highlight this in particular, which actually has a comparative study between 25 case-matched DCD livers compared to 50 standard cold-stored DCD livers. And in this trial, using the OrganAssist device, they were able to demonstrate a reduced incidence of cholangiopathy with essentially no cases of cholangiopathy in the machine perfused compared to 22% cholangiopathy in the cold-stored DCD livers. They also reported lower incidence of biliary complication and improved one-year graft survival at 90% versus 69% in this case-matched but non-randomized controlled series. There is a randomized trial of normal thermic machine perfusion, which was published in Nature in 2018 from Europe. And this used the OrganOx device, a large series of 335 patients with just 37% being DCD. They were able to demonstrate less graft injury based on the enzymes in bilirubin with a lower graft discard rate of 12% versus 24%. However, with the more notable endpoints of, say, biliary complications as well as patient and graft survival, these were noted to be equivalent. And this is just a photograph demonstrating this, the pump and how it looks. So what is left? Well, there are actually really multiple pending trials, large pending trials, which will hopefully provide additional clarity on exactly what the benefit of the machines would be and in which patients they should be selected for, with multiple large trials still pending from hypothermic perfusion devices such as LiverAssist and LifePort. I've listed the largest trials there, but there are also some smaller trials which are pending, as well as the normal thermic perfusion, the organ oxmetra, and the transventic OCS, with those trials from the US of 300 and 266 patients, which we should see this data very soon. Answer these key questions, which were also posed in this excellent review from seminars in liver disease, which are the cost of the device and whether this would be anticipated to be spread across the whole DSA or whether it would just be for the patient and the time and location of the perfusion. Also highlighting pitfalls for studying these devices, including when to randomize, whether it should be at the time of acceptance or offer, and the importance of using clinically relevant endpoints, such as graft failure, rather than things like enzymes being elevated, because in the long term, this may not actually impact any notable outcomes. They concluded to note that it is likely that these pumps will be most useful in the setting of DCD or for grafts with significant steatosis or a prolonged cold ischemic period. So moving on to the recent allocation changes and how this may affect patients, first I would like to walk you through what has and has not changed about organ allocation. We're still allocating levers based on MELD, which ranks candidates on their risk of weightless mortality from liver disease. However, we are distributing levers over a broader sharing area in order to attempt to reduce the disparity in access to transplant, which is based on geography. The standard MELD exceptions are still offered for patients with specific diagnoses in which transplant provides a benefit, but the risk of weightless mortality is not captured by MELD sodium. However, for non-standard MELD exception requests, in order to improve the efficiency of the system and standardization across regions, the regional review board has changed to a national board system. So specifically, the national review board started in April of 2019, and it consists of three specialty boards. So if your patient has a non-standard MELD exception for HCC, you would go to the HCC board. If it was a different condition, like HHT or some other condition, you would go to the adult other diagnosis board, and all pediatric non-standard exceptions would be reviewed by the pediatric board. The process of appeals is quite similar to how it was previously. You would go back to the same group with an appeal if your initial exception request is denied, and if that is not approved with that same group under appeal, then you actually go to a separate conference call system. And again, if that does not result in a successful appeal, you still have the option to review further with the liver and intestine committee as it was previously. However, the system of assigning scores has changed considerably. The MELD elevator, where the score went up every three months, has transitioned to a fixed score. And the reason that is is that previously, non-exception candidates have been transplanted with higher MELD scores, with higher waitlist mortality, worse survival on the waitlist for non-exception candidates. And we've also noted this MELD inflation across the country. This system also adjusts for differences in access to liver transplant based on regional differences in the median MELD at transplant. So what we're doing is assigning a fixed score, three points below the median MELD at transplant for the area of distribution. For standard MELD exceptions, and we anticipate that the non-standards would also be targeted to this median MELD system in a similar way with an adjustment based on the patient's clinical condition. How has this performed? Well, the time to review under the NLRB system is shown in brown. And as you can see, that is quicker than it was previously under the regional review board system that highlights the efficiency of the system that is performing well. And we also see that the percentage of transplants performed with an exception under the RRB system has gone down to under the NLRB system for adults and for overall, though for children as shown on the top, that's essentially stayed the same or slightly increased when we move from RRB to NLRB system. So the other policy change related to the distribution of livers, which as I mentioned is now over a broader sharing area, this is called the ACQUITY Circle Model, which was adopted in February of 2020, so very recently. Our initial goal was a population-based circle, but we had to settle for something called the ACQUITY Circle Model, which essentially uses a large circle for the most urgent, the status one patient, and then does following groupings of various MELDs, increases from 150 nautical mile circle to 250 nautical miles to 500 nautical miles over these various MELD groupings, where we only move to the larger circle if there's no patient in the smaller circle with that MELD, say 37 or higher, then it would go to 250 looking for a patient 37 or higher, and then it would go to 500. And if they found no patient, then it would move down to the lower and only when there was no patient in the smaller circle would we share over the broader area. We also were able to create a pediatric priority for pediatric donors. So basically a pediatric donor would essentially go to a pediatric candidate across the country before it would be offered to an adult, and that is a change that has meant benefit on the pediatric waitlist population. We have seen since adopting this policy, unfortunately, we adopted this policy right before the national COVID pandemic. So there's clearly an impact of that on the waitlist risk of death. But following that, as we were sort of evolving beyond that timeframe, we're seeing a reduced incidence of death or removal from the waitlist or being too sick after adoption of the policy. So that would be the goal. And that does appear in the very, very early data. We're also seeing sort of a reduction in the differences with very high MELD scores and lower MELD scores around the country. Everybody coming to this sort of more homogenous, but it's very, very early, but the goal would be everyone having access at a similar MELD score. So getting back to our case, our 42-year-old female with decompensated psoriasis and a very high MELD, we did accept this size-matched NAT positive donor, which was actually allocated from a different region. So under the new system, we had access to this donor. It was a short flight time of one hour and 10 minutes. We transplanted the patient. The HIV viremia was detected at a high level. She was started on DA therapy on postoperative day three and discharged on postoperative day seven. And her hepatitis C NAT was essentially undetected on postoperative day 18 with an uncomplicated recovery. So the key takeaway is that liver transplantation for hepatitis C graft into hepatitis C negative recipients requires early antiviral treatment, but provides excellent graft and patient survival in a very short-term analysis. So at this point in time, we could safely consider well-selected hepatitis C liver allografts for many wait-listed patients, but the data is still early. Machine perfusion may provide better utilization for DCD and perhaps reduce early allograft dysfunction. Whether this will have an impact on endpoints like clangiopathy, it needs to still be demonstrated. And we are awaiting these trial data and approval of these devices in the United States. The acuity circle allocation and the NLRB systems have been implemented. Thus far, they're performing as expected. However, the early data is certainly impacted by COVID and we will need to follow this closely to see what additional modifications are needed. Thank you very much. It was delightful to visit with you today. The title of my talk is Transformation of the ACC Management Paradigm. These are my disclosures. My name is Dr. Jorge Marrero. I'm the Medical Director of Liver Transplant at UT Southwest. A paradigm change has occurred with systemic therapy for ACC. In my talk, we will discuss the management of those with advanced ACC, given the fact that this is where a lot of the new data and changes to the paradigm has occurred. We will discuss a case. This is a 67-year-old gentleman with a history of hep C cirrhosis, treated in 2016 and developed an SVR. It is well, he is well compensated. He's found to have an elevated AFB. He's diabetic, no significant alcohol or tobacco use. On exam, his BMI is 32, has no ascites, jaundice or edema. Laboratory data showed an AFB of 165 nanograms per ml, a normal overall synthetic function of the liver. This is his MRI. There's a large mass in the right lobe of the liver. By most of it, there are other legions in the right lobe. The left portal vein is patent and the right portal vein is expanded and there is a tumor thrombus in the right portal vein. Biopsy showed a moderately differentiated ACC. So this gentleman is classified as a advanced ACC or BCLC stage C. And the talk will be centered on what is the best treatment option for this gentleman? This is a figure in the 2018 guidance for ACC sponsored by the ASLD. In stage B, not much has changed since the 2018 guidance. However, the treatment algorithm and levels of evidence for advanced ACC or stage C is now obsolete. So let's go and discuss each of the treatments. So this is the REFLECT trial. This is a phase three study of lenbatinib versus serafinib for the first line treatment of unresectable ACC, the majority being BCLC stage C. Lenbatinib has activity against VEGF receptors one to three, fibroblast growth factors of receptors one to four, platelet-derived growth factor receptor alpha, KIT, and REF. This is the overall survival, the primary endpoint of this study. And this shows a medium survival of 13.6 months for lenbatinib compared to 12.3 months on serafinib. This is the hazard ratio and the confidence interval. This is a non-inferiority trial design, so the confidence intervals that we're seeing were within the range of a predetermined confidence interval set a priority. And therefore, the study concluded that lenbatinib is non-inferior to serafinib for advanced ACC. This is a tumor assessment, and this showed that there were a significant number, 38% that had partial response, and 2% had a complete response, and this was higher than serafinib, and a potential advantage over serafinib. This is a side effect profile, and this is just to show that lenbatinib has a typical AE profile, typical of TKIs as well as anti-angiogenic inhibitors. This next study is the RESOURCE trial. This is a phase three study of regorafenib versus placebo for the second line treatment of serafinib progressors. The majority of the patients were PCLC stage C. Regorafenib has a similar mechanism of action to serafinib, but it has greater potency against the VEGFR receptor kinases, and overall broader kinase activity, specifically against angiopoietin-1 receptor, KID, and RET. This is the overall survival curve, the primary endpoint of this study, and showed that regorafenib had a significant improvement in probability of survival over placebo, with a median survival of 10.6 months compared to 7.8 months for placebo. This was statistically significant. The AE profile was similar to lenbatinib and other TKIs, and this is now approved as a second line agent for ACC. The next trial is a CELESTIAL trial. This is a phase three of cabozantinib versus placebo for the second and third line study for advanced ACC. Cabozantinib has activity, it's a tyrosine kinase inhibitor that has activity against MET, VEGFR receptor 2, AXL, and RET. This is the overall survival graph that shows that cabozantinib had a better overall survival compared to placebo, with a median survival of 10.2 versus 8 months for placebo. This was statistically significant. And again, this is now approved as a second line therapy for unresectable ACC. The REACH-2 is an interesting study of, it's a phase three study of ramuzirumab versus placebo as a second line to serafinib, but specifically those with an elevated alpha-fetoprotein of over 400 nanograms per ml. This is the first biomarker-based study in ACC. Ramuzirumab is a VEGF receptor 2 monoclonal antibody. Ramuzirumab, this is an overall survival graph, and it showed that ramuzirumab had an improvement in survival compared to placebo, with a median survival of 8.5 months versus 7.3 months in placebo. Interestingly, in terms of survival rate, the survival rate at 18 months was much higher with ramuzirumab versus placebo, indicating the durability of the effect of ramuzirumab. It had pretty much the same tolerability and AE profile as the TKIs and other anti-angiogenic agents. And it is now approved as a second line treatment for ACC. Immunotherapy has changed the paradigm of how we approach cancer. And it has been going for 10 years or so. And there are several approaches. One is boosting the existing immune response to the cancer. And this, we have checkpoint inhibitors, blocking inhibitory cytokines, vaccine and oncolytic viruses. And the other approach is stimulating a de novo immune response than what is already happening with the tumor. And this include antigen-targeting antibodies, adaptive cell therapies, as well as vaccine and oncolytic viruses. We will concentrate on the checkpoint inhibitors with anti-PD-1 and CTLA-4 antibodies as this is where a lot of the activity and recent data has come out. But ongoing clinical trials with these agents are actively enrolling and following up. So we will know in the next year or so what's happening with these other strategies of immunotherapy. So the first agent is nivolumab. This is checkmate 040. It's a phase two study in non-reflectable ACC as a first and second line. This is the dose escalation cohort that includes uninfected hep C and hep B uninfected. After this dose escalation, a dose of three milligrams per kilogram was chosen and an expansion cohort was recruited at this dose of nivolumab. This is included seraphinib-naive or intolerant, as well as seraphinib progressors, hep C and hep B infected. This is a survival curve in terms of the expansion cohort. This is a seraphinib-naive group with a median survival of 28.6 months, which is quite significant. And the seraphinib experience group had a median survival of around 15.6 months. These are the outcomes of the patients treated with nivolumab. And about 19% had a significant response, the majority being partial responses and a duration of response of about 10 months. This is the side effect profile of anti-PD-1 or checkpoint inhibition. But I wanna highlight the ALT and ASD elevations, which occurred 6 and 7% respectively, with a significant portion being grade three to four. These patients require liver biopsy and steroid management for this autoimmune-like hepatitis. So hepatologists will need to be aware of this and help our colleagues in hematology oncology. And these patients should be managed in a multidisciplinary fashion. This next study is Keynote 224. This is pembrolizumab, an anti-PD-1 agent in advanced ACC, specifically for the second line after progression on seraphinib. This is a progression-free survival, which is around five months, and the overall survival, which was around 13 months for these patients as a second-line treatment. About 17% had an objective response, and this is similar to the nivolumab data for this data period. The AE profile is similar to nivolumab. These are the phase three randomized trials of nivolumab and pembrolizumab. Checkmate 459, first-line therapy. Overall survival is the primary endpoint. These are the medium survival for nivolumab and seraphinib, but the hazard ratio is negative for survival, and therefore is a negative study. Keynote 240 is a second-line agent, a second-line study. Overall and progression-free survival were the primary endpoint. As shown here, this is the medium survival. Interestingly, the overall survival and progression-free survival were statistically significant with the p-values. However, the p-values were higher than the predetermined p-values, and therefore, this study, even though it confirmed an antitumor activity, they are negative. This is the game-changer in the paradigm shift in ACC. This is the IAMBRAVE 150 study. It's a phase three study of the combination of atezolizumab and bevazizumab, and this combination is compared to seraphinib in unrespectable ACC, the majority advanced, as first-line therapy. Primary endpoint was overall survival and progression-free survival. This is a graph for overall survival, and it shows a significant improvement in overall survival with the atezolizumab-bevazizumab group compared to seraphinib alone, as shown here. The progression-free survival, as well, was significantly better in the combination group compared to seraphinib alone. Not only did it improve survival, but there was a significant amount of complete and partial responses to the combination therapy compared to seraphinib alone. This is a game-changer. This is the first time with the systemic therapy for ACC that such a high response rate has been seen, and to some extent, it approximates the response rate seen with transarterial demobilization, radiomobilization, and other local regional therapies that are used in the intermediate-stage group. So this is a massive improvement for systemic therapy in ACC. The adverse events were similar, although the serious adverse events were occurring more frequently in the combination group compared to seraphinib alone, and word about the upper GI bleeding, which was seen in the combination group in 7%, mevazizumab has shown a side effect of bleeding when used in colon cancer and other therapies, as well in other cancer, as well as in the early studies of ACC. The enrollment criteria for the IAMBRAVE 150 study included endoscopy within six months, and at enrollment, the patient had to have grade one or smaller varices, and no bleeding within six months after enrollment. They were required as an enrollment criteria. This highlights the side effects of this combination therapy and upper GI bleeding, and again, I'm gonna highlight the need for a multidisciplinary approach to the management of these patients. I wanna highlight a combination therapy of lambatinib and the TKI inhibitor, as well as pembrolizumab anti-PD-1 in ADVANCE-ACC as first line. These are open-label, 67 patients, a 45% response rate, which is great, a significant progression-free and overall survival were seen. 67% had grade three or higher treatment-related adverse events, and were able to be managed. So we're waiting for the phase three study, LEAP-002, which will define this therapy even further. The other game changer is this combination of two checkpoint inhibitors. This is nivolumab, a phase two study of nivolumab and anti-PD-1, and ipilimumab, a CTLA-4 antibody. These were in ADVANCE-ACC, and that's a second line to progression from serafinib. There were three ARMs that had different doses of the two checkpoint inhibitors. ARM-A had a much higher median survival of 22.8 months compared to ARM-B and ARM-C. And therefore, this is the ARM-A was the one that has been approved at the FDA and had the most improvement in survival. In addition, ARM-A had a higher objective response rate compared to the other ARMs, as well as a higher disease control rate as well. Therefore, ARM-A, as I mentioned, has been approved by the FDA as a second line treatment. 20% had an adverse reaction to this combination of two checkpoint inhibitors, as shown before. Interestingly, 50% required systemic theroids to manage these side effects. Therefore, again, these therapies can cause significant adverse reaction and careful follow-up is needed for this patient. The PHASE III study has been launched. There are a lot of ongoing studies, and I'm just highlighting a few in terms of the different strategies that are ongoing. There are two other anti-PD-1, as shown here with camrylizumab and tizolizumab. There's a study of combination of TKI and an anti-PD-1, which is apatinib and camrylizumab, as well as another combination of TKI and anti-PD-1 with cabozantinib and tizolizumab. These are in either PHASE II as second line or PHASE III first-line studies. There's a combination of two checkpoint inhibitors, durvalumab and tremelilumab, which are the two checkpoint inhibitors as first-line treatments. And this is the Himalaya study. And a combination of anti-PD-1 or VEGF receptor, which is durvalumab and vevacizumab, a combination. And interestingly, this last one is in the adjuvant setting of either taste or resection and ablution. So more to come in the near future. How do we put all of this together? In terms of first-line therapy for advanced ACC or unresectable ACC, the first choice is clearly a tizolizumab and vevacizumab. If a patient is not a candidate for these medications, then the second choice would be sorafenib or levavib. For the second-line treatment of all the ones that we discussed and are available and approved by the FDA, durvalumab and ipilimumab clearly have the best results and should be the first choice. Regorafenib, nivolumab, ramusirumab, cabozantinib, pembrolizumab are other potential options available. Interestingly, most of the results of second-line therapies are after progression on sorafenib. So we do not know what is the best strategy after progression to limbatinib or the best strategy after progression on this combination of these two checkpoint inhibitors. We also don't know the best strategy after a tizolizumab and vevacizumab. Key takeaways. The main takeaway is a tizolizumab and vevacizumab combination is the first-line treatment for advanced ACC and unresectable ACC, not candidates for local regional therapy. This is the game changer. Nivolumab and ipilimumab appears to be the best second-line treatment after sorafenib progression. And multiple studies on various combination of checkpoint inhibitors and TKI and as well as other approaches to immunotherapy are likely to change the paradigm further. Areas of need. Earlier transition to systemic therapy and perhaps use more systemic therapy in the intermediate group. How to do that is unclear. The sequence after progression of first-line therapy and we need better biomarkers that predict who responds to immunotherapy and targeted agents. Thank you for your attention and enjoy the meeting. Hello and welcome to session five, revising our goals in viral hepatitis being held at the liver meeting, digital experience 2020. I'm Michael Freed from the University of North Carolina at Chapel Hill, and I will be serving as the moderator for this session. We have three outstanding speakers. The first, Dr. David Thomas from Johns Hopkins University will be speaking to us about hepatitis C. Cure, yes, but we're not done yet. Our second speaker will be Dr. Anna Locke from the University of Michigan who will be speaking on hepatitis B and delta hepatitis. Can we now talk about a cure? And finally, our last presenter will be Dr. Jordan Feld from Toronto Western Hospital Liver Center who will be speaking to us on other viruses affecting the liver, including SARS-CoV-2. I know that this will be an extremely informative session and I am delighted that you're here with us today. Hi, I'm Dave Thomas. I'm the Director of Infectious Diseases, I'm the Director of Infectious Diseases at Johns Hopkins, and I'm delighted to participate in the postgraduate course this year and talk about this important topic of hepatitis C and what to think about beyond the cure. I have these disclosures which don't materially impact the content of my presentation. Well, first, before talking about going beyond the cure, I want to recognize just how transformative the cure of hepatitis C has been. Being able to virtually cure every patient in our clinic has been one of the most exciting events in medicine in the 30 years I've been practicing and was worthy of the Nobel Prizes given to Michael, Charlie, and Harvey this week. But in my lecture, I'm meant to look out beyond the cure. I'm looking beyond the cure in an individual patient, but mostly, I'll be looking beyond the cure in the population and taking advantage of a public health individual as opposed to a clinician. Let's start out with what we need to know besides curing our individual patient. What do we think about after the sustained virologic response? I want to make three points. First of all, if there's continued risk of infection, then it's important to consider repeat testing for hepatitis C RNA for reinfection. But we don't need to do that in persons without residual risk. That's because in many studies that have looked and carefully characterized the pre-treatment and post-treatment risk behaviors, persons without continued risk have almost a zero chance of hepatitis C RNA being detected again, whereas those with risk, such as someone with ongoing injection drug use, have continued risk and have to be screened at least yearly, if not more often, for recurrent hepatitis C infection. Another important group of individuals are those who have other forms of liver disease. And if the ALT or AST remain elevated at the end of treatment, it's important to consider that there might be intercurrent NASH or alcohol-related liver disease and to engage in appropriate therapeutics and diagnostics for those conditions. And then finally, and most importantly, in individuals whose pre-treatment liver fibrosis stage is F3 or F4, we're talking about cirrhotics here, but allowing for the uncertainty and the lack of sensitivity in our staging measures, we can include F3. We have to continue to surveil for varices and complications of varices by using upper GI, as well described in the ASLD and AGA guidance. And in addition, we need to continue to look for hepatocellular carcinoma with six months ultrasound screening and or alpha-theta protein testing. And in my experience, this is the most important to remember, that in patients with pre-treatment F3, F4 fibrosis, that we have to continue to engage them in care, continue to engage them in screening. And that's especially important if they're older than 60. And we can even consider a gradient of risk having to do with the pre-treatment liver fibrosis. Let's say we use elastography and we have someone with a 30 or a 20. Even if they're compensated, we know that they have portal hypertension and we know that they are at the highest risk of getting HCC. Likewise, those more than 60 are going to be much higher risk than those who were young. And in some studies, those whose fibrosis markers, such as FIB4, elastography, fail to drop after treatment, the risk seems to be highest. So continued surveillance for hepatocellular carcinoma in those with cirrhosis. Besides this, with persons in our clinic who we cure, we can more or less say they're free of hepatitis C, take hepatitis C off the problem list, and send them back to their primaries. But we're also meant now to look out and take this population advantage and consider what's going on with hepatitis C outside of our clinics, what's going on in our cities, what's going on in our countries, what's going on around the world, and how are we going to eliminate hepatitis C. This figure gets at that point. It looks at the percent of persons cured in the Y-axis and then two different groups. In the green, you'll see this widely celebrated achievement of progressive improvements in the likelihood of getting a cure. At the individual level, we're up to 95-98% cure with the advent of the DAA therapies. But at the population level, now just saying what percent of all those of the 71 million people in the world that have hep C, what percent of them have been cured, notice that the percent who are cured has hardly even risen, despite the DAAs coming out in 2014, 2015, all over the world, and yet hardly anyone at a population level benefiting. In fact, some of the models show that as many people have hep C today as had hep C in 2015. Just as many new infections as cured infection. So that's kind of what brings us to this issue of what are we going to do at the population level? How do we eliminate hepatitis C as a public health threat? Notice that eliminating it is somewhere in between eradicating it or combating it, eradications like what we did with polio, getting rid of every conceivable case so that it won't come back even if we stop trying. Combating is just sort of working hard in one particular area to get it under control. Prevention is defined with regard to what the situation was in 2015 and looking out to 2030 following the UN Sustainable Development Goals in 2030, such as those established for HIV, tuberculosis, and malaria. And for hepatitis, we define it this way. You got to do two things. You got to drop mortality by two-thirds, 66% reduction in liver-related mortality, and this is for B and C, and a 90% reduction in incidence. So how are we going to do that? How are we going to drop incident infection by 90% and mortality by two-thirds? Well, the WHO boils it down to these basically five types of measures, and these are our interventions, if you will, and then this is how much better we need to do on them from 2015 up to 2030. Brief injections is medical practices, not in this case drug use, but syringe use for giving medications in hospitals and non-hospital settings, and we need to get that up to 100%. That's the dominant route of hep C transmission around the world, so that's the one that has a lot of opportunity for improvement. We have to screen the blood supply better, go from 97% up to 100% of blood donation screened. We need to improve harm reduction services for persons who inject drugs by tenfold from this metric of 27 syringes per person per year up to 300. And then to reduce mortality, we've got to, of course, expand diagnosis and treatment from this dismal figure of a fifth of people recognizing they're infected and only 1% treated up to 90% diagnosed and 80% of those diagnosed being cured. So that's how we're going to get there, and this is sort of where they came up with those figures, if you will. This is what I consider to be the best published model for that, and here we're looking first at the incidence on the y-axis and then 2015 and 2030 there. And if you don't do anything and you just kind of let the ongoing reductions and improvements in safe medical practices around the world continue, you'll have a reduction in new infections like this. But if you add to that improvements in blood safety, you get a lot of bang for your buck. So by expanding education about safety, reuse of syringes, single-use type measures, that will have the biggest impact worldwide in incidence. In places where drug use is the dominant route of hep C transmission, you get the big bang from your harm reduction measures, okay? Worldwide, that's thought to be about 29% of new infections, and here they're projecting if you can extend them to 40%, then you'll reduce by 7% all new infections, an additional 7%. And then, interestingly, if you expand testing and treatment, even though we're talking about incident infection here, by eradicating the reservoir of infection, we can have further impact on new infections, such as has been shown really nicely in Australian prisons and in some high-risk patients like MSM, HIV-positive MSM. Now, in the switching our focus from incidence to mortality, see on the y-axis, now it's mortality, the model shows that hep C-related mortality, if we don't do anything, is going to stay high. If we do these measures that are meant to diminish incident infection, we do get some reduction in mortality because, of course, fewer new infections means fewer hep C-related deaths. But the big bang for the buck comes from treatment, and this is offering DAAs to everyone with infections that are diagnosed, but we don't really do better with diagnosis. To really have a reduction in mortality, we have to expand testing and offer treatment to everyone who's diagnosed. And this is where we get the big impact around the world in hep C and begin to get some control over the mortality that's expected. Now, it's instructive to consider around the world some of the examples of how different groups have been able to implement these control measures. And so I'll just go through a few of them. There are so many, and I won't have the opportunity, and I apologize in advance for that. But here's one that is illustrative of high-risk group. So here's Swiss HIV-positive MSM. There have been outbreaks of hep C and these HIV-positive MSM that have well been described for more than a decade. And so by bringing public health control measures in and expanding testing, so not just waiting until people happen to get tested in their clinic, but by this program that offered expanded testing throughout all the different venues, they found 177 RNA positives, and 150 of them got DAAs, and of course, all but one were cured. That's how well, even at the population level, these treatments can work. They came back a couple years later, repeated testing here, now testing 83% of 3,538 that are left, still in follow-up. And now there's only 13 RNA positives, used to be 177, now there's 13, a marked reduction in the burden of hepatitis C in the country. And fascinatingly, as they've cured 95% of all their infections, they've dropped incident infections where there's been this sort of raging outbreaks of hepatitis C in this population. So they've reduced incident infection, proof that treatment can also prevent infection. And one of the success stories, that only caveat here is that they have had reinfections that have come back, and may be an important caveat as we look to the future. Another success story has been in Egypt. As you probably know, Egypt has really the most dense hepatitis C infection of any country in the world, related to the use of antimonyms to try to combat schistosomiasis years ago, and overspreading the population with genotype 4 hepatitis C. So this is an example of a national program in just one of their villages. It's really phenomenal to appreciate what's going on throughout Egypt during some very difficult political and practical circumstances. But here in this village, expanding testing to test 4215 of 4721 in the village, so 89% testing in one village. They found 312 hep C RNA cases of hepatitis C, and then treated 300 with sofraba varm, which was what was available through their national program, 24 weeks of sofraba. They got 98% cure, and then also were able to improve to prevent new infections. So this is the kind of elimination program, if you will, micro-elimination that's working around the world in different venues when these principles that the WHO has advanced are employed. We also know, though, that there's places in the world where elimination is not occurring, and I'll pick a bit on the United States, unfortunately, as an example of that. Hepatitis C-related mortality has risen in the United States as the baby boomer population with hep C aged, and despite hep C treatment. Now, DAAs really didn't roll out until 2014 and 2015, and I will say that the most recent report of this is showing a flattening and even a reduction in hep C-related mortality in the United States. But nonetheless, the trajectory is clearly going in the wrong direction with mortality. But you don't have to dwell too much on the mortality. The hep C incidence is really where we're supposed to reduce incidence by 90%, and instead, we've had a three-fold increase in incidence over the last decade. We're supposed to be going down by 90%, and we've gone up by three-fold in incidence because of course of the opioid epidemic. So we're really not on track to eliminate hepatitis C in the United States, largely because of our inability to effectively control our opiate epidemic. Well, how are we going to do this around the world? How are we going to make greater strides for elimination of hepatitis C? I think new tools could help. We had, for the first time this year, a trial reporting the intent to prevent persistent hepatitis C through vaccination. That trial failed, but the fact that I'm here in the end of 2020 saying that it was the first real phase two trial underscores the lack of real sustained effort. And a hep C vaccine would be an amazing adjunct to the tools that we have for harm reduction and might help us eliminate hep C in the United States. We also need better and more available harm reduction services. It's been shown that harm reduction services are rarely readily available in many of the places where we have high incident hep C infection. So it's hard to imagine. It's like putting DAAs into your ear when the virus is in your liver. It doesn't work when you do it that way. And so having harm reduction services in a major city and having incident hep C out in the counties and in the countryside doesn't work. We need... It's possible that new point-of-care testing, especially point-of-care testing that's inexpensive, could have a big difference in our ability to detect hep C infections around the world. But of course, you can't... You don't really want to expand testing until you can expand treatment right alongside of it because it would be almost unethical to tell people that they have a treatable infectious disease and not be able to offer them treatment or to leave them without that prospect. And so we also are hopeful that some of the advances and development of long-acting treatments that we've enjoyed in psychiatry, that we enjoy now in HIV medicine, that are being considered for tuberculosis, that are helping with other... And that we had, actually, for hepatitis C with pegylated interferon and rop, pegylated interferon at one point, that those kinds of things might be very helpful and might lead us to a possibility of a test and cure kind of a program. We also have to need improved surveillance, so we'll know if we're achieving elimination. But most of all, we've got to invest. It's not surprising that where there's been breakthroughs around the world is when there's public health programs and investment. It doesn't just happen passively. It doesn't just happen waiting for people to come to the clinics. It requires investment. So my key takeaways for this talk are hepatitis C cure is one of the most transformative advances in medicine. No question about that. But we do have these challenges. We have these challenges at the individual level. I underscored the importance of hepatocellular carcinoma screening, but also the challenge of eliminating hepatitis C at the population level. We need, more than anything else, to invest. We know how to do it. We just have to get the right investment and possibly some new tools to really eliminate hepatitis C around the world. Thanks very much for your attention, and I hope you enjoy the rest of these lectures. I would like to thank Drs. Chung, Brown, and Friedman for inviting me to share my perspective whether we are ready to talk about a cure for hepatitis B and hepatitis D. I'm the director of clinical hepatology and assistant dean for clinical research at the University of Michigan. These are my disclosures. In this talk, I would discuss current treatments, which are aimed for suppression of the virus, as well as some new treatment, which are aimed at a cure. I focus on the first part of my talk on hepatitis B. This slide summarizes how we assess response to current HPV treatment, biological, biochemical, histological, and clinical. Biological response is defined as undetectable sero-HPV DNA by sensitive PCR assays, and for antigen-positive patients, antigen loss and seroconversion. The ultimate goal, however, is S-antigen loss and seroconversion. Clinical response is defined as normalization of ALT, and histological response as decrease in hepatic inflammation and fibrosis, although this is rarely assessed in clinical practice. Ultimately, we would like to have a clinical response where there is decrease in incidence of cirrhosis, decompensation, HCC, and death, although very long durations of follow-up would be necessary to witness those outcomes. With hepatitis B, we currently have multiple treatments, including interferons and oral antivirals, the NAs. Nowadays, we focus on only three of these NAs, entacavir, tenofovir, disuproctovirate, and tenofovir-elophanamide, because these are more potent and are associated with very low rate of drug resistance. The current treatments have very potent antiviral activity, and they not only suppress HPV replication, but they've also been shown to reverse hepatic inflammation and fibrosis, as well as prevent progression to cirrhosis and liver failure, and decrease the risk of liver cancer. Moreover, at least the NAs, they have an excellent safety profile, and this is a very important consideration in the development of new drugs. But current treatments also have many limitations. They do not eradicate CCC DNA or integrate to HPV DNA. They associate a very low rate of ascension loss, particularly with non-A genotype. And thus, for most patients, a very long duration of treatment is necessary to maintain viral suppression and clinical benefit. And while the risk of CCC is reduced, it does persist at a lower rate. As I've indicated, current treatments associate a very low rate of ascension loss, particularly with the NAs, where even with 10 years of continued treatment, only 3 to 5% of the patients achieve ascension loss. Calculated interferon is associated with a higher rate of ascension loss, with about some 10% with one year of treatment and after several years of follow-up. These are overall rates, however, and the rates are much lower for non-A genotypes. Because some current treatments suppress but do not eradicate hepatitis B virus, guidelines recommend indefinite treatment in patients with cirrhosis. For patients without cirrhosis who are antigen-positive, guidelines recommend continued treatment until antigen circumversion, an undetectable HPV DNA, and a further 12 months of consolidation therapy. This means that most antigen-positive patients would need to be on treatment for at least 5 to 6 years or longer. For antigen-negative patients, current guidelines recommend treatment until ascension loss, which for most patients would mean lifelong treatment. Recently, several studies have observed that antigen-negative patients who stop NA after more than 2 to 3 years of treatment appear to have higher rates of ascension loss compared to those who continue NA, prompting ESO as well as APASO to recommend NA can be withdrawn in selected antigen-negative patients who do not have cirrhosis. Most of those studies were retrospective, but there are a few prospective studies, including one presented recently at the Digital ILC. This study called a STOP-NEW trial randomized patients who were antigen-negative without cirrhosis and HPV DNA suppression for at least 4 years on NAs. It was randomized to either stop treatment or to continue. And at 96 weeks after randomization, arm A, which stopped treatment, had a 10% ascension loss compared to none in arm B. And the surface antigen level at the time of randomization was the best predictor of who ultimately lost S antigen. In the patients with low S antigen level, 28% lost surface antigen compared to only 2% in those with S antigen level more than 1,000. As expected, in a group that stopped treatment, a third of these patients experienced ALT flare, although none of them decompensated. Also be noted that two-thirds of these patients did manage to maintain off treatment at the end of therapy. In this study, although the stopped therapy group had a high rate of S antigen loss, it was only 10%, much lower than the previously reported data by the same investigators in the pilot trial. But why is it so difficult to eradicate hepatitis B virus? We know that HBV exists as a CCC DNA or covalently closed circular DNA in the hepatocyte nucleus. The CCC DNA is not affected by the NAs and only partially impacted by interferon. They have a long health life and they replenish not only by new virus entering the liver cells, but also recycling of the core particles from the hepatocyte cytoplasm. Hepatitis B virus DNA can also be integrated in the host genome, making it very difficult to eliminate, and patients with chronic hepatitis B infection have impaired immune response. Also, existing therapies act only on a few steps in the HBV life cycle. Before we review how effective new drugs are in curing hepatitis B, we need to be on the same page regarding how we define a cure. We would all like to have a complete sterilizing cure as if the patient had never been infected. There would be surface antigen negative, anti-surface antibody positive, with no traces of virus not only in the circulation but also in the liver. Liver disease would have been completely resolved and the risk of liver cancer completely eliminated. But most of us do not think that the ideal goal would be feasible. Instead, we settle down on a more realistic functional cure definition. This would be similar to patients with chronic hepatitis B infection with spontaneous antigen loss. There would be surface antigen negative and over time seroconvert to anti-surface antibody with undetectable HBV DNA in the serum and antigen negative. HBV DNA, however, can still be detected in the liver even though it is not transcriptionally active, and they would still have integrated HBV DNA. Liver disease would be quiescent and fibrosis would regress over time and liver cancer risk would be decreased but not completely eliminated. How can we get there? To do so, we are going to need to have antivirals targeting multiple steps in the HBV life cycle. Current treatments only attack limited steps in the HBV life cycle. The NAs block only one step, and that's HBV DNA synthesis. Interferons have multiple potential steps, but the antiviral activity is very weak. Fortunately, in the last few years, we have drugs targeting additional steps. Viral entry, the HPX protein, nucleocapsid assembly, translation of HBS engine, as well as assembly and secretion of virus particles. Let me just go through some of these examples. First, RNA interference, or RNAi, or antisense oligonucleotides. How do they work? They have the potential of blocking the production of pre-genomic RNA, HBV DNA replication, production variants, as well as service engine. And in so doing, there is a potential of restoring immune response. This is one example of an RNAi used in combination with a nuke. In this study, 40 patients received three doses of JNJ3989 four weeks apart. Almost all the patients had greater than one log decline in service engine level. But what is more interesting is that the effect appears to be durable, and at least in a subset of patients, 40% of them, they experienced a greater than one log decline in service engine level that persisted up to nine months after the last RNAi dose. Another group of compounds are the capsid assembly modulators, called the CPAMs. The main action is to prevent proper assembly of the core particles resulting in aberrant or empty core particles. This results in decreasing HBV DNA replication, export of variants, as well as production of HBV proteins, such as service engine. At higher doses, they may also decrease the recycling of the core particles and replenishment of CCC DNA, as well as prevent the proper disassembly of the core particles and establishment of infection. There are many CPAMs in clinical trials. In this Phase 2 trial, patients who received one of the CPAMs, ABI0731 together with Antacuvir, experienced a greater reduction in HBV DNA, as well as pre-genomic RNA, compared to the patients who received Antacuvir alone. There are also studies looking at triple combination. In this particular study, the patients received siRNA in a CPAM plus a nuke. You can see that in blue line, all the patients experienced a greater than 1.5 log decline in service engine level. More importantly, the triple therapy was well tolerated. So far, I've shown you new combos that can decrease service engine levels after a very short course of therapy. But few, if any, patients receiving these combos have lost service engine. To date, the only class of antivirals that seem to result in a high rate of antigen loss is the nucleic acid polymers, or the NAPs. We don't completely understand how the NAPs work, but they're believed to target host factors to block the assembly or secretion of subviral particles, the service engine particles that do not contain HBV DNA. And by decreasing circulating HBs antigen, they may restore immune response. However, the NAPs do not appear to directly block HBV replication. And they are associated with very high frequency of hepatitis flares. And some of these flares can be very marked with ALT level going up to 1,000. For this slide illustrates the results of one of the studies of NAP, in which 40 patients were pre-treated with tenofovir. And then they were either randomized to continue tenofovir with addition of paculated interferon, or addition of both paculated interferon, and one of the NAPs, RAP2139 or RAP2165. You can see that in this group, in orange lines, once the NAP is being added, they have a dramatic drop in S-engine level, increase in antiservice level, as well as some continued decline in HBV DNA. More interestingly, with continuation of follow-up, up to 48 weeks of stopping treatment, many of these patients are able to maintain undetectable surface antigen, roughly half of them, and roughly 40% of them met the criteria for functional cure with undetectable surface antigen, undetectable HBV DNA, as well as normal liver enzymes. These results are... In addition to new antivirals, multiple approaches to stimulate immune response or to remove inhibitory pathways of the immune response have also been evaluated. They include therapeutic vaccination, checkpoint inhibitors, direct stimulation of innate immunity using TLR agonist, for example, or mechanisms to recover exhausted adaptive immunity. However, to date, none of these approaches have been shown to have significant antiviral effect or to have significant effect on decreasing surface antigen production. A lingering question is whether immune modulator therapy is needed or a combination of potent antiviral therapy that not only suppress HBV replication, but also S-antigen production will be sufficient to restore antiviral effect. Or whether S-antigen production will be sufficient to restore immune response. I'll now move on to discuss treatment for hepatitis D. The definitions of response to treatment of hepatitis D is similar to that of hepatitis B and include assessment of biological, biochemical, histological, as well as clinical response. The ultimate goal, obviously, is S-antigen loss. The short-term goal, however, is to achieve undetectable HDV RNA at the end of treatment and preferably also 24 weeks post-treatment. Although long-term follow-up studies show that even in patients with undetectable HDV RNA 24 weeks after stopping treatment, late relapse can occur. Some experts have suggested that a greater than two log decline in HDV RNA during treatment should be considered an intermediate endpoint as it is generally associated with improvement in ALT levels. Unlike hepatitis B, in most countries, there's no approved treatment for hepatitis D. Although in Europe, EMA announced in August of 2020 an approval of Mercudex, which is now called Belathetide, for hepatitis D, even though the phase three clinical trials are still ongoing. Interferon has been tried and shown to have some activity in hepatitis D. NAs, however, have no antiviral activity when used alone and no incremental antiviral activity when combined with interferon. It is, however, recommended to use NAs in combination with new HDV treatment to prevent hepatitis flare, secondary to HBV reactivation when HDV is being suppressed. This slide shows the results of the HIDDT2 study. This is one of the largest studies on hepatitis delta and it's a randomized controlled trial of 120 patients in which everyone received paculated interferon alpha and half of them also received additional tenofovir for 96 weeks. You can see that at the end of treatment, the combination group appeared to have a higher rate of undetectable HDV RNA. However, at 24 weeks after treatment, there was no impact either on undetectable HDV RNA or on S antigen loss. And in 40% of the patients with undetectable HDV RNA at the end of treatment, there was virological relapse when treatment was stopped. Some studies have suggested that longer duration of interferon treatment would achieve a more durable response. In this retrospective study, in 99 patients who had received at least six months of interferon therapy, maintained virological response defined as undetectable HDV RNA for at least two years after treatment was discontinued was indeed observed at a higher rate in patients who continued treatment for up to five years. Now, the five-year duration is cumulative duration and many of these patients received multiple courses of treatment and some of them up to eight courses of treatment. But among the patients who maintained virological response, there was a fairly high rate of subsequent S antigen loss, 50% of them after 10 years of treatment discontinuation. Obviously, we all know that interferon treatment is associated with a lot of side effects and very few patients would be able to tolerate such long durations of treatment. Therefore, there's a need for newer therapies and there are new therapies including Mercutus-B, which is an entry inhibitor, RAP, which we've discussed as a release inhibitor, and lonafenib, which blocks assembly of the virus and is a pharyngeal inhibitor. First, Mercutex or Bufetadine in association with PAK interferon or tenofovir. In an earlier study, patients received 48 weeks of treatment and followed for 24 weeks. The combination therapy group resulted in a higher rate of HDV RNA suppression compared to Mercutex alone or PAK-related interferon alone. Subsequently, Mercutex has been combined with PAK-related interferon and compared to combination of tenofovir. You can see the combination with PAK-related interferon resulted in higher rate of HDV RNA suppression than combination with tenofovir. What about lonafenib? Lonafenib, it results in dose response antiviral effect and higher dose achieve much better results and higher dose achieve much better results but is associated with many GI side effects. Therefore, ritonavir boost has been tried and this can allow maintenance of antiviral activity using lower doses of lonafenib with fewer side effects. An addition of PAK-related interferon also appeared to have additive effect. Most recently, lonafenib has been tested in combination with both ritonavir boost as well as PAK-related interferon alpha and you can see that this results in the best rate of HDV RNA suppression with 11 of 26 patients with undetectable HDV RNA after 24 weeks of treatment. However, surface antigen response was not reported. What about RAP? In this study, it appears that RAP not only can block S-antigen production but may have direct effect on HDV RNA replication as well. In this study, RAP was initially started and then followed 15 weeks later by the addition of PAK-related interferon. You can see a drop in surface antigen titan in some of the patients, rise in HBS titan as well as some suppression of HDV RNA. When the patients have been followed for three and a half years after off-treatment, about 40% of the patients remain S-antigen negative with continued suppression of HDV RNA. Again, very promising data but very small numbers of patients and these results definitely need to be confirmed. In summary, sterilizing cure for HPV and HDV is unlikely to be feasible but functional cure may be possible although not imminent and is likely going to require combination therapy whether this would be combination of just two or more direct actin antivirals or antiviral together with immune modulator therapy. It's unclear whether PAK-related interferon would be the immune modulator therapy of choice. We know that we need to first suppress virus replication and then decrease surface antigen production. What's unclear is whether immune modulator therapy would be necessary to restore immune response or whether immune response can be restored after direct actin antivirals can be sufficiently potent to clear surface antigen. Thank you for your attention. Hello, my name is Jordan Feld from the University of Toronto and after hearing about hepatitis B and C, I'm now going to talk about other viruses that affect the liver, including the notorious SARS-CoV-2 that causes COVID-19. Here are my disclosures, none of which are relevant for today's discussion. So we'll start with a case, a 52-year-old South Asian man who's notably born in Canada and he comes to the emergency room with nausea, abdominal pain, and a low-grade fever, mentions that he's recently been to India to visit family but was well while he was there and he's got diabetes and hypertension and takes medication for them. He's found to have an ALT of 312, an AST of 286, but a normal alkaline phosphatase, synthetic function, and a pretty normal-looking CBC. He's immune to hepatitis B and negative for hepatitis C antibody, has an ultrasound which shows some mild fatty liver but no stones, and so he's sent home. But he comes back two days later and his ALT is now up to 614 and he still has a low-grade temp and still feels pretty nauseated. So what could this be? Well, of course, there's many things that could be, but I'm going to talk about three viral infections that could present this way. Hepatitis A, I'll focus on some of the changing epidemiology. Hepatitis E, I'll talk a little bit about some of the unique presentations and treatment options, and then I'll spend a fair bit of time talking about how SARS-CoV-2 or COVID-19 can affect the liver and our patients with chronic liver disease. So what can be new about hepatitis A? This is a virus we've known about for years. Of course, we all know it's spread by fecal-oral contamination, and we typically think of this as being spread by kids in daycares or people getting it when they travel, and then the odd food-related outbreak that makes the news. Most people are aware that severity is very much associated with age, where young children typically have no or mild symptoms, but it can cause severe ecteric hepatitis in elderly individuals. And of course, it's vaccine-preventable, even in the post-exposure setting. Well, we have noticed a change in the face of hepatitis A. Instead of travelers returning from all-inclusives, in the last few years, we've started seeing it affect the most vulnerable populations in our society, homeless, people who inject drugs, and other marginalized groups. And what we've seen is this big spike in reported cases of hepatitis A since 2016, and when you look around the country, although this outbreak started in the southwest of the United States, it's now spread around the country with 33 states reporting cases, a total of almost 35,000 cases, and remarkably leading to 21,000 hospitalizations, reflecting the older population affected and resulting in 333 deaths as of October this year. This recent study from the Midwest showed that they looked at what was associated with a bad outcome. So they matched 110 fatal cases with 414 age-matched controls. Now they matched on age, so they couldn't look at that in this cohort, but they did look at people who died. Were they younger than the overall population who got hepatitis A? And as you might expect, the people who died were older, with a median age of 47 to 58, compared to 36 to 39 in the different states, but I would point out that 47 to 58 isn't that old, so these are still middle-aged people who had a higher risk of death. They found African Americans had a lower risk of mortality, and then in addition to underlying chronic liver disease, they noted that cardiovascular disease and a history of diabetes were associated with a higher risk of death. In addition to very severe liver presentations, they noticed that even just having an AST to ALT ratio above 1 and a platelet count below normal were associated with more severe outcomes, and this might reflect having underlying unrecognized chronic liver disease. Now they did not note that homelessness or drug use were associated with mortality, but other studies have found this association. So why is this happening? Well, it's really a fact that a high percentage of the adult population remains susceptible to hepatitis A, so when it starts spreading in the community, it spreads quickly, and when we look across the U.S.-born population, you can see that despite vaccination being present since 1999, that's really only affected the very young population, with over 80 percent of people between ages 20 and 60 remaining susceptible to hepatitis A. Now the numbers are lower in foreign-born populations, particularly elderly groups, as many would have been exposed to hepatitis A prior to immigration to the United States. And similarly, when you look in different ethnic groups, whites have a higher rate of susceptibility, whereas black and Hispanic populations, to do likely with socioeconomic factors and maybe immigration, have lower rates, particularly in the elderly. Now when we look at high-risk populations, these are really missed opportunities. So you can see among people who have ever used drugs, three-quarters of people remain susceptible to hepatitis A despite their higher risk of worse outcomes, and you can see that people with chronic liver disease, so they're seeing hepatologists, and yet over half with chronic hepatitis B or C remain susceptible to hepatitis A. And in this nice small study from the VA, they actually looked at patients coming in for hepatitis C treatment and noticed that 75 percent were susceptible to hepatitis A, and yet only 8 percent of those patients got vaccinated in the course of their DAA therapy for hepatitis C. And given their worse outcomes, this is really a missed opportunity. So as we do outreach programs to reach the tough-to-reach hep C folks, we've got to remember to make sure they get vaccination for hep A and of course B as well. The CDC has been trying to get the message out to the groups at risk with a big education campaign, but I think a lot falls on our shoulders as healthcare professionals as well. Now what about outside North America? Well, it's important to remember that hepatitis A is really associated with wealth of countries and highly correlates with GDP, particularly in low- and middle-income countries. And you can use this measure called the Ampere Age at the Midpoint of Immunity to hepatitis A, and you can look around the world and you see that in the countries in yellow, you can see very poor countries, over half of the population will have been exposed to hepatitis A by just age 5, whereas the darker green populations, this is over the age of 40 and may be quite a bit over the age of 40 before half the population has been exposed. But even within countries, there may be variability, so you think about Brazil, where the North is much poorer than the South, and you may have very different ampes in different parts of the country. And even within specific regions, socioeconomic status and even rural versus urban residents may have big effects. Of course, it's a smaller world with globalization, so you have to think that we are going to see cases coming in from around the world, and that's certainly the case. So if we sort of think about when would you introduce vaccination, well, in low GDP countries, exposure in childhood is near 100%, so you have very few susceptible adults and you see very few cases, so it really doesn't make sense to vaccinate. Now, if you go to high GDP countries, you have very little exposure in childhood, so you have a lot of susceptible adults, but as long as there's not much virus spreading around the community, there's still very few cases, so vaccine's not usually necessary. The sweet spot is really in these middle-income countries going through the so-called epidemiologic transition where you still have a lot of exposure in childhood, so still a lot of circulating virus, but many people reaching adulthood still susceptible to hepatitis A, so a lot of cases and potentially severe cases. So here, vaccination saves lives and proves to be cost-effective. But of course, things like globalization and travel with a high susceptible adult population means high GDP countries can still end up with growing case numbers as hepatitis A is introduced into the population, and in that setting, vaccination certainly may save individual lives and might become cost-effective. Now, figuring out the exact timing can be tricky. Here are data for Thailand, and you can see the red bars decreasing infant mortality rate as the blue bars increase with rising GDP, and the black line shows the age at 50% of exposure to hepatitis A, and certainly at the low end, when 50% of the population was exposed by age 5, there's no role for vaccination, but now that it's up to age 40, you've got a lot of susceptible adults and a risk for severe disease in them. So should it be introduced? Well, you've got to figure out the cost-effectiveness, and it really varies very much by country to country. So the bottom line on hepatitis A in 2020, North American outbreaks are seen in the poor and homeless people who use drugs. So there's opportunities for vaccination, particularly we work in these populations reaching out to find people with hepatitis B and C, and we've got to make sure that we get them vaccinated. Globally, we've got to find that sweet spot for cost-effectiveness to figure out when vaccination should be introduced, especially with a globalizing world, and it would be nice to have treatment options for people who present with severe hepatitis A because right now we're stuck with supportive care in adults. I'm now going to keep in the positive strand RNA hepatitis-causing viruses, and you can see that hepatitis A, E, and C actually have a very remote common lineage, but although they have some common ancestry, there are some important differences. We often think of E and A as being very similar. They both are viruses that cause a self-limited hepatitis, and although they have a lot of common elements, they have some important differences. So I showed they have a similar ancestry, and interestingly, were both discovered by experimentally infecting people, and indeed the discoverer of hepatitis E was experimentally infected, and they have this interesting quality where they have this non-enveloped or naked form of the virus that's quite stable in the environment and leads to the fecal oral transmission. But they've also got this semi-enveloped form, which is present in the blood, and actually shields the virus from neutralizing antibodies, yet the vaccine, at least for hepatitis A, works very well. Now, interestingly, hepatitis A has no chronic form, not so clear why that's true, even with severe immunosuppression. Hepatitis E has some unusual characteristics. It's got this zoonosis, so it circulates in swine and a number of game, as well as other animals. It's got this association with high mortality in pregnancy. This is all we see in genotype 1, and I'll talk about that. And then chronicity, particularly in genotype 3, and we'll discuss that a little bit more. So when we look at what we see with hepatitis E, we still see outbreaks, largely in refugee camps, classically right now in East Africa with high mortality, and then we continue to see high reports of high mortality in late pregnancy, and this is predominantly genotype 1 infection. And then in immunosuppressed populations, because of primarily zoonotic transmission, this risk of chronic infection in genotype 3. And even though we think of hepatitis E as a hepatitis virus, it actually replicates in a number of non-hepatic tissues. Here are data showing that it replicates quite well at that fetal maternal interface with the decidua and the placenta. And interestingly, what you see is that hepatitis E genotype 1 replicates much better than genotype 3 in this region, which may at least partially explain the aggressive nature of the disease with genotype 1 rather than 3. You see more significant cytokine production in that setting, and what's the reason for this? Well, it may be to do with interferon induction. So neither genotype 1 or 3 induce strong type 1 interferon, but genotype 3 normally induces a pretty good type 3 interferon response, whereas genotype 1 seems to be impaired in inducing this response. The mechanism is not so clear, but this might be relevant because, at least in cell culture, interferon lambda, type 3 interferon, can suppress hepatitis E, both genotypes. And so if it were produced in genotype 1 infection, that might prevent the severe outcomes in pregnancy. In addition to seeing related to pregnancy extrahepatic replication, the other classic one is neurological replication, and this was, again, borne out in this large series from Scotland, where they showed that about 5% presented with neurological complications, and this typically happens in immunocompetent patients with acute hepatitis E. Now, importantly, they have a variable severity of hepatitis, so you've got to think about this. You see neurological complication in hepatitis, think HEV, and the classic one is this neurologic amyotrophy, which is a brachial plexus problem, and it's typically bilateral when it's associated with hep E. Occasionally, with things like Guillain-Barre, you can end up with more permanent sequelae. Now, for our patients with chronic liver disease, acute hepatitis E can be a real problem. You can see in this cohort that in patients with compensated cirrhosis, a high percentage developed acute on chronic liver failure, and some without really severe transaminase elevation, some with it less than 200, leading to sometimes a delay in diagnosis and incorrect treatment. In those patients who are immunosuppressed, the problem is that they can develop chronic infection, which is defined as remaining viremic for more than three months, and this is typically seen in the transplant arena, patients with hematologic malignancy or advanced HIV, and this is almost exclusively genotype three. Importantly, these patients can have rapid progression to cirrhosis, and a key clinical point is that they might have negative antibodies, so you need to measure the HEV RNA if you've got a high index of suspicion, and you've got to remember prevention because, unfortunately, our treatments are not very effective. The EZO guidelines recommend reducing immunosuppression as a first approach, and if that's not successful, you can consider a course of ribavirin, and interestingly, a high lymphocyte count might predict a better response, and so a reduction in immunosuppression may aid with that, but ribavirin resistance is a problem, and it doesn't work in everyone, so there was a lot of hope for cefospivir based on some in vitro data showing it could suppress the virus, but this recent study from Germany showed that just nine patients with chronic HIV were treated for six months with cefospivir monotherapy, and although you see this very modest decline in RNA and ALT, they rebound quickly with stopping therapy, and nobody was cured. So clearly, for HEV, prevention is the key. Good sanitation is really important, and for our patients that are immunosuppressed, avoidance of zoonotic transmission, hopefully the vaccine that's currently available in China will get broader availability. Key clinical scenarios to remember, late pregnancy for genotype one, acute on chronic liver failure for patients with cirrhosis, chronic infection for immunosuppressed patients, and don't forget the neurological presentation, remember, typically in acute immunocompetent patients. Ribavirin has modest efficacy, but resistance is a problem, so we need new drugs, and fortunately, there's a lot of research going on of repurposing or developing new agents for HEV. But of course, now we couldn't have been today without talking about COVID-19. It enters every conversation, and this is why we're doing this remotely with an empty exhibit hall at the ASLB. And I'll first direct you to some great resources that the ASLB has on their website, this really excellent webinar series of COVID-19 and the liver, chaired by Oren Fix and Betsy Verna, as well as this ASLB expert panel consensus statement, which is updated, giving guidance on a number of aspects. I can't cover everything in the next few minutes, but I will try to talk about liver enzyme elevation and COVID-19, its relevance, and what about patients with chronic liver disease that get it, and finally finish with some comments about transplantation. So enzyme elevation can happen for a number of reasons, either directly affecting the liver, or potentially just because patients get sick, and they get very sick. It's not that uncommon to see liver enzyme elevation, and of course, if they've got underlying chronic liver disease, even more so. So it is reported pretty frequently in patients with COVID-19, up towards a 50% of patients may have enzyme elevation. It's typically mild, one to two times the upper limit of normal, and it's typically a hepatocellular or mixed pattern. It does seem to be associated with more severe COVID-19, and it's notable that at least some patients have very severe hepatitis with ALTs peaking above 1,000. In this study from China, they looked at hospitalized patients, and what they found is that this hepatocellular or mixed pattern of enzyme elevation with above three times the upper limit of normal was associated with a higher risk of severe COVID-19. And interestingly, they highlight the point that it's not always the virus. Lopinavir-ritonavir was used early on in the pandemic as a hopeful therapy. Unfortunately, it's not proven to be very effective, so it shouldn't really be used anymore, but it is associated with liver enzyme elevations. Now, there were some early reports that remdesivir caused liver toxicity, and you can see in this small series from Italy that five patients with remdesivir who had previously had other agents seemed to have a rise in ALT when they started the remdesivir, but notably, it came down after stopping. And so the FDA recommends that it should be stopped if the ALT rises above five times the upper limit of normal and can restart when you get below that threshold. And there have been a couple of case reports of severe drug-induced liver injury with remdesivir, but typically with other drugs in the mix as well. Now what's the role of histology? Well, we don't have a lot of data, but it's interesting that ACE2, the receptor for the virus, is expressed on cholangiocytes, however, there's limited evidence that we see really biliary injury with this infection, and there's really not a lot of evidence of even replication in cholangiocytes, although it should happen. As I mentioned, it's typically a hepatocellular injury, and most biopsies, when they've been done, have really showed very nonspecific features like steatosis, which are hard to relate to the virus. But a couple of recent cases of acute hepatitis preventing with ALTs above 1,000, and you can see here, in this case, a very significant mixed portal infiltrate, as well as this interesting observation in panel C of a cholangiocyte undergoing apoptosis, which might be related to the virus, because as you see in panels D and at the bottom, they were actually able to identify the virus with RNA scope and electron microscopy. So you can actually get replication of SARS-CoV-2 in the liver. The challenge really is our patients with chronic liver disease. There's now a couple of large studies that show that patients with underlying chronic liver disease have an adjusted hazard ratio or relative risk of a death or in-hospital death, and it's quite significant, a relative risk of death of three, and if they have cirrhosis going up to 4.6, so quite significant in these large cohort studies. Now, when you look at specific diseases, there was an association initially reported with fatty liver disease. It might be real, but it's very hard to separate this from diabetes and hypertension, which are clearly comorbidities for worse outcomes. These COVID liver registries, one that's housed at the University of North Carolina, Secure Cirrhosis, and the COVID Hep Registry, which is run by Eazl, are quite useful. They allow you to enter de-identified HIPAA-compliant data. It does require submission, and I encourage you all to use this. It's quite easy to do, but make sure you do it on all your patients, because the problem with registries is if you only put people in with bad outcomes, we get biased data. But at least so far, the data look pretty good and are consistent with other studies, and here you can see 386 patients with cirrhosis compared to 359 without across 29 countries over a three-month period, and what you see is that patients with more advanced cirrhosis—well, with cirrhosis and with more advanced cirrhosis—had increasing likelihood of all these different complications in hospital, and most importantly, of mortality. What you see in red on the right panel is that these patients died at younger ages, so really associated with more severe disease. An important point is that respiratory failure was still the most common cause of death, but liver was next on the list, but importantly, some patients didn't have any respiratory symptoms at presentation, so we have to test our patients if they present, even if it's just with new decompensation. And when they really looked at this more carefully using propensity score matching, you can see that not surprisingly, really cirrhosis is the issue. So when you think about it, it's like any other infection. Cirrhotics do badly when they get infected, and bad cirrhotics do very badly, and this is consistent across studies. Another study here from seven sites across North America showing that patients with COVID-19 and cirrhosis do worse than patients with COVID-19 alone, but not any worse than patients with cirrhosis alone. So it's really about the cirrhosis. Now what happens in the transplant world? Well, when the pandemic was first announced, there was this initial reduction in the number of transplants, but they quickly rebounded and have come back up to normal levels, and a small series of post-transplant COVID-19 from New York shows GI symptoms being a little more common. They do show some more severe disease, but it's not exactly clear how to manage this. Now notably, immunosuppression, there's not been a clear association with worse disease with either this virus or previously with SARS or MERS, and small series with autoimmune hepatitis and in transplant don't show great concerns, maybe a little worse outcomes with solid organ transplant, but not very well controlled data. However, immunosuppressed patients have higher levels of virus, so they might be more infectious. The key point is prevention is important as it is for everybody, but don't reduce or avoid required immunosuppression. In patients who have active infection, you may consider reducing the dose, but the data supporting this are not very strong. So let's go back to our case, our 52-year-old South Asian man with nausea, fever, and an anechthoric hepatitis with an ALTF 600. Could be Hep A, he was born in Canada, so no exposure previously and has a recent travel history. Could be Hep B, he has a travel history, but no other exposure or neurological clues. But we actually swabbed him and it turned out that he had COVID-19. Now fortunately, despite having a very high ALT, he actually did well and resolved without any consequences. I refer you back to these great resources on the ASLB website, the webinar series, and the expert panel consensus statement. And just to summarize hepatitis A, don't forget to vaccinate your patients with chronic hepatitis B and C. Remember that comorbidities and liver disease predict poor outcome. Hepatitis E, don't miss the neurological presentation or chronic hepatitis E in our immunosuppressed patients. Ribavirin is a reasonable option for treatment, but really looking for better options in the future. And SARS-CoV-2 or COVID-19, we know that liver enzyme elevation does seem to be associated with more severe disease, but the real issue is that patients with cirrhosis that are at greater risk of decompensation as they are with all infections and direct and severe hepatitis seems possible, but quite rare. Transplants are proceeding. Outcomes might be slightly worse than the general population, but not terrible. And hopefully we can manage our patients through this. And with that, I'll thank you for your attention. Thank you very much.

portal vein thrombosis

cirrhotic patients

anticoagulation

thrombosis extent

transplant status

protein C deficiency

medical intervention

Hepatitis C treatment

cure rates

public health challenges

WHO elimination goals

blood safety

screening protocols

hepatitis B treatment

COVID-19 pandemic