Hello, everybody, I'm Omar Massoud. Welcome to this Hepatitis C Significant Interest Group webinar organized by the ASLD. The title of this webinar is Chronic Hepatitis C 500 The Advanced Course. Our webinar today includes three great presentations by three international hepatitis C experts. Our first presenter today is Dr. Brian Perlman. Dr. Perlman is a professor of medicine at Medical College of Georgia and Emory School of Medicine. He completed his medical degree at the University of Miami, Florida, and his postgraduate training at the University of Texas, Southwestern, and Baylor University, Dallas, Texas. Dr. Perlman is a faculty at the American College of Physicians, fellow of the American Association for Study of Liver Disease, and a member of the American Academy of HIV Medicine and American Gastroenterology Association. He's widely published in leading journals such as Hepatology and Gastroenterology. Our second presenter today is Dr. Preeti Rashamwala. And Dr. Rashamwala is a distinguished physician in transplant hepatology at Emory University School of Medicine. She's the director of the Fatty Liver Clinic, and she's also the director of the Transplant Hepatology Fellowship Program. She has led and participated in many clinical trials on the treatment of hepatitis C. She co-directs hepatitis C management in liver transplant patients. She has been an advocate for using hepatitis C positive donors for hepatitis C negative recipients. Our third and last presenter today will be Dr. Gene Michael Polosky. Dr. Polosky is a professor of medicine at University of Paris, France. He's the director of the National Reference Center for Viral Hepatitis. He earned his medical degree in hepatology and gastroenterology in 1992. In addition, he earned his thesis in molecular virology from University of Paris, and he's a graduate in virology from Pasteur Institute, Paris, France. He has been acting general secretary of the European Association for the Study of Liver Disease and associate director of hepatology. Dr. Polosky published more than 500 articles and book chapters, and he has more than 600 invited lectures. Now let's start with our first presentation for today. The title is Sustained Virologic Response in the Hepatitis C Infected Decompensated Serotics by Dr. Brian Perlman. Great. Here are my disclosures, and I do want to thank the SSLD for the opportunity for allowing me to organize this webinar, and thank you, obviously, to Dominique for your technical help as well as Katie, and thank you to my esteemed co-lecturers and moderator for joining me in this webinar. And thank you, of course, to the New York audience for participating today and letting us impart some knowledge to you. Now this first warning slide from the AASLD is a shot saying, please don't try this at home in a sense that this is for non-novices, moderate or severely hepatically impaired patients, Childs B or C, and they should be referred to do this to a medical practitioner with expertise in the condition, ideally in the liver transplant center. And with that start, here's the outline of what I hope to cover in the next 20 minutes or so, maybe less, and that is recommended regimens and those that aren't. Now you may say, why on earth would I put on the non-recommended ones? And that is simply because I think there are some teaching points and some nice take-homes from these data that are worth going over. Real-world treatment, of course, is important in any sense in that patients that are excluded from clinical trials, those that are ill, more comorbid conditions that would get excluded are not accounted for otherwise, and real-world is helpful. Predictors of response, who is more apt to decompensate further, have another decompensating event, or even reversely or conversely, rather, those who would improve and go to, say, a child's class A. The benefits of treatment, the therapy failures, what to do in that case, and even talk about, in the context of primary hepatocellular carcinoma, primary carcinoma of the liver, what to do with these patients. So the non-recommended regimens are basically anything containing interferon, which you're well aware is not only outdated but contraindicated in this population, and any protease inhibitor-containing regimen. The reason for the protease inhibitor prohibition, of course, is because of the higher drug exposures in these patients, and there are some good examples of this, even in the data we're about to show. And, of course, hepatotoxicity, there was a peritapovir, which is an older protease inhibitor in the 3D regimen, which is branded the cure pack in the U.S., and multicenter cohort in the Middle East, acute liver failure occurred in seven patients, including one death. So this is the beginning of, at least, the red flag, among others, that this is not the safest population, those with protease inhibitors in their regimen. So what about PIMSOF, our old friend, semepivir-cifosavir, semepivir being a second-wave, first-generation protease inhibitor, and SOF, of course, being a nucleotide polymerase inhibitor with the old antiviral ribavirin. This was a non-randomized trial, but instructive nonetheless, 42 patients from two centers in Texas, most of whom were Child's B, and two-thirds, most common events or adverse events, it was generally well-tolerated, but it has had adverse events that we typically see in the non-decom population. Notice the hypo…and these are grade 3 or 4, this is not hepatotoxicity because these high bilirubin levels were not associated with, obviously, ALT or liver dysfunction. So this was a reflection of the receptors and, excuse me, the metabolism. And in this case, it was not hepatotoxicity. One of the themes behind these, and you'll see this again and again, is that many of these data sets show that the adverse events were really just adverse events related to advanced liver disease and not necessarily those engendered by the treatment itself. So the overall SBR in this group, 74, again, relatively small sample size, C did better than B, which is a common theme we'll be seeing, and the 1Bs are better than the 180s, and there's more to that. The limitation of this, again, non-randomized, ribavirin was at the discretion of the investigator, and we didn't see, at least it wasn't reported, improvements in MILD and Child's class, and we'll see that on these other data sets. Here are three that I put together in some older regimens just to give you the abbreviations. So, SBR, GZR, Grisopravir, Proteus Inhibitor, Eldesphere, EBR, NS5A Inhibitor, DCV, recall is the first NS5A inhibitor approved. Now, the first and the third in this data set are from Phase II open-label trials, and in the left, it was called C-SALT, and you can see all of them had, all these three studies, rather, had yellow boxes there indicating Child's B in the study. And in the center was a European Compassionate Use Program, again, sicker patients involved because they wouldn't necessarily qualify for two- or three-phase trials. And you see the, in this case, interestingly, I think it's because of the small numbers, you see C actually improved SBR relative to B, but that's not the take-home, that's an exception. Most of the time, the Cs do worse because of the baseline function worse. In case you're wondering, the overall SBR was 91% in this middle Compassionate Use set, and Genotype 3, as typical, especially in these advanced patients, had worse SBRs, 82% in the case of Genote 3. Now, some other instructive points on the C-SALT study on the left, that Phase II open-label trial using Grisopravir, Eldesphere, the adverse events were less in this Child's B group than were in a control group of non-serotics that would likewise receive this regimen. And more importantly, the levels of Grisopravir in this dosing was 50 milligrams, which is, if you recall, that's about half, that is half the dose of what the FDA European Union proved this is for this regimen in non-decomps or non-serotics or compensated serotics, which is 100 mg. So, despite that 50 milligram dose, half the dose, these patients had actually much higher levels of Grisopravir plasma exposure than relative to the non-serotics with double the dose, again, showing that pharmacokinetics are different in these populations. Now, there were no significant adverse events or decomp in the C-SALT trial to the left, and in the center, the numbers, 19 patients had severe SAEs, but again, related to advanced liver disease, 10 patients died of those liver-related causes that were not felt to be causal by the drug per the investigators. And very similarly, on the right side, this is a Medprevir study, there was more hyperbilirubinemia that was felt to be related to the drug and not hepatotoxicity. Recall these patients had that. And at week eight, similarly, the pharmacokinetic exposure was over three times higher in the patients with the child's B versus the A, which are not depicted here. So, long story short, the protease inhibitors are the wrong drugs in this population, despite the fact, though, that the post-SBR mils were improved in the majority. And this is a common theme you'll be seeing in these data sets, no change or improved, much more apt to occur than a worsening. The problem with this and the limitation of this is these are 12 or 24-week follow-ups at best, and the short-term may not necessarily reflect the improvement long-term. Of course, this is not unique to hep C and hep D. If we show viral suppression, aporemia, these patients also have less improvement, I should say, in function because of suppression, probably because of decreased hepatotoxicity and injury, at least related to the ongoing viral infection. So, improvement is the bottom line. Now, these, again, not recommended, the protease inhibitors. Just a few thoughts on this. Glucaprevir, which is now part of the FDA-branded U.S. laboratory, has no data in decompensated, at least published data. And voxelaprevir is part of the softbill, Voxvocepi-branded treatment. Again, that's a protease inhibitor. So, class 3B, these should not be used outside of a clinical trial or outside of an emerging indication. The recommended regimens, however, are actually fairly easier to recall, and we have now single tablet regimen, soft and lodipisphere, and lodipisphere, of course, being an NS5A inhibitor, with ribavirin. Now, there was no choice on the investigators to give ribavirin in either of these two large studies, SOLAR I, SOLAR II. These are both Phase II, open-label. On the left is a U.S. study, 29 U.S. sites, and on the right are 34 sites from Europe, Australia, New Zealand, Canada, et cetera. They're about 10% genotype 4s in SOLAR II, whereas virtually all the rest, especially in SOLAR I, are genotype 1s. And we're going to focus on Cohort A. You might look at these numbers and say, wow, I thought there were many more subjects in SOLAR I and II than what are depicted here, but the reality is this is just a sliver of the data, focusing on the cohort deemed A that had not undergone liver transplantation. My colleague in the second lecture, Dr. Reshamwala, will discuss some of these data for the transplant. I'm not going to be touching the transplant issue per se, although I'll have a few things to say on it, but that will be for next. Now, both of these studies were also common in that they were randomized. The patients were randomized in one-to-one to a combination of lodipazirazoft and riba for 12 weeks versus the same lodipazirazoft-riba triple therapy for 24 weeks. And I didn't show the SVRs for 12 or 24 because they were not statistically different in either of these trials, so it's not helpful, but I did show, again, an improvement in the SVR or decrement in SVR in the Cs relative to the Bs, at least numerically here. Now, adverse events, we always need to talk about that because of the population. Twenty-three percent of SAEs, serious adverse events, the majority were decomp events and were not felt to be related to the drug, with the exception being the ribavirin causing some severe hemolytic anemia. And, again, focusing on this non-transplanted population, important to state. Now, when we add and we look at the outcomes, again, short-term outcomes at least, among the non-transplanted patients who had MILs over 15 at baseline, that's the level at which we would consider transplantation effective, 80% of them fell below 15 post-SVR. And, again, this may get into the whole MIL purgatory issue, which the second lecture might well discuss, and we're not going to go into that too much, but I think the take-home point is short-term improvements in MILs, the SAEs were worse in 24 weeks versus 12, forgot to mention that, but there was no efficacy improvement in 24 versus 12 weeks in either of these trials. Now, how about the pangenotypic inhibitor, NS5A inhibitor of Velpatasvir, combined with SOP, also single-tablet regimen, plus or minus Riva. We're going to start on the right. This was an open-label Japanese study comparing SOP-VIL versus SOP-VIL-RIVA, both are 12 weeks, only 12 weeks in Japanese study, and these patients are stratified by child's B and C, and genotype 78% genotype 1, 20% genotype 2, again, this is in Japan, open-label, mostly were child's B, though. And ultimately, you can see the SVRs in the larger group being quite good, and 60% in the Cs, it really didn't matter much with or without Riva, there was a 2% improvement, so numerically, not statistically, in the yellow, or 96 overall percent, so the child's Bs, Riva, a little bit better, and in child's Cs, without Riva was 80% versus 70% with Riva, so no particular difference, at least in that group. Now, the more important of the two trials on the left, more importantly, because it was a big sample size, a multinational ASTRO4 study published in the New England Journal some years ago, 47 sites in the United States, phase 3 open-label, these were all child's B, that's the yellow, and no red bar, treatment naive, 45%, treatment experience, 55%, so about half of those, but the treatment experience, you have to understand, was not more advanced regimens, these are the older regimens, including older PIs, some of these patients even had interferon-based therapies, so no one has failed current NS5A plus polymerase inhibitor, like Cephosphere. In this case, the baseline RASes, there is always a question on that, and I'm going to just mention it very briefly, we're not going to have time to go into this too much, but the baseline RASes for NS5A were 28%, and those patients had an 89% SVR. If you compare that to those without the baseline RASes, it was a 92% SVR, so there really wasn't much improvement, no difference, statistically, for having baseline or not having baseline RASes. Of course, when people did fail, the majority had NS5A resistance post-failure. The randomization schema, if you don't recall, was Sofville 12 weeks, Sofville 24 weeks, and then Sofville RIBA for 12, so two 12-week arms, one with and without RIBA, and one 24-week arm, and statistically, not much difference, certainly not important, and no difference in post-hoc analysis as far as that wasn't powered to detect differences on some of these subgroups, but more likely to have improvements. I will show you the milled improvements as before. In this case, some were reported in childs, but as far as the 15 mil, that threshold we've discussed, in the patients with higher mills in the ASTRO4, 81% improved, which is really a very nice improvement, higher than if they had less than 15 at baseline, where only 51% improved, so a lot of numbers here, but more likely to have improvements at the higher mills to start, and again, my next speaker will discuss the impact on transplant, and what is an optimum threshold for that. Okay, so just a teasing out, post-hoc analysis, no difference in the SVR rates among the three treatments, just numerically, whether this is for all genotypes combined, or likewise for genotype one, in which the SVRs range from 88 to 96%, but really no difference among the three arms as far as that, probably the most important difference was among the three arms in genotype three, again, we're going down the slivers of patients, subgroup analysis, we're down to, you know, 30 patients, but instructive nonetheless, the genotype 3s did much better with the addition of ribavirin by a whopping 35% difference, at least numerically. Too few non-geno 1s and 3s to make conclusions about them. And again, NS5A-RAS as a baseline had no association, even in geno 3s, with improvement. Now, on to the real-world data. On the left is the UK real-world expanded access program. This treatment cohort was compared to untreated, and the majority, again, are CPTB, 73%. About 10% were Cs. But the overall SBR, as you see, is 80%. Genotype 1s had 90, a little higher than the overall group. But geno 3s, this is an important study because there were a sizable number of genotype 3s, 172 subjects for geno 3. It's not nice to have that number of decomp geno 3s. And their SBR was well below the 90% with geno 1. They're actually 69%, and they were statistically different. So, geno 3 was definitely a poor prognostic indicator, at least in terms of SBR. There is something unique also about this. Detectable RNA at two weeks was an independent predictor of treatment failure, which is not something we typically look at. Many of these folks we check at four weeks. Some have it, some don't. We don't normally think of that's going to portend a worse response. But in this case, it did. Detectable was independent predictor of treatment failure, which served better than baseline mil. And notice the mil improvements on the left and the right. Again, the same kind of themes. We're going to talk about the one on the right. This is Target. And hepatitis C Target, you're probably familiar with the real-world database. For full disclosure, we have one of the sites. This is 46 academic sites, 16 community sites in the U.S., Canada, Germany, and Israel. And these patients gave informed consent, and their patient identification was redacted and submitted to a central database. Interestingly, 25% or so had three or more improvement in mil at the time of follow-up. And what's unique about this follow-up was that it's very long relative to these other studies. Four years of follow-up in this Target database to the right. Notice that the NS5As were predominantly with diphosphere soft, but some could be bell, hepatosphere, or daclatosphere. But in general, all NS5A plus soft regimens. Again, this was registry data. But overall, though, despite the four years of long-term follow-up and that sliver that improved by three or more in the mil, overall, there was really a minimal improvement if you're looking at the big picture in terms of who improved long-term. So you get this early improvement in mil, but it may not necessarily correlate with long-term outcomes. We're going to talk about that momentarily. So, in summary, the decompensated serotics, 12 weeks of soft plus NS5A, specifically with diphosphere or a bell, hepatosphere, pangenotypic, and ribavirin, starting at 600 mg's in the ASTRO4, it was weight-based. But really, the average turned out to be a very low dose of ribo, the mean was 600 milligrams in each participant. So, yes, you can get them up to weight-based dosing. That is the Target, but it wasn't always the case of these patients getting there. Now, how about those who cannot tolerate the ribavirin? Because that was triple therapy. If they cannot, the recommendation is both from the double SLV depicted here and easel to basically eliminate the ribo, of course, but extend the 12-week duration to 24 using either of those two regimens. So double therapy for double the duration as opposed to triple therapy for 12 weeks. So what are the predictors next of response? Who's going to do better, and what are these benefits? And this is really what we should be most focusing on, not minutiae about SVR rates, more about what are we going to do? How can you predict ahead of time who is going to have an improvement, say, from child B and C down to A? And that was the clinic, the mean endpoint of this study showing you this was based on retrospective data, but it was a nice analysis of four decompensated trials, three of which we've already discussed, SOLO1 and 2, ASTRO4, and another one that was Gilead sponsored, which was SOP and ribo together for 48 weeks and an open label phase 2. And they used all four of those databases and calculated, there were actually 500 Bs and 120 Cs, and they were able to, using this data, choose the endpoint that they thought was clinically meaningful, and that meaningful endpoint was a reduction, regardless of where you started, B or C, but a reduction down to child A. And secondary endpoints were no less than 15, et cetera. But they wanted a clinically meaningful one, and SVR was associated with significant reduction in the likelihood of transplant or death, which is not surprising. But in multivariate analysis, the authors identified five factors in that pentagon to the left that were associated with the reduction to that child A. And those are relatively slim patients under 25 BMI, ALT over 60, so the higher ALT is better, more inflammatory activity, presumably, and a serum albumin over 3 1⁄2, so synthetic function preserved, no encephalopathy, no ascites. What's most important of those is actually the no encephalopathy and no ascites, so no decompensating events prior to just poor function. But nonetheless, the reason this is important is I think it's good to be able to pretreatment this BE3A, that's what it's called, it's a way to remember these five factors, to be able to predict if there was one, if a patient had zero or one of these positive predictors, they had less than a 5% chance of reaching that primary endpoint of going down to A. Whereas, if they had a four or a five, there was only one patient with a five, and most of them fours, these patients who had four or five of these pentagonal points that are on the left, they had amazingly a 75% chance of reverting to child A. And this was felt to be a stronger predictor than a baseline milled at predicting someone improving at that point. So, now what about the converse of that, if we're able to go to, the converse of this is trying to predict who's going to do worse at treatment. So, we just showed an improvement, how about those can we predict who are going to do worse? This was 114 patients from an international cohort, Canada, Germany, Netherlands, these are Bs and Cs, a baseline treated with relatively advanced therapy, although there was lazipesia riba, but there was also some Simsoft and soft riba in there. But the independent predictors of the decompensation were three, child B and C only, of course, and in those were low albumin, higher milled, 14 plus, or genotype three, the highest being the lower albumin. So, if one factor was present of these three, the SVR was still relatively high, about 75%, with about a 20% decompensation rate. So, relative to the decomp rate, the SVRs were important and good. So, meaning this might be helpful to predict should you treat someone who may not be a transplant candidate, who isn't able to get transplanted, for example, is it worthwhile treating that person, as opposed to if they had two or three of these risk factors, the decomp rate was as high as the SVR rate, and these patients obviously wouldn't benefit necessarily to higher risk. So, it's helpful for risk benefit decisions, I think these prediction rules. And to repeat this, we've shown you this, just many of the slides showing this study showing improved milled, improved child's class. I'm not going to dwell on that, but again, these are relatively short term. And in contradistinction, we have this very important VA study that is now showing SVR, follow-up 1.6 years, SVR independently associated with improvement in mortality. What's more important is the history of decomp. So, even if you're relying on a FIB-4 to make the cirrhosis decision, the overall mortality improvement is important in the decompensated patients. So, if you don't believe the FIB-4 is a noninvasive tool, these patients had a history of a decompensating event, and still, and they were therefore, those were cirrhotics, and they were still improved mortality by 67%, which is not as good as the 80% for all the cirrhotics, but it's certainly a nice number to see an improved mortality. So, I'm going to just whiz through the final slides. I'm a little bit out of time, and I apologize, a lot of data here. And, but treatment failure, there really are no data. That's the problem with treatment failure. And we have virtually no data on treatment failure for NS5As and SOF combined. So, the bottom line is use 24 weeks of these regimens. They're not recommending using necessarily RAS testing at baseline. Now, what about HCC, my final mini-section? Basically, I'm showing you the AGA's guidance on this, which came out last year. No conclusive data, of course. The controversy has been put to rest that DAA therapy engenders a worse HCC recurrence or aggressive rates, aggressiveness, and it's not related. The presence of active HCC is associated, though, with a decrease in SVR. If you are treating these patients with active carcinoma, there are rates, there are several data sets internationally that confirm that. On the other hand, what's more importantly, and I think the take-home point is, should you defer these patients until after HCC treatment? And my final slide is, if it advances, is these two from North America and Europe. You might recognize some of these. One was from Gastro. Admittedly, both retrospective, but what both of these studies showed was those who had complete response to HCC, no matter what that response or how that response was achieved, and that could have been a radioablation, a taste tear, whatever it was, resection, that you were able to cure these patients. Once they were cured and they were given DAA therapy, did it have an impact on survival? And the definitive answer seems to be yes. At a follow-up of over four years, you can see the DAA therapy on the top of the North American study associated with lower mortality, 46%. This was only improved, though, in the patients who had SVR, not necessarily those that were treated. So ultimately, it was those who were treated and had SVR, the lower mortality was there. The problem is, it's retrospective cohort, there's selection bias. As you would guess, these are the ones who were treated were probably weller, better performance status, et cetera, and maybe that had an effect. Likewise, in Europe, on the bottom in Barcelona, similarly, patients who weren't treated versus treated propensity matched, and the patients were all cured, of course, of their HCC, but then were treated for the hep C, and SVC, excuse me, SVR was a significant predictor of their overall survival. Not only that, but HCC recurrence and further decompensating events, which, so liver-related and overall survival. So, in summary, we have avoid the protease inhibitor containing regimens for the treatment of these decompensated serotics, mostly because of the hepatotoxicity and higher levels. Treat with Sofplus and MS5A, plus Riba if they're tolerable, or if it's not contraindicated, rather, usually for 12 weeks. Baseline clinical data like serum albumin may be predictive of both the mild improvement and further decompensating events, SVRs tend to be less than with compensated serotics, but some pretty impressive numbers despite that, child's B do better than C, one B's better than one A's, and better than the hardest to treat, which are genotype threes, and the adverse events typically are not related to the drug themselves, but a reflection of the natural history of this. Achieving SVR may engender overall mortality reduction, but less than the mortality reduction in the compensated cirrhosis data sets, although there are less data to judge that. Treating HSC patients after they achieve complete response to their cancer may be associated with improved liver-related and overall mortality, and thank you for your attention. I'll hand that over next to Dr. Priti Rashamwala, who's going to discuss the transplantation. Dr. Berman, thank you very much for this excellent presentation. Our next presenter today is Dr. Priti Rashamwala, and the title of her presentation is Hepatitis C Treatment, Considerations Pre- and Post-Liver Transplantation. Good afternoon, everyone. Thank you for the invitation to speak today. I will be taking the next 15 to 20 minutes to discuss with you hepatitis C treatment considerations for the listed patient, as well as treatment considerations in the transplant recipient, and these are my disclosures. Today, I will review strategies for optimal timing of hepatitis C treatment for the listed patient, and also for the patient who has already received a liver transplant. I'd like to look at the short- and long-term consequences of hepatitis C clearance in the listed patients, and review the various direct, the DAA treatments available for these patients. And finally, I'll just whet your appetite a little bit and spend a couple of minutes discussing the new and somewhat controversial topic regarding offering liver transplantation to hepatitis C negative recipients with positive donors. And in full disclosure, there will be a future upcoming AASLD conference dedicated solely to this topic, so we'll be just grazing the surface of this topic. Dr. Proma just reviewed with us the remarkable data regarding our available DAAs and their efficacy and safety with excellent SVR rates, even in cirrhotic and some decompensated patients. So we know we can treat these patients, which is quite remarkable considering if you were practicing just 10 years ago, we would very infrequently attempt interferon-based treatment for the sick listed patient. So the debate now shifts from can we treat this patient to when is the optimal timing of treatment of hepatitis C in transplant candidates? And there's a few strategies that we can take. We'll spend some time discussing pre-liver transplant hepatitis C treatment. I think most people on this call would agree that not treating a patient for their hepatitis C after liver transplantation is not a viable strategy, given all of the available drugs we have. And then we'll finally review some data on post-liver transplant hepatitis C treatment options. So again, we know we can treat these patients with cirrhosis and decompensated liver disease. The more nuanced question now becomes should I treat my patient with hepatitis C before or after liver transplantation? And there are several factors that play into decision-making when considering this question. First of all, what is the likelihood of meaningful clinical response to DAA therapy? And we have to define for each individual patient what constitutes a meaningful clinical response to therapy. Second, what are the expected virologic responses and do they translate to desired treatment outcomes? And then finally, as a transplant provider, it's very important to understand our patient's access to liver transplantation. As every transplant provider on this call knows, the very first question that a patient asks once they are listed is, how long until I get my liver? And as a transplant provider, you patiently re-explain the MELD system as well as the expected disease progression in transplant process. However, it's also important to understand transplant trends and practices in your area. For example, do you practice in a region that has a high number of hepatitis C positive donors? And is your center one that accepts these donors pending donor biopsies? What is your center's median MELD at transplant and how long does it take at that score to draw an organ offer in your region? Does your patient have access to a living donor? If so, there can be an opportunity to eradicate hepatitis C prior to a scheduled living donor liver transplant if the patient can tolerate drug and wait that long. Does your patient qualify for exception points? Currently, for the most part, that will grant a patient a median MELD minus three points. Will that score make a patient competitive for an organ in your area? I have COVID-19 listed as a variable here as well. For those out there in the transplant community, the majority of us saw a significant decrease in transplants from March through early June, where only the sickest of patients with ACLF or high MELDs were being done in an effort to conserve hospital capacity and PPE. Subsequently, you notice in the transplant community have done a remarkable job ramping back up after this initial surge to pre-COVID volumes. However, we all recognize that we are in yet another surge and additionally with the flu season on top of us in the cold winter months ahead, it is quite possible that we will see a change in transplant volume related to COVID in the coming months. And finally, distribution changes have also affected transplant centers across the country. UNOS implemented in February of this year distribution changes in an effort to provide more equal access to liver transplantation to areas in the country that seem to have a higher MELD at transplant. Organs may now be matched to patients within a 500 nautical mile radius from the donor hospital site. Although the data is not yet robust, there does appear to be a shift in organ distribution in this country. For example, in region three where I practice, there appears to be a net export of livers to other regions. So more to come on this topic as data becomes available. So one of the first studies to look at clinical outcomes at the time of SVR-12 was ASTRL-4 published in New England Journal of Medicine which Dr. Pearlman just reviewed. Briefly, I will recap in this study of over 220 cirrhotic patients divided into three arms. One arm received soft valve for 12 weeks. The second arm received soft valve plus weight-based riba for 12 weeks. And the third arm received soft valve for 24 weeks. SVR rates were similar across all groups, although the study was not powered to detect small differences in the study arm. However, this was one of the first clinical studies to look at clinical outcomes such as change in child score and change in MELD score at SVR-12. So if we look at the top graph, 47% of patients had a mainly one to two percent, one to two point improvement in their child score. 42% remained this at the same child score and 11% got worse. In essence, a little less than half of patients had a one to two point improvement in child score. When we look at outcomes based on MELD score at SVR-12, for those patients with a MELD less than 15, about half had an improvement in MELD, mainly by a decrease of one to three points. 22% maintain their MELD and 27% had a one to two point increase in MELD. And finally, if you look at the group of patients, about 27 treated in this study, whose MELD range from 15 to 20, we see that about 81% had a modest improvement in MELD. So we see that DAA therapy can have excellent SVR rates, even in previously difficult to treat patients. And we can improve the child score and the MELD score in half or more patients treated. But what does this clinically mean for our patients? And so this next study sought to evaluate this question by looking at clinical outcomes of patients treated with DAAs while awaiting liver transplantation. This is a study of Spain that was an observational multi-center retrospective study from data collected from 2013 through 2015. They looked at all of the patients listed for transplant with a diagnosis of active hepatitis C. And of those patients, 238 were treated with various regimens of DAAs based on what was available and clinically appropriate for the patient at that time. Of these patients, the group on the right had compensated cirrhosis and HCC that we won't review today in today's discussion as it's a different disease process and HCC patients often may not be able to obviate the need for liver transplantation. We'll instead focus on the group on the left who had decompensated cirrhosis with no HCC, of which 29 of 122 patients who were treated with DAAs achieved SVR and had sustained improvement at a median of 50 weeks out, so long-term follow-up after SVR. And this translated to about a quarter of the patients in the group. These patients were able to be safely delisted from the transplant list. Two of them, however, did go on to require relisting due to new occurrence of HCC. And when we look at the data further, we see that the cumulative incidence of delisting by competing risk analysis is about 27% in this long-term follow-up cohort here in blue. We do, however, note that the majority of patients go on to require liver transplant noted by the curve in red, and there is a background rate of death and disease progression noted by the green line. In regards to dynamic variables, the only variables that was found to predict delisting was a delta MELD, that is a decrease in MELD score of greater than four points had the highest cumulative incidence of delisting, followed by those patients with a delta MELD between two and four points, followed by the lowest incidence of delisting if the delta MELD was less than two points. It should be noted that no patient with a MELD score greater than 20 was able to be delisted. So again, we recognize that patients with cirrhosis and decompensation can be treated with DAAs, we can achieve SVR, and about a quarter of appropriately selected patients can go on safely long-term to delisting. Based on these studies and similar studies that mirror the results we've just looked at, there are some clinical features that can help predict favorable response to antiviral therapy and possible delisting from the transplant list. And one such factor is having a baseline low MELD score between or less than 16 to 20. Also having a baseline low child score, which likely reflects that the patient has an absence of severe complications of portal hypertension. This group certainly recognizes that MELD score does not necessarily capture disease severity in all patients, especially those with difficult portal hypertension. A delta MELD of greater than four points, some studies have suggested three points is clinically meaningful change, can also help predict favorable response to DAA therapy, and an increase in albumin of half a gram per deciliter at SVR has been associated with long-term improved liver function and probability to delist. However, of significant concern in the transplant community is that using the MELD score or other dynamic variables as a surrogate marker of disease may lead us to treat patients on the liver transplant list for their hepatitis C to improve their MELD score. We recognize that a decrease in MELD score can translate to a decrease in waitlist mortality. However, there's the possible unintended consequence of delaying liver transplantation by moving patients further down on the transplant waiting list. For example, your patient with a MELD of 17 who has a modest two-point improvement in MELD with SVR, but continues to require use of healthcare resources for complications such as sarcopenia, frailty, and quality of life measures that are not well measured in these clinical trials. Have we now disadvantaged this patient by making liver transplant less attainable? This is, of course, balanced with the risk of not treating the patient and having progression of decompensation, possible HCC development, and possibly dropping off the transplant list. It's important to recognize that improved MELD score does not necessarily equate to improved health status in all patients, and that the MELD limbo or the MELD purgatory can be a very real and very difficult situation for patients suffering poor quality of life and complications of portal hypertension. So we've reviewed a bit about how to define what is a meaningful response to therapy individualized for your patient. Let's move on to expected virologic responses and treatment outcomes. This table summarizes data from many of the trials that Dr. Pearlman has already reviewed for us. I'll point out that as the child score and MELD score increases, our SVR rates decrease. This table lists current AASLD recommendations for the treatment of decompensated patients based on child class. The addition of ribavirin should be strongly considered in ribavirin-eligible patients who have otherwise some unfavorable characteristics such as previous failure of treatment or relapse. There is an increased rate of development of resistance-associated substitutions with repeated treatment failures, especially in more advanced disease, which may possibly make antiviral therapy post-transplant more difficult. And again, note that there's no protease inhibitor-based regimen included in this table due to increased metabolite levels and risk of hyperbilirubinemia and progression of liver failure with this class of drug. Taking all of this together, this is a proposed treatment algorithm for hepatitis C positive liver transplant candidates awaiting liver transplant. And this approach is mirrored by several international transplant societies and other transplant bodies. So if we start on the left here, if the patient has a high MELD score, MELD exception points, or liver transplant is otherwise unavoidable, it is generally recommended to treat hepatitis C preemptively after transplant. For the child's A patient, in discussion with the patient, it would be reasonable to attempt to treat the patient for pre-transplant clinical improvement with the goal of to obviate the need for liver transplant, or at the very minimum, to prevent hepatitis C graft infection if transplant is ultimately required. For the decompensated child B or C cirrhotic, we can further stratify by MELD score. So if the patient has a MELD less than 20 or has a living donor, consideration should be given to treating the hepatitis C pre-transplant, again, for clinical improvement. But in the case of a living donor, treatment can be offered prior to a scheduled liver transplant if the patient can wait for this duration to achieve SVR. This will also ensure that there is no hepatitis C infection of the donor graft, the donor hepatectomy. For MELD score greater than 20 and acceptable renal function, there should be shared decision making with the patient with consideration given to quality of life issues, access to transplant, and assessment of likelihood of clinical improvement versus risk of MELD disadvantage or MELD limbo. And finally, for the decompensated cirrhotic with a MELD greater than 20 and significant renal dysfunction, given our limited options, lower SVR rates, and the general level of acuity of this type of patient, treatment should be deferred until after transplantation. Moving on to hepatitis C post liver transplantation, at this point, it is clear that all patients should be offered treatment for their hepatitis C after transplant. Most centers now offer preemptive treatment for hepatitis C generally one to two months after the liver transplant when surgical issues have resolved, as opposed to waiting until there's clinically apparent hepatitis C infection in the graft, which was previous practice. Selection of DAA regimen is based on several things, genotype, presence of mutations, presence of graft dysfunction, renal dysfunction, and again, consideration should be given for certain drug interactions with immunosuppression. This table summarizes several clinical trials and real world studies on DAA treatment efficacy post liver transplant based on whether the patient has graft cirrhosis. You'll note that the pangenotypic agents have excellent SVR rates. For those in certain parts of the country where payers may have formulary obligation to treat with other regimens, Sabasivir and Lidipasivir has high SVR rates for genotype 1, 4, 5, and 6. There's one small study looking at Sabasivir, Velpatasivir, Vaxilipravir for the treatment of patients who are DAA experienced with good SVR rates. In the post transplant setting, it's important to consider drug interactions. Sabasivir, Velpatasivir, and Preventasivir do not have major drug interactions that would alter management of immunosuppression other than what we would normally do, which is careful monitoring of immunosuppression level and liver function tests. However, there does appear to be a five-fold increase in Glicopravir AUC when used in combination with cyclosporine. So this combination is not recommended if the patient is on a dose of cyclosporine of greater than 100 milligrams per day. Similarly with Vaxilipravir, that has a nine-fold increase in AUC when used with cyclosporine, so that is not recommended. However, overall, we have very effective and well-tolerated medications to treat hepatitis C post-liver transplantation. And finally, for the last couple of minutes, I will briefly touch upon the new and exciting possibility of increasing organ availability, especially to the sickest of patients, by transplanting hepatitis C viremic donors into hepatitis C negative patients. And this is a practice that never would have been considered prior to the approval of highly effective DAAs. There's a small but increasing body of literature out there, mainly single-center experiences, mostly with liver and kidney transplant recipients, but also with some minimal data in heart and lung recipients. And these small case series reflect very good success rates with 98% or so hep C eradication when treated immediately with DAAs after receiving an organ from a viremic donor. However, there's very little medium or long-term data on outcomes of such patients. And this study by Dr. Tulivath and his group from Baltimore reflects the most long-term data available at this time. And this study was published just a few months ago, and this group queried the UNOS database from 2014 through 2018 on all subjects who received liver transplants stratified by donor hepatitis C antibody status, donor hepatitis C viremia, which is NAT positivity, so they had active virus at the time of donation, and recipient hepatitis C seropositivity. And we'll focus on this group here, the so-called hepatitis C negative recipients who received actively viremic donors. And we can see on this bar graph in yellow here that the majority of these transplants happened in 2018 with a very few in 2017, again, after the widespread availability of DAAs. And when you look at the unadjusted graft and patient survival rate for patients who are hepatitis C negative who have received a viremic organ compared to those who received a non-viremic organ, there appears to be a trend towards decreased survival in those recipients who received a viremic NAT positive organ. However, when adjusted for recipient variables, such as MELD score, the need for dialysis, length of hospital stay, need for pressers, measures of how sick the patient was, receiving a NAT positive organ, receiving a viremic organ, was not a negative predictor of survival. In fact, the data suggests that the sickest patients seem to be receiving these donors. However, it's evident that we need more granular data on the outcome of these patients. Some earlier reports suggested increased risk of rejection or infections in these transplant recipients. Unfortunately, the UNOS and SRTR datasets are not granular enough to determine if such increased risk exists. Most importantly, it's imperative that transplant programs go about this process in a thoughtful manner and have standardized preemptive hepatitis C treatment protocols established. At my center, transplant providers, including transplant pharmacists and administrators, we have all agreed that treatment will begin as soon as the patient can take medications by mouth or at the latest by post-op day seven. Transplant pharmacists will submit to payers all necessary information for drug approval by post-op day one, regardless of what day of the week that is. And if there is any delay or denial in a patient getting medication, our center has committed to being financially responsible for DAA medication to ensure not only the highest quality care, but seamless care coordination. Again, there's much more to come on this exciting topic in the months ahead, so please stay tuned. And I thank you for your time. I'll turn it over to Dr. Pawlowski. Dr. Oshamwara, thank you very much for your excellent presentation. Dr. Pawlowski? Yes, thank you very much, Dr. Massoud. I hope you can hear me. Good afternoon, everybody. Good evening here from Paris. I would like first to thank ASLD for inviting me. It's good to be with ASLD in spite that we're not together at ASLD, but let's say this will come very soon. So today, the topic I've been asked to discuss is DA failure with rare, unusual HEV genotypes. This is my conflict of interest disclosure. And first of all, I would like to remind you that there are currently eight known HEV genotypes, numbered one to eight, that have been discovered. But each of these genotypes splits into a very large number of subtypes, and only a few of these subtypes have spread over the world in the past centuries. You know them very well. They are what we call the frequent HEV genotypes, 1A, 1B, 2A, 2C, 3A, 4A, and to a lesser extent, 5A and 6A. But as you can see on this slide, there are many other subtypes, and these subtypes can be found sometimes with a relatively high prevalence in their countries of origin, essentially in Africa and in Asia. And these genotypes have not spread broadly over the world, but they can be highly prevalent in some regions of the world. And most importantly, they can also be found in migrants who were born in these regions and emigrated to Europe or to North America or to Australia. This slide now shows you a number of patients who were referred to our French National Reference Center for Viral Hepatitis B, C, and D at the Henri Mondeau Hospital in Paris. And we had over four years, 114 patients who failed the faux-de-vir-ver-pet-as-vir of the capre-vir-par-brent-as-vir therapy. And among these 114 patients, to our surprise, 27, which represent approximately a quarter of them, of these failures happened in patients who were infected with rare, unusual HEV subtypes, meaning that these subtypes represent a very tiny proportion of the patients in France, but a high proportion, 24%, of the patients with a sophage-vir-ver-pet-as-vir or a glycapre-vir-par-brent-as-vir failure. You can see here the patients who had sub-viral failures on the left, and you can see that there were several unusual subtypes of genotype 1, of genotype 2, and of genotype 4. And similarly for GP failures, we had a patient with genotype 1c, a couple of patients with unusual subtypes of genotype 2, and of genotype 4, and one patient infected with genotype 6q. So now I would like to show you some examples of these rare, unusual genotypes that are inherently resistant to the NS5A inhibitors and therefore are prone to failure with even the most recent drug combinations. The first story is about unusual African HEV subtypes in South London. This is a study that was done in a hospital in London. They followed 2,200-plus patients, and among these 2,200-plus patients, 4.1% were born in Africa. And interestingly, 47 of these 91 African patients, 52% were infected with an unusual genotype. This included a non-subtypable genotype 1, or non-1A1B genotype 1, or non-4A4D genotype 4. And on the right, you can see a figure showing different distribution of these rare genotype subtypes in different regions or countries of Africa. And as you can see, the samples coming from patients born in Nigeria were completely different from those from Tunisia or from Chad or from South Africa or the Congo Democratic Republic. Interestingly, these investigators observed a low SVR rate in unusual African subtypes in this population based in London. And you can see here on the slide that the SVR rate overall, and this is a real-world study, was 89% in all patients together, but in patients infected with an unusual genotype 1, it was only 75%. And treatment failure could be explained by the presence at baseline of NS5A polymorphisms that were naturally present, not selected, but they were part of the nature of these viruses, especially at positions 24, 30, and 31, that conferred reduced susceptibility to all available NS5 inhibitors. The second story I want to tell you is about another subtype, subtype 4R. This subtype is quite prevalent in Central Africa and our attention was drawn on these rare subtype but frequent in some regions. By the shared trial, this is a large scale trial with sofadivir and adipovir that was done in Rwanda in Central Africa. 300 patients included, 83% of these patients were infected with G-type 4, 16% with a combination of G-type 1 and G-type 4. So you see that overall G-type 4 is highly prevalent in this region. And the surprise was to see that patients infected with subtype 4R had only a 56% SVR rate whereas the other subtypes of G-type 4 had the usual 93%, 90 plus SVR rate and therefore a very significantly lower SVR rate for subtype 4R. We did a study in patients from our center and especially in patients who emigrated from Central Africa and live in France and same thing, we found a high proportion of subtype 4R in patients who failed to achieve SVR in this population. And interestingly, this could be explained by the frequent presence of NS5 erases at baseline that were subsequently selected by DA treatment. And usually these patients infected with G-type 4R are characterized by a double or a triple combination of resistance associated substitution in the NS5A region. The L28V plus L30R always plus or minus the L31M and this combination confers a more than hundred fold reduction in G-type 4 replicant susceptibility to the deepest SVR for instance. And in contrast, the Y93H RAS was exceptionally present. It is not naturally present in this genotype and not frequently selected. This explained that these patients had baseline resistance to NS5A inhibitors but in addition to that, we observed the frequent selection of the NS5B S282C or T RAS which can first reduce susceptibility to sofobivir and this suggested that this RAS is also frequently preexisting at baseline although at low level. And indeed it was detected in several cases by deep sequencing whereas it was not detectable by population sequencing. This is the example of one patient from our series, patient born in Africa, infected with G-type 4, subtype 4R. And as you can see in this patient at baseline, the patient at the L28V substitution in the NS5A region that can first reduce susceptibility to NS5A inhibitors, he also had the L30R substitution at the major population and the L31 was Y-type and in the NS5B region, the S28 was also Y-type. As you can see at treatment failures, the two RASs that were present at baseline, L28V and L30R were still present. And in addition, the patient that selected the third substitution, the L31N, that was present as a majority variant, so triple substitutions in the NS5A region, plus in the NS5B region, the patient had selected Sophobivir-resistant populations with a majority of S282T, 75%, and 5% of S282C and this clearly explained the preexistence of RASs that can reduce susceptibility to NS5A inhibitors and to Sophovivir. This clearly explained the frequency of treatment failures with the current DA regimens in these population of patients infected with subtype 4R. So we spoke about a couple of examples in patients with unusual subtypes from Africa, but this also happens in patients in Asia and especially there is currently a concern with a certain HEV subtype, HEV subtype 3B. HEV subtype 3B represents a large proportion of patients in many places in Southeast Asia and in China and you can see here the results of the single arm open-label phase three trial that was performed in China with Sophovivir-verpatasvir and in that population, 11.2% of patients were infected with genotype 3B. The overall SVR rate in the large series of patients was 97%. It fell to 89% in patients infected with subtype 3B with no cirrhosis, but in patients with subtype 3B and cirrhosis, the SVR rate was only 50% and this was not with an old treatment. It was with Sophovivir-verpatasvir. Another study was published from China. This time it's also a phase three trial, the YH1 and 2 trials in truly naive and truly experienced patients. China, genotype 1 to 6 with or without cirrhosis, but this time the other treatment was Glicaprovir-verpatasvir and similarly, you can see here that the rate of response to Glicaprovir-verpatasvir was significantly lower in patients infected with genotype 3B, 70%, as compared to the other subtypes in which the usual 99.4% SVR rate was achieved. So it is very clear that subtype 3B in China and other parts of Asia has a problem even with the most recent combinations of HDV-DAAs. So what is the explanation? The explanation is shown here. As you can see, you have different substitutions, the A30K, the L31M and the Y93H. You can see here in green what is often found in patients infected with genotype 3A and in orange what is found in patients infected with genotype 3B. And patients with genotype 3B naturally have at baseline a combination of the A30K and the L31M. And you can see that this combination on the right can first reduce susceptibility to Daclatasvir, to Velpatasvir, very much to Elbasvir and a little bit, but significantly less to Pibrentasvir. And the presence at baseline of these two substitution explain that these patients who are infected with subtype 3B are inherently resistant to the action of NS5A inhibitors. And you can see on the left with the blue line as well, then another subtype of genotype 3, genotype 3G also has the same mutations at baseline and these genotypes is also inherently resistant to many NS5A inhibitors. So which other HDV subtypes are inherently resistant to the different drugs and especially the most recent ones? This slide shows you the results of an in vitro study. Complicated, but not that much. You can see that each box is a different subtype that has been studied here. 1L, 3B, 3G, 4R, 6M, 6V. And the reference is genotype 2A, the JFH1 strain. Each letter at the bottom indicates a drug, D for Daclatasvir, L for Oedipasvir, Elbasvir, Velpatasvir and Pibrentasvir. And the higher the dots, the higher the level of resistance to NS5A inhibitors. So if we focus only on Velpatasvir and Pibrentasvir, you can see that genotypes 3B and 3G are highly resistant to all NS5A inhibitors, including Velpatasvir and slightly less, but still a bit to Pibrentasvir. Whereas other genotypes are resistant to many of the NS5A inhibitors, including a small level of, let's say, reduced susceptibility to Velpatasvir, but appear to respond to Pibrentasvir, which is known to have a higher genetic barrier to resistance than the other NS5A inhibitors. However, this is only a snapshot of drug susceptibility, including NS5A inhibitors. You know that in a combination, you have a second drug. I've shown you that for genotype 4R, there is an issue with reduced susceptibility to Sopalvivir, and some of these genotypes may also have reduced susceptibility to Glicaprevir, which has not been studied here, which might explain that, for instance, for genotypes 3B, although we see that there is a better sensitivity to Pibrentasvir, the clinical results indicate that genotype 3B is inherently resistant to the GP combination and that there may be more failures with this genotype with any of the combination than with other known subtypes. So all of this information has been taken into consideration when drawing the final update of the ESL recommendations on treatment of hepatitis C, and the panel has decided to make recommendations for these different subtypes, and the recommendations can be summarized as follows. What ESL says right now is that migrants from countries where distinct, less treatment-susceptible HEV subtypes are known to be prevalent may benefit from determination of the genotype and subtype by means of population or deep sequencing of the NS5B or any other coding region, followed by phylogenetic analysis to identify HEV subtypes inherently resistant to NS5A inhibitors in order to avoid treatment failure. The second recommendation is that in geographical areas or settings where HEV subtypes inherently resistant to NS5A inhibitors are present, the HEV genotype and subtype should be determined whenever possible by means of population or deep sequencing of the NS5B or another coding region, followed by phylogenetic analysis, but we all know that in many of these regions, this type of analysis and tests are not available or not affordable, and therefore, biological studies are required in countries in Africa, Asia, and Latin America to determine the epidemiology, distribution, and prevalence of HEV subtypes inherently resistant to NS5A inhibitors, and thus to optimize treatment decisions without the need for individual HEV genotype and subtype determination. This is the recommendation, and if we look now at the global recommendation, which is not coming on my screen, yes, it is coming, you can see here what is recommended. First of all, we have to remember that first line, a simplified therapy with no genotype and subtype determination, and this is really to fine-tune the treatment we do for specialized centers. In specialized centers, patients infected with subtype 1L, 4R, 3B, 3G, 6U, 6V, or any other subtype naturally harboring one or several NS5A RASes, and many of these may be discovered in the future, regardless of the presence or absence of cirrhosis, and regardless of the fact their treatment name or treatment experience should not be treated first line with sofodimivir, verpetazivir, with bricapavir, pibrentazivir, until more data has been generated, and we know that some of these subtypes are inherently sensitive to these treatments, and therefore the ESO recommendation right now is 12 weeks of sofodimivir, verpetazivir, and voxelapravir as first line treatment, with the understanding that three drugs will, in all cases, do better than two drugs, and it will be possible to optimize treatment. The example we can take is, for instance, Rwanda, where you've seen that there is a very high prevalence of subtype 4R, and there is also a goal for elimination of HCV that has been set by the government for 2030. It is obvious that if, in this country, we decide to treat with a treatment which is not adapted to the strain that circulates in the country, the goal will not be achieved, and therefore, epidemiological studies, description of the population, and using first line, the right treatment, to eradicate the HCV infection is something which is absolutely crucial, and this is what was aimed at being covered by ESO in these recommendations. So this brings me to my conclusions. First of all, Africa and Asia harbor a high genetic diversity of HCV strains. Some HCV subtypes carry natural polymorphism that confer high-level resistance to DAAs, which we call RASes, but in that case, they have not been selected, they are here naturally, and this makes them unlikely to respond to at least several of the available HCV DAA regimens. Epidemiological studies describing the prevalence of these rare, unusual HCV subtypes in their regions of origin, but also in migrants from these regions living in North America or Europe are lacking. I think we have some examples of such studies in migrants in Europe that I've shown you, but we have very little data coming from North America. This is important to generate. And finally, pending specific information on their susceptibility to pan-genotypic dual therapies, such as cefalovir-valpatasvir or bleucaparvir-pibrentasvir, patients infected with rare, unusual genotypes that are inherently resistant to the NS5A inhibitors should be treated with a triple combination of cefalovir plus an NS5A inhibitor plus a protease inhibitor, and this triple combination, depending on availability, especially as a generic in these countries, could be subvalvox, or eventually soft plus bleucaparvir-pibrentasvir. On this, I thank you again for inviting me, and we'll take any question you may have. Thank you very much. Dr. Polsky, thank you for the excellent presentation, and we have a couple of minutes for a question. And I will have the first question to Dr. Rashamwala. Recently, there has been a lot of interest in transplanting hepatitis C-positive organs to hepatitis C-negative recipient. So the question is two parts. What would make this an attractive option now? And part two, what are the risks associated with this procedure? Sure, well, expanding our pool of organs for the sickest of patients, many of whom do not have hepatitis C, because now as hepatitis C is becoming eradicated, we're seeing less listings of patients who have active hepatitis C, but more other causes of liver disease, alcoholic liver disease, non-alcoholic liver disease. So these patients do not have active virus. So being able to expand the organ pool for this population is very attractive. And that's one of the major reasons why we consider offering these patients viremic organs. Additionally, because we have these excellent DAAs, and the initial studies suggest that the SVR rates in all different organs, liver recipients, kidney recipients, and even some heart and lung recipients, we've been able to eradicate the hepatitis C and not develop significant hepatitis C liver dysfunction or graft infection with these drugs. It allows us to expand the pool, treat patients, and transplant the sickest patients first, whether they have hepatitis C or not. And is it risk-free process? No, no, of course there's, one of the biggest risks that we worry about is treatment failure in these patients. You know, we're iatrogenically giving hepatitis C to a patient who does not have it. So you worry about not being able to treat the patient or the patient developing, for example, fibrosin cholestatic hepatitis C in their liver. So those are significant risks. There's also risks, there's also some published data out there suggesting that there may be increased risk of both T cell mediated rejection as well as antibody mediated rejection and infection in these particular recipients, the negative recipients who received positive, hepatitis C positive organs. So that data has yet to be fleshed out and we have to understand that a little bit better, but thus far in the small series that have been published, the response rates to DAAs have been very good. So this remains a viable option, but again, we need more prospectively collected data on these topics. Thank you. And I have a question for Dr. Polosky. Do we know if the unusual genotype of hepatitis C, do we know if they have different natural history than the more common genotypes? No, first we don't know it, but it's very unlikely that they have a different natural history. I think the problem is that in any case, it's very difficult to find them if we don't look for them because they would not be identified by the usual leap assay or the assays we use for genotyping. And therefore I think there is a real need for more epidemiology in the countries of origin, but also in migrant populations in Europe and in North America. And this is the only way to know if there is any difference in natural history, but I really don't think there would be a difference in natural history, but there is a real difference in treatment history. Thank you. I think we came to the end of our webinar for today. I would like to thank Dominique and Katie and the ASLD for organizing this webinar. I would like to thank all presenters and all participants. You will get a survey shortly after this webinar. Please take a time to fill it. It's very important for the ASLD for future selection of webinar topics and other activities. Thank you and stay safe.

Chronic Hepatitis C 500: The Advanced Course

hepatitis C-positive organs

transplantation

risks and benefits

treatment failure

rejection and infection risks

rare genotypes

medication resistance

triple combination therapies

treatment decisions

direct-acting antiviral drugs