Hello everyone, and welcome to this AASLD webinar, COVID in Focus, Outpatient Therapeutics and Managing Liver Transplant Donors and Recipients. My name is Mike Providence. I am staff at AASLD. I'm a Senior Manager of Patient Engagement, and I welcome all of you to this webinar. Today's presenters and moderators are listed here. The moderators are Jennifer Price from the University of California, San Francisco, David Mulligan, Professor and Chair of Transplantation and Immunology at Yale University. Presenters include Daniel Call, Director of Transplant Infectious Disease, University of Michigan, Ricardo LaHoz, Associate Professor of Transplant Infectious Diseases at the University of Texas Southwestern Medical Center, and we have an additional panelist with us, Shemal Shah, Professor of Surgery from the University of Cincinnati. This webinar is being recorded. We appreciate your saving your questions until the panel portion of this webinar, which will take place about halfway through. I'd now like to transition this over to Dr. Jennifer Price, Jennifer. Thank you. Hi, everyone. I wanna welcome you to the webinar. My name's Jennifer Price. I'm a Transplant Hepatologist at UCSF, and I'm co-moderator of today's webinar. And although we all would like to be done with COVID-19, I think it's clear that COVID-19 is not done with us yet. Having said that, we recognize that we're in a very different place in the pandemic now than we were two years ago. Our understanding of the virus, as well as the tools that we have to fight it have evolved. But so have the challenges that COVID-19 poses to our patients, particularly our liver transplant patients. So during this webinar, we will focus on many of the clinical questions we encounter managing liver transplant donors and recipients in the current COVID-19 era. We are thrilled to have an excellent group of presenters and panelists joining us. Dr. Call will start us off with a brief presentation on outpatient therapeutics. Then Dr. Mulligan will give an introduction to the current status of COVID-19 in the liver transplant community. And Dr. Lajas will review the experience thus far using COVID-19 positive donors. And then we'll end with a panel discussion. And we really want this to be as interactive as possible. So please use the chat or the Q&A features to ask your questions during the panel discussion. I want to also note that the webinar is being presented by the AASLD COVID-19 Task Force. The AASLD is actively monitoring events related to the COVID-19 pandemic and provides timely information and resources to support healthcare providers as well as their patients and caregivers. On the AASLD website, you can find a resource page that's updated regularly, including our recently updated COVID-19 vaccine consensus statement, as well as an archive library of COVID-19 webinars and other excellent resources. And now I'm pleased to introduce Dr. Daniel Call. Dr. Call is a professor of medicine and directs the Transplant Infectious Disease Service at the University of Michigan. His research interests include the epidemiology of opportunistic infections after solid organ transplantation and the diagnosis and management of viral and other opportunistic infections after stem cell transplantation. Dr. Call is also a valued member of the AASLD COVID-19 Clinical Oversight and Education Subcommittee. And he will be speaking with us about COVID-19 therapeutics. Thanks so much, Dr. Price. So yeah, I'm going to give a brief overview, about 10 minutes, update on COVID-19 therapeutics. Next slide, please. So these are just my disclosures and acknowledgements. Next slide. So what we'll cover today is monoclonal antibodies, which really have been quite useful, but have been really limited by evolution in the spike protein, which can limit the activity of these viruses. We'll talk about, or these monoclonal antibodies, and we'll talk about antivirals agents. And we do have a number of highly effective antivirals, which don't have those limitations since they don't work at the spike protein, and thus the kinds of mutations that make the virus more able to spread in an immune population don't really affect these antivirals. But there are some real issues with drug interactions, particularly in transplant patients. And just a little bit about inpatient treatment, because I think the focus now is really on trying to identify people at high risk early and get them on some of these very effective early treatments. Next slide, please. So for monoclonal antibodies, these are engineered to bind to the receptor binding domain of the spike protein, and thus kind of act as a neutralizing antibody. And even though many of the preparations have been dual antibody preparations, have targeted conserved regions, for example, with cetrovimab, there have been quite a few mutations that have rendered many of these products inactive. Next slide, please. And so there were four indications, really three that have been approved by EUA, one which has some support, but was never approved. And those included post-exposure prophylaxis, and both Lily and Regeneron were able to show in either a nursing home setting or in a community home setting that these agents could really reduce the risk of transmission to exposed persons, but that's not available currently. And for severe COVID-19, that's never been approved under the EUA, but there are certain circumstances where these agents are probably helpful. So what we're left with right now is primary prophylaxis and use early on in infection before somebody's hospitalized or has really a significant pulmonary involvement. Next slide, please. And so in terms of primary prevention, what we're really focused on is people who are gonna have limited response to vaccination, and that includes our solid organ transplant recipients, particularly those who are on microphenolate or who are early after transplant, people with hematologic malignancies who may be on B-cell active agencies, but much less so people with chronic liver disease who are not otherwise immunosuppressed who have a pretty decent response in general to vaccination. Next slide, please. And so for that, we have Avicheld. So Avicheld is a product produced by AstraZeneca, which is a long-acting monoclonal antibody. And you can see that in the PROVENT trial, which really only included three or 4% of these, about 5,000 participants were really immunocompromised. They were generally high risk in other ways, while events, meaning symptomatic COVID, were relatively uncommon. You can see there was about a 77% reduction that held up for almost six months in the development of symptomatic COVID. Next slide, please. So on that basis, the drug got approval under an emergency use authorization. It's given as a deep IM injection. Initially, it was a milliliter and a half. Now it's three milliliters, one shot in each gluteal muscle. And this does create some limitations on use for people who may have bleeding disorders. And there was this funny note of increased cardiac toxicity in those with previous risk factors for cardiac toxicity in the licensing trial that hasn't been observed with other monoclonal antibodies, and it wasn't observed in their PEP trial, but nonetheless, it can limit use somewhat as well. Next slide. The good news about Avicheld, and I'll tell you when I was spending many hours a week trying to get this set up in our program back in December and January, I was a little discouraged as it became clear that activity was much more limited against BA1, and particularly BA1.1, which was, until really a few weeks ago, was the most widespread variant in the United States. But the good news is that BA2, which is taken over now, the drug is quite active, whether you use a pseudotype viral-like particle or an authentic virus. So at least for right now, Avicheld is likely quite helpful for folks who are immunosuppressed. Next slide. And in terms of hospitalized patients and monoclonal antibodies, it's quite interesting that if you take out vaccine-induced immunity, people who come in and have been sick for a little while, but haven't generated antibody, do a lot worse than people who come in and have already generated SARS-CoV-2 antibody. And in those people, if you stratify them by their ability to generate antibody on their own, those that are negative, you can actually show a mortality benefit by giving a monoclonal antibody if it's active against the type that's circulating at the time. But that doesn't have any UA authorization, so it has to be approved in a different way. Next slide. And so the problem, of course, is that resistance has emerged, and that maybe isn't unexpected when you target the area that creates immunity in the population. So even citrovimab, which was a single product that was actually isolated from SARS survivors 20 years ago and works on a more conserved portion of the receptor binding domain, if you just hit the next slide, the advance, that doesn't work against BA2. So we've kind of lost that. And if you hit the next slide, again, both the Regeneron and the initial lily antibody combinations, neither of those work against Omicron. So next slide. So we're kind of down to the last Mab standing, which is bebtolivimab, which is a lily product, which actually has no interpretable placebo-controlled data because there were so few events in that trial, but does have in vivo and in vitro activity. In vivo, meaning if you take it after it's been administered, take out the serum, you can show some activity against all Omicron, including BA2. So that's really the only active monoclonal antibody we have left. And while COVID is low generally right now, so there is access to it. If we have an increasing outbreak, we're gonna probably get into trouble in terms of availability. Next slide. And so it really raises questions about this whole program for pharmaceutical companies developing these drugs and then resistance develops, and it's required massive government support. And we'll have to see how this evolves going forward. And hopefully, I don't even wanna talk about future pandemics, but it's something to think about when you target the area that is most kind of vulnerable to mutations or has the most push for mutations. Next slide, please. And I'll just mention that we have quite a few patients that develop COVID that they can't clear usually because of receipt of drugs like Rituxan. And we've had quite a bit of success using a combination of monoclonal antibodies and remdesivir and clearing these folks, but also possibly encouraging the development of mutations, which occurs in about 10 to 15% of those people. So that's another potential use, but again, has to be done with an emergency use authorization through the FDA for that individual patient because it can't be used under the EUA currently. Next slide. So now we'll move on to antivirals. Next slide. And so Paxlavid, which is a protease inhibitor, which is a combination of two drugs, including ritonavir, which we've used for years in HIV, which is a very potent P450 CYP3A4 in particular inhibitor and an irreversible inhibitor of that. So it kind of poisons that isoenzyme and that raises the level of the other component of the drug and is very effective if given within five days of symptom onset and is not affected by any of these spike protein mutations. So it doesn't really matter which variant, but you see a 90% risk reduction. And in this trial, 13 deaths in the placebo group, no deaths in the treatment group. And it works even better in those who are greater than 65 years old, didn't seem to add anything to monoclonal antibodies. So next slide. The problem of course with Paxlavid is that it includes ritonavir and while that's great for raising the levels of the nirmitelavir in the Paxlavid, it's also gonna be a very potent inhibitor of P450 and cause all sorts of problems with the calcineurin inhibitors. So if you do HIV transplantation and you have people on ritonavir, maybe their tacro dose might be a half a milligram every 10 days, right? So, and because that inhibition can last well after the drug stopped, you have to monitor people up to a week after they've stopped it to figure out if they can go back on their tacro. So if you're trying to get a drug into people within five days and you have to hold the say long acting tacro for 48 hours, you can see why this becomes very difficult. Next slide. So we put together a whole kind of algorithm that involved our pharmacists and nurses and linked into the way the drug is obtained in this state. And it's very difficult. So I think monoclonal antibodies make more sense if you can get them for transplant patients. Next slide. I'm just gonna mention briefly, molnupiravir, again, another different mechanism of action that works at the RNA dependent RNA polymerase and is a non-terminating polymerase inhibitor. So there is concern about creating more mutations and keratogenicity. The problem with it, it just doesn't work that well. So initially it looked like 60% and then the second tranche of data was no percent. So they wound up with 30%. So we really haven't used this cause I'm just not sure it does anything all that useful even though it's easy to use from a drug interaction perspective. Next slide. The other thing that turned out should be entirely unsurprising in a way, but remdesivir, which didn't look that great in hospitalized patients is actually a really good antiviral if you give it early to people within seven days of symptom onset, you see an effect similar to Paxlivid but very difficult to implement because you need to give an infusion to someone with COVID. They've got to come in and you got all the infection prevention issues and they've got to come in three times. And so that's a real challenge, but it does work and it's fully approved and widely available at least in the United States. Next slide. So in summary, I think it's still about early diagnosis and getting treatment into people early. So even though we'd all like COVID to be over, I think we have to tell our high-risk patients, get tested, get tested. If you get sick and let us know so we can try and get some of these treatments implemented. Focusing on monoclonal antibodies, I think post-transplant and getting Avuchel to people at least for right now while we have BA2 where it does seem to work well. And with that, I'll finish and thank you for your attention. Thanks so much, Dan. That was fantastic. And it totally brings up a lot of the questions that we have, next slide, that we're gonna talk about with our next speaker, Ricardo De Los. One of the things that I think is so exciting about this webinar is that we've had a lot of experiences Ricardo is going to present to us with using COVID positive donors. And they come in different shapes and sizes that Ricardo is gonna illustrate for us. And we've been transplanting COVID positive recipients as well. Some of the unusual effects that we've seen that I've been hearing about and talking to colleagues about are some of the things that can come up on this webinar that we can talk about so that we can look at the safest possible ways to use these donors and to use transplantation for our recipients that have had COVID in ways to avoid some of the interesting side effects or complications that we've seen with some of these. So without further ado, it gives me great pleasure to introduce Ricardo De Los. He's the chief infectious disease and transplant infectious disease at UT Southwestern in Dallas. And he's also the chair of the disease transmission advisory group for the OPTN. And so he's been doing that the past couple of years through this pandemic. And it's been great to have Ricardo here with us today and also to have him be able to update us on the latest data that we have for SARS-CoV-2 and transplantation. So Ricardo, take it away. Thank you, David, for that kind introduction. So next slide. So I have no disclosures for this talk. Let's move on to the next slide. So let's speak about the sine qua non of a solid organ transplant donor-derived COVID-19. And I'm going to focus on non-lungs. I guess the first concern that everybody had when using these donors was the possibility of a donor-derived event. So for a non-lung recipient, we will have to think about the possibility of viral particles in the blood. A systematic review revealed that 10% of patients with COVID-19 will have RNAemia. But the same study demonstrated that although there were particles there, viable virus could not be isolated. The second possibility in which a donor-derived event could occur to a non-lung recipient is the possibility of viable viral particles in the tissue allopathy. And there's conflicting data regarding this possibility. And I guess the most compelling one is the presence of subgenomic RNA in tissue from donors that died from severe COVID-19. At the same time, the association between subgenomic RNA particles and the presence of viable virus is non-linear. So today, the most convincing evidence to summarize has occurred in patients dying from severe COVID-19 with some subgenomic RNA particles. So let's, next slide. Here, I've basically summarized the data that I've mentioned to you briefly. And again, I'll just emphasize. RNAemia doesn't equal viralemia. Viable virus hasn't been isolated from blood from patients with COVID-19. There's a lot of conflicting evidence regarding the presence of viable viral particles in non-lung tissue autopsies. So next slide, please. I guess as our ability to test donors ramped up, the first frontier was the use of SARS-CoV-2 upper respiratory tract positive donors with a history of COVID-19. And at least from what we know from the biology of COVID-19, these donors would not harbor viable viral particles in the respiratory tract beyond 10 days if they had mild disease or beyond 21 days, even if they had severe disease. So Vivek Q summarizes very nicely the experience from these donors with satisfactory short-term outcomes without evidence of disease transmission. So next slide. The next frontier was the use of SARS-CoV-2 upper respiratory tract positive donors, but they did not have the history of COVID-19. I would just like to point out that CDC has investigated all potential donor-derived transmission events reported to DTAC since the start of the pandemic. And the last analysis was performed some time ago, but there were, out of 40 events, there were three that occurred in this scenario. And there were five non-lung recipients from donors that tested positive around the time of recovery. And there was no clinical evidence of SARS-CoV-2 infection in the recipient or attributable outcomes in the recipients. Then the study from Christine Koval used five kidney donors for 10 recipients, and those donors didn't have the history of COVID-19. And there were satisfactory short-term outcomes in those kidney recipients without any attributable outcomes. So next slide. Unfortunately, three donor-derived events to lung recipients occurred. And I'll just summarize. In these events, the donors tested negative by upper respiratory tract sample, but either retrospectively or at the time of the implant, those lungs tested positive. Unfortunately, those lung recipients developed severe disease, and one of them died. But with those three lung recipients, there were also three non-lung recipients, and none of them developed evidence of COVID-19. Next slide, please. So on the other hand, in Italy, the group from Paolo Grossi decided in November of 2020 to use donors that tested positive for SARS-CoV-2 into previously infected liver candidates. There were a total of five donors that had the positive lower respiratory tract NAT at the time of organ recovery without the history of COVID-19. And again, there were no attributable outcomes, and there were no donor-derived events reported. So next slide. So with that in hand, the data from the three donor-derived events in the United States and the data from Italy, some centers, including ours, ventured to use lower respiratory tract positive donors without the history of COVID-19 for infected or even unvaccinated recipients. And here we published our first two cases. We had young donors without significant past medical history that died from causes unrelated to COVID. The donors, as far as we knew, they were unvaccinated. Again, they tested positive in the lower respiratory tract. The CT values were relatively high. They had CT abnormalities in the chest, but it's difficult to attribute them to COVID. And as you can see, the donor risk index for liver transplantation on those donors was quite favorable. So next slide. The recipients, one of them had the first one that we performed had a pretty high MELT score. And at least at 81 days of follow-up, there was no evidence or clinical evidence of donor-derived COVID-19 and no attributable events in the first one. And in the second one was a patient that had hepatocellular carcinoma. So it was in a sort of MELT purgatory where the laboratory MELT didn't really reflect the acuity of the disease. And at 40 days post-transplant, there was no evidence of donor-derived and no attributable events. So next slide. So there's a report on the UNED website that can filter according to the use of SARS-CoV-2 positive donors. And at least our center has the second largest experience with 22 liver transplants from SARS-CoV-2 positive donors. And each of you can enter that analytics part of UNED and see your own utilization. But next slide. It's not only the experience of our center. As part of the lower respiratory tract policy, we implemented a monitoring plan to have an idea of how many of the lower respiratory tract positive donors are being used. And here I present to you the nine month monitoring plan. And as you can see, there's been a total of 455 lung transplants performed from SARS-CoV-2 positive donors from 176 recipients. And if you look at the utilization and discard rates for the different organ types, it actually mirrors those of the negative donors. In this timeframe, the OPTN DTAC has not received any reports of proven or probable donor-derived events to these recipients. Next slide, please. So I think one of the most challenging things during the pandemic is to really balance the tangible risk of mortality on the wait list. That is one of the few things that the pandemic hasn't changed. We need to be humble and know that we don't have data regarding long-term outcomes from these donors. And we also have to be humble that the numbers are relatively small. But at the same time, does the knowledge of the biology of the disease, the published literature, does it support a signal of risk so far? I think that rare events may occur, but these rare events are probably many fold lower than the tangible mortality on the wait list, in particular for a liver transplant candidate. So next slide. So what are the factors that need to be taken into account when accepting donors that test positive for SARS-CoV-2? I've highlighted those that I tend to put the highest weight on, and it's the severity of COVID-19 and holographic quality. I think those are the two most important factors. The severity of COVID-19 is just because there is an association between severe COVID-19 and the risk of thrombotic events, both macro and microvascular. But also the severity of the disease is linked to potential end-organ damage. On the recipient side, I think the mortality on the wait list is the most important guiding principle. The next one will be the quality of donor-recipient match. We've had multiple scenarios in which for size, in particular in thoracic patients and heart transplant patients, that we've gone for a SARS-CoV positive donor just because that was the donor that best suited our recipient. For us in Texas, vaccination is not mandatory for being listed for transplantation, so we've performed these transplants even in unvaccinated recipients without any adverse outcomes to date. Probably the most important other factor that needs to be mentioned to recipients during the consent process is the unknown long-term outcomes. So next slide. I think at this point, like I said, the most challenging thing to date is how to balance the tangible mortality on the wait list versus some of the theoretical concerns of using SARS-CoV-2 positive donors. And that needs to be addressed between the transplant team and the patient, and the patient needs to be aware of all the published data and all the potential events and clearly all of the unknowns that we have to date. So thank you very much. Thank you so much, Ricardo. And I think both the presentation you and Dan gave are so inviting to open to the audience and the panel to address a lot of these things like how should we treat the recipients or should we treat the recipients with any of these agents that Dan reviewed with us? Not only do we have a COVID positive donors, but which COVID positive donors are ones that you're more worried about and which ones aren't you worried about? What is it about the COVID? Clearly not the transmission, but there may be some other things that we wanna be watching for. And if we can, how do we prevent those types of things from happening? And then finally on our COVID recipients and how do we look at the best timing and what we can do to avoid those complications? So what we'd like to do is move this to a panel discussion and starting out our panel, we are really fortunate to have Dr. Shimmel Shaw join us to give his experience. Shimmel's a professor and chief of transplantation at the University of Cincinnati. He and his program have had a tremendous amount of liver transplants and had success in using COVID positive donor organs and transplanted COVID positive recipients, has some experience with those organs as well as with those recipients. And so I'd like Shimmel to tell us a little bit about their experience in Cincinnati and then open it up to the audience to have questions that Jennifer and I can help screen for our panel. So Shimmel, welcome. Thank you, Dave, and thank you, Jennifer. And it's gonna be hard to follow these two great talks because I think I have more questions than answers, which is always fun in liver transplant. Just a couple of things about our program. So we have not done a COVID positive recipient. We followed our institutional practice. Everyone gets a COVID test and we have done a mandatory wait of 21 days if someone becomes COVID positive. And that gets really tricky when you have an inpatient with a MELD score of 40, but we have not crossed that line and have not done that. So I'd be interested to know what the experiences are like. And about a month and a half, two months ago, maybe even closer to three months ago now the vacations and stuff, we went to a mandatory vaccine policy. So unlike UT Southwestern, we are mandating the vaccine and for all our abdominal transplant recipients, not necessarily the donors, but in the recipients. And that has really created some strife for waitlisted patients, for patients in evaluation, and they have gone to other centers. I'm okay with that. I do think it's the right thing to do to have them get vaccinated. But by the same token, we as an institution, and we'll be interested in both speakers' thoughts on this, we as an institution have struggled with the role of antibodies. We all know that the Johns Hopkins group has really pushed getting your antibodies checked and knowing what the level of the titers is and stuff. We have not done that at all. We've asked for the vaccine to be done pre-transplant, we've even done a post, but we have not checked antibodies. And so we're not using that as a marker to determine how things are going. In the donors, like the experience in Dallas, we started using COVID positive donors and our first transplant was in April of 21. And so it was with the Delta virus. And we started getting a bunch of organs from the South where Delta was predominant. And with the national allocation system, the organs are more spread out, obviously. And we've done now approximately 20, 20 on the dot, and have really opened things up. We're only doing vaccinated recipients. We are essentially not using COVID positivity as any kind of exclusion, whether it's liver or kidney, and are also doing active COVID. And basically we wrote up a protocol, the patients come in and if we can do it, we are checking on their admission, if they're coming in from home or if they're already here, but checking for COVID antibodies before the transplant, just to see so we have a record of it. I am doing biopsies of the liver to look for COVID. And then on day seven, usually prior to going home, we are doing a repeat COVID test. In every single one of our cases, we have not had a COVID positivity, except for one patient who already was COVID positive at the time of the transplant. And then we're not doing much surveillance after that. And all patients have done well with no evidence of COVID disease, no evidence of thrombosis. So we've had a great experience and we'll continue to use them going forward. So recently I opened the floodgates and said we will do any one, including people that have died of COVID, that have COVID lung disease. We don't believe that it goes to the abdominal organs. We'll have data on that soon because we're checking for the RNA in the liver. And we'll have some idea on this. We were gonna do day seven biopsies, but I know every program is different. We have a tough time doing surveillance biopsies just because, so interested to hear the experience of others. So we haven't done the day seven biopsies because the patients have done well. So sorry if I took too long, Dave, but those are my thoughts on the recipient side and the donor side. So like I said, more questions than answers, but interested to hear people's thoughts. That's fantastic, Shenal. I think that it's really interesting to hear a lot of the experiences. And I think, to your point, to Ricardo's point, we're definitely finding that the risk of transmission, except for lung recipients, from these donors is extraordinarily low. And if I'm interpreting Ricardo's center's data correctly, that includes recipients that are not vaccinated, which is really pretty amazing and fortunate. I guess the question comes, one of the things that I think, Ricardo, you were telling me at the beginning of our conference was the recipients that your team has been using in COVID positive donors are not actually using the donors that have actively died from COVID, however, of donors that have had COVID. Can you tell us a little bit more about choosing a recipient that regarding their vaccination status and everything, would that ever come into play if you started using donors that died from COVID? Would you be more concerned? That's a great question. I guess my omnibus answer is that there is, the risk needs to be proportionate to the mortality on the way. So I don't think I have a standard answer for saying we won't use these donors, we will only use this. I think it's proportionate to the mortality on the way. And somehow in the spectrum of risk, and not necessarily risk of transmission, because I do feel the same way, like I outlined before, the risk of donor derived disease, based on what we know from the biology of the disease is very low. But I think at the same time, there is a risk of thrombotic events. And there is, from what we know from the clinical presentation, the severity of the disease is linked to that. So we have used donors that died from severe COVID, but in situations where the mortality of the intended recipient merited that. At the same time, like I said, we used the kidneys from a donor that was immunocompromised and died from severe COVID. But it happened that those kidneys were a 10 out of 10 match for the recipient. And I think it was worthwhile using those kidneys in particular, given the 10 out of 10 match that it represented for our recipients. So I tried to outline on my last slide, what are the factors that I put the most weight on? And I think severity of COVID-19 is one to pay attention to, yet I don't think it's prohibitive. Because like it's been mentioned, if the melt is 40, I think that if we rolled that dice 100 times, we will be more likely to help that recipient with a melt of 40, that really harmed them with that liver. Will unusual things happen? I am sure we need to be humble. They may happen. The numbers are still small. Plus we don't know the long-term outcomes. But I think it's a constant risk versus benefit that we need to do. And unfortunately, one thing that the pandemic hasn't changed is the mortality of our liver kidneys. Absolutely. Jennifer? So Ricardo, we have a question about whether the recipients of your COVID positive donors receive monoclonal antibodies, and if it varies depending on their vaccination status. And I'm also curious to hear from the other panelists. I know Shamil, you said that these organs are only going to the vaccinated recipients, but I'm wondering what your practice is about monoclonal antibodies as well. Well, thank you, Jennifer. That's a great question, but I would like to point out that the times in the pandemic where we have used these donors more frequently, and there was a day that we did four transplants the same day from these donors, is during the waves. And during those waves, there's a shortage of monoclonal antibodies. The number of transplant recipients that are in need of a monoclonal antibody to prevent severe disease is quite tangible. And the number needed to treat in that scenario, let's think about our liver candidate, our kidney candidate, heart, lung, the number needed to treat is going to be way low. So based on what we know of the biology of the disease, and based on what we know about the risk of transmission, we chose not to give monoclonal antibodies even for the unvaccinated recipients, and we haven't seen any adverse effects. Now, the shortages currently are not what they used to be, but we, like Dan has pointed out, we only have one monoclonal antibody left, and I guess at a certain point of production may not mirror the need. So I much rather use that monoclonal for a post-transplant at high risk for severe COVID than use it on the rare event, a really super rare event of donor-derived disease. When we wrote our protocol, I forgot to mention this, we actually had the monoclonal antibody to be administered on post-op day one because they didn't have COVID yet. And we got that through no problem, and we did it for about 10 patients. And then the committee came back to me and shut it down because it was an experimental use and there was a shortage. So our last 10 we have done regular and haven't felt a difference, but we were a little nervous initially. I'm not sure what it does, but we were giving it, and it was free of charge, actually. So it was a freebie, so to speak. I mean, I think one, I don't see any, I'm not worried really about donor-derived in non-lung now. I think that's shared. I think these are, you know, the issue of thrombosis is there, and maybe this isn't that surprising because as I think Ricardo had mentioned when we were talking earlier, you know, we looked at 10 years of donor-derived disease from respiratory viruses, right? And you mentioned this in your talk, and it's primarily confined to lungs. And even during the influenza H1N1 in 2009, it's basically small intestine and lungs. So that's true of other respiratory viruses. So I think now we're, you know, two some years into this, and there's yet to be a proven case of donor transmission in the recipient of a visceral organ. I do think if you want to give people monoclonal antibody, what we've been doing is before people are discharged, we just give them EviSheld because they qualify anyway. And you know, even though we do require vaccination now, you know, perhaps with immunosuppression, new variants and so forth, there may be some benefit to that. So we've been doing that just about at discharge. So we've been offering the EviSheld also at discharge, but a lot of patients are concerned when we go through the whole consent about the cardiac toxicity. I'm wondering if you're encountering that as well. Yeah. I mean, that's an issue. So the answer is, I think if you, you know, that was a real finding, right? I mean, it was a clinical trial and you saw, you know, it was less than 1%, but nonetheless, those were real hard cardiac events, MIs and things. Some of them occurred many, many months after the drug was administered, but it was a placebo controlled trial and it occurred more in the treatment arm than the placebo arm. Everybody had a cardiac history or significant cardiac risk factors who had an event. So in the absence of those, and I think we can be very reassuring in the, what they called storm chaser trial, which was a post-exposure prophy trial, they did not see those events. That was generally a healthier population than the primary prevention trial, but they did not see any difference. So that's a little bit comforting mechanistically, not clear. This doesn't happen with other SARS-CoV-2 monoclonal antibodies, any kind of cardiac toxicity. And I've had a number of patients who have declined on that basis, but what I'll often tell people as well, you know, your risk of a cardiac event is a whole lot higher or cardiovascular event if you get COVID, even if it's mild, then there's very low risk. And, you know, we've, you know, it's been well-published strokes, other cardiovascular events going months and months after COVID infection. So for those reasons, I think in general, it's probably in most people's benefit, but we've certainly had some people who have declined on that basis. Yeah. And I think, you know, Dan, your point is really well taken about these delayed, you know, and, and unusual kind of thrombotic events in some of the patients and, you know, maybe, maybe patients that have had COVID and potentially patients that received a COVID positive liver might warrant some studies with D-dimers and some other, some other assays to help us look at preventing some of those issues, because, because one of the things that I've been hearing from colleagues around the country is a series. And in the largest, the largest group I was just talking to Ricardo about from my colleagues at Mayo Clinic in Arizona was that they had several unexpected portal vein thromboses and some of the hepatic artery thromboses and candidates that they really didn't expect to see that. And then I know in our center, we had one case of a recipient that had COVID. We cleared them after 21 days, you know, the protocol that we were using at the time was 21 days, a negative PCR or a positive PCR with a cycle threshold that was, that was 35 or greater. He was in the latter group, got, got a liver a couple of days later, SLK, and then segment six artery went out, you know, right after the transplant. There was no, not expected with the quality of the donor organ age, there was nothing, you know, that would, that would, would lead us to do that. But I've heard several stories of patients developing some thrombotic kinds of things and wondered if, and this would be a great question to our audience, if anyone would like to submit some questions or some comments that, you know, are we seeing anything that, that would make us want to try to do any further analysis on our, on our patients who are either recipients who had COVID at some point in time and, and at what range would they consider investigating or from donors that had had COVID and of course, how recent that COVID was. Are there some things that we may want to think about and make sure the patients are at least on aspirin or should they be on something more than that postoperatively to try to avoid any of these bizarre kind of thrombotic events? I had a question for, for Daniel and Ricardo, if that's okay. Yeah. Two, I guess two questions. One is, I just brought this up to our group this week. Is it premature to say maybe we can remove the vaccine mandate if we can ask them to get EvaShield after the transplant? And is that one way around it, especially if it's going to be effective? And the second question is, you know, based on Ricardo's data, we're not chasing COVID positive organs, only 130 livers. That's really, really low. I was shocked to see that number. And when you talk about weightless mortality, is this something we need to reach out to our OPOs and say, chase these more? Because there's some centers that will use them. Yeah, I mean, I can, I can go ahead. I was just going to say, I can say that from the OPO directors that have been here at the transplant management forum, that many of them are very, they're, they're very gung ho about the deceased donor, the brain dead donors. They're having some flex on the, on the DCD donors that they've got COVID. So, so I think that that's a question for the group on that. COVID positive DCDs, because as you know, that's becoming a larger percentage of our donation community. And I think the OPOs are a little bit concerned in that subset of patients. Open it, open it for thoughts on that. I think certainly there appears to be some sort of deja vu in my mind that going back to hepatitis C viremic donors, hepatitis B, antigenemic positive donors, have been not positive. I think we need to partner with OPOs to make them aware that centers will be willing to use them. I think after two years of pandemic, the PPE is quite effective at preventing transmission to healthcare workers. The CDC recommends vaccination of all healthcare workers. So in, in, in, I think that if we, the OPOs follow all the PPE recommendations, all the vaccination recommendations, the risk of transmission, even with a DCD donor to the OPO members is probably low. It certainly was a factor when we wrote our first summary of evidence in the OPTN, and we emphasize the safety of both the recovery team and the safety of the OPO team. But I think at this time, after two years of pandemic, I do think that the vaccines work. I do think that the PPE works. And I think we owe to our transplant candidates, you know, the opportunity to access these donors. So I think we need to partner. I think we need to discuss the concerns. I think we need to present the data. And I think that needs to guide our future decisions. I can address Dr. Shah's question about Avishal and vaccination mandates. So specifically in the emergency use authorization for Avishal, they, they put a statement in there. This is not a substitute for vaccine. We struggled a little bit about that in people who had not been vaccinated, because it seems to me that those are the people who are likely to benefit the most. And we certainly didn't withhold it because it really wasn't a substitute. They weren't making a decision between Avishal and a vaccine. They decided not to get vaccinated. And in some cases, really, that came from their doctor because they were on rituxan at very high, or very high frequency, and they really weren't going to respond to vaccine most likely. So I would probably not do that. And there's, I think there's a whole bunch of other reasons. One is that, you know, vaccine, you got one shot, right? Because, well, three shots or four shots or five shots now, but you got to get them before they're transplanted to have the best response. And so that opportunity won't be there once they're immunosuppressed. To me, every monoclonal antibody just sits on a razor's edge, right? Because one more mutation happens, and then they become useless. And that certainly may happen to Avishal. And finally, I think we should recognize that while we're hopeful for Avishal, certainly with BA2, this is like EUA data on one study that didn't include immunosuppressed patients, except three or 4%. We just don't know. The FDA doesn't know the right dose, really, right? They've doubled it, even though it's probably not necessary. The duration in the most recent authorization said, well, we'll let you know when they have to get another dose. So, yeah, and you don't get any T cell immunity. It's a passive process, right? And so personally, like in our center, we definitely have that vaccine mandate. Our discussion has more been, should we require three doses? Because initially, we went with two. Medically, you can definitely make a case to say, especially with Omicron, you really need three doses of an mRNA vaccine. So that'd be my view on it. Any thoughts about Shemal's point about antibody monitoring? What do you all think on the panel about following our transplant recipients and especially some of the ones that are longer post-transplant, and how do we protect them the most with this? And should we be doing as, you know, Dory, Segev, and the Hopkins group has been trying to advocate, you know, do more antibody monitoring for their care? It's a hot potato, isn't it, Ricardo? Yeah. I'll let you take it, then. I think that there is, in some of the trials on healthcare workers, there was a significant There was a signal in which those that had higher anti-spike, anti-neutralizing antibodies had better protection than those with lower. At the same time, I do think that there is quite a moving target on what is the level of protection, in particular in the face of new variants occurring. So, what you could have been protected for the delta wave is not protected for the omicron wave and so forth. But also, I do think that although there is data suggesting that there's T cell activity, even with the lack of the presence of neutralizing antibodies, the complete implications of that T cell response are understood. What I do fear is a false sense of security or a false sense of doom for that transplant recipient that really has this checked. And is there some correlation? Yes. Could it help us? Yes. I think it really helps us with that that clearly has no antibody response. But what is that magical number? I don't think we have it. So, I think, ideally, you want to transmit the right balance of risk versus benefit to our transplant recipients. And I do think that we need to keep on emphasizing many of the things that have been mentioned by Dan. Masks, hand hygiene, vaccination pre-transplant, able-shelled pre-transplant, early testing. I think that is something that unfortunately may not be occurring at the same rate that it was happening before. Because if we catch it early, we can prevent the mortality or the severe effects. Do the antibodies contribute? They may. I think the wheels are turning. I am not sure that I will completely tell a transplant recipient that has a high titer, you can do whatever you want. I think that will may create a false sense of security. And I'm unsure that the complete negativity equals, you know, doom in the future either. So, complicated topic. Dan, I will be interested in your thoughts. Yeah, I agree with much of what you said. I wish we had a blood test. You know, there are these T cell tests out there, too, that would tell us you're protected. But what do we really know about this, right? We know neutralizing antibody titers peak fairly quickly, and then they wane fairly quickly, right? We know we have, you know, memory B cells and plasma cells that may turn on. And so, you know, we're just measuring this thing at one point in time while we have an evolving virus. And to be able to tell something really useful to patients on that information probably does, potentially does more harm than good for the reasons that you nicely outlined. And so, I think there are real, real problems with doing that. And, you know, I've had patients who've had 15 antibody tests, you know, and then they keep trying to get more doses. And, you know, I think that gets into kind of a crazy situation for an individual. So, the only time we really use it systematically is whenever you show first came out, you know, we had 600 pages in our spreadsheet of people on Rituxan in our system, right? And so, we had 110 doses of Avicheld. So, I thought, well, at least in the solid organ transplant group that's been vaccinated, we're going to try and risk stratify with any lung. But otherwise, we'll see if they have, if they don't have antibody, we'll just prioritize Avicheld. That actually made giving Avicheld a lot harder. And in retrospect, I wish I hadn't done that. We got rid of it fairly quickly. It kind of has supply ramped up. So, in general, you know, I think there's a fairly limited use for it, but patients do want it. Yeah, we've talked about it in the context of Avicheld and sort of guiding our decision making about it, but we, you know, didn't protocolize that and haven't adopted it universally. So, you have two patients, one, same meld, there's an organ available, same blood type, they're right neck and neck to one another. One, you check antibodies and they have none, and the other has, have 20,000. And you have a COVID positive donor within, you know, 10 days or less than 10 days, say within five days, COVID positive donor, but not proned on ECMO, but a recent COVID infection. Would you, would you use the COVID positive donor preferentially into the patient with a, with high, you know, higher levels of antibody, or would you just, would you just put it into either of the patients, if they have the same risk of mortality on the wait list? Since we, we, unfortunately, I would like to clarify that as a state institution, we need to be aligned with the state legislature. So, we, we cannot have a, a vaccination mandate at my center, I will still try and tease out, which is the recipient with the highest mortality on the wait list. If there's, I'm sure there can be some nuances, but my, at least my approach to this is to always try and allocate that organ to the recipient with the highest mortality. And, and then it's again, based on the biology of the disease, based on the, you know, the based on what we know, if there's going to be, we spoke about the, the pretty low risk of disease transmission at this point, we're speaking about the potential for thrombotic events. I'm unsure that the vaccinated recipient truly has a, a lower risk of, of thrombotic events. So, I will again, try and tease out the nuances of, of the mortality on the wait list, even though the male score is the same for both recipients. That will be my approach, but I am not claiming that's the right answer. I'm sure that it could be done more than one way. Shemal, what were your thoughts? I guess if in your scenario, I would probably give it to the person that has the antibodies. If I had the information like that, I mean, it's hard to deny that maybe some advantage they might have to protect them. Like I said, our experience is growing, the data is still premature. It doesn't seem like it matters. But you gave me two things and their males were the same. I guess antibodies. I mean, we, we, we, we make some of these decisions when you think about it for hep B, you know, times, you know, we will, we'll preferentially, you know, pick a patient, if all things being equal, as much as we can tell, you know, we'll, we'll, we'll give a patient who's got hep B antibodies, you know, you know, hep B positive organ. I may just push back slightly. I just think that they're constantly all these patients and that Dan wrote a very nice editorial with a very catchy title on what happens when we turn down organs, what was formerly known as increased risk donors, and that there was a mortality difference by passing on those. I am sure that one day we'll do the analysis of passing on hepatitis C by REMIC donors, and I wouldn't be surprised. Older donors, you know, above a certain age, there's also studies that suggest, do we have enough data to really say that that passing or, or benefiting one, one donor over the other, I will still try and tease out which one carries the highest mortality. And I think it's just, again, borrowing from prior studies, I will try my best to tease out which is the one that has the highest mortality. Great. Hi, everyone. We are at 6.01 Eastern time, and this concludes today's webinar. I want to thank all of our panelists and moderators for their time today and for sharing their expertise with everyone. This webinar was recorded and it will be shared on AASLD's website. With that, I'd like to say goodbye to everyone and thank you for participating in today's webinar. Thanks, everyone. Thank you.

AASLD webinar

COVID in Focus

Outpatient Therapeutics

Managing Liver Transplant Donors

Managing Liver Transplant Recipients

Monoclonal Antibodies

Antiviral Agents

Paxil-Ovid

COVID-positive Donors

Transplantation during COVID-19