Next up, for the con side, we have Susanna Nagy, who's an ID physician and researcher from Duke University, and is going to tell us that we should keep this in the research domain. Thanks very much, Susanna. All right, so I'd like to thank the organizers for providing me the highly sought after position of defending the con side of should we be doing this as standard of care or as research? This is my disclosure slide. So, those that have come before me have really summarized this quite nicely, so I'm not gonna repeat a lot of things. But what we, I think what we do know is that there are no existing policies or regulations, for example, from OPTN, governing the transplantation of HIV-virus donor organs into HIV-negative recipients, meaning no one's saying you can't do this. As you've already heard, the AST consensus document in 2017, so now two years old, suggested that we were not at a place where we should be doing this as standard of care, and that really we needed to collect adequate, well-controlled data through research to be able to move the field forward and to understand what the standard of care should be. And I think the real question today is, do we feel that we have sufficient data to understand what the standard of care should be? You've already heard that this is a convergence of medical discovery, DAAs. I would argue that this is not a discussion about the efficacy and safety of DAAs. We're all quite comfortable with that. And this really devastating epidemic of the opioid crisis. We have to acknowledge that patients die or get sicker while waiting on transplant lists. But you've already heard, I think very nicely summarized that there's a risk associated with the receipt of HCV-viremic organs, and what we're really talking about here is the concept of de novo HCV transmission via organ transplant. We have heard of complications like death from the Mayo Group, potentially related. FCH, membranous nephropathy, post-transplant non-EBV lymphoproliferative disorder has been now reported. And I would actually put approval by payers, which is not universal in this setting, as a risk. I would also argue that the best way to convince payers, like CMS, to pay for this as part of standard of care is to create adequate data that is not disputable in terms of the benefit of doing this and understanding the right approach. And you've actually heard all the speakers kind of really say that we have lots of different options. And the question is, if I ask the people in the audience today, which one do you think is right, we would have a disagreement. And that's why research continues to be really critical. I would also emphasize that it's not about saying you shouldn't do this, it's saying that we should all take the effort of doing this under IRB oversight and through research protocol so that we can ultimately learn from this in an organized fashion. So again, for those of you who know me, I'm an optimist, that's why I'm in academics. So there's lots of room for optimism, you've heard this. But I think if we really summarize some of the bigger studies, the ones that you've heard about today, I think what we clearly see is that there's a lot of variation. And I don't know if that's showing up, maybe I can do this pointer. All right, anyway, so a lot of variation. So right, different organs, which obviously have different challenges. The numbers are quite small. The bottom line is it's hard to refute that the numbers are still, we're still working with very small numbers. You've already heard that we're looking at different approaches to treatment. Are we doing reactive? Wait till someone is infected and then treat them. Are we doing preemptive? Kind of the concept that we talk about quite a bit in other transmitted viral infections in transplant like CMV, where we have very large randomized controlled trials that help us understand the appropriate management of those chronic infections that our patients deal with. And again, lengths of treatment, you've already heard. We're talking about a variation and potential of seven days to 24 weeks. What's the right answer? What do we recommend to our patients? And how do we actually have that really critical discussion with our patients about what we think is the best thing for them? So I actually thought I'd see this slide kind of every single time. And the point of this, which is from Verna et al in hepatology recently, is that there's been a 30-fold increase in the use of HCV viremic organs since 2015, which is exceptional. So in some ways, the field's kind of moved on. But I think for what's most concerning is that we still have so much to learn. And if we do this as part of standard of care without collecting the data adequately and in a protocol format, we lose the opportunity to truly draw, I think, conclusions. So research is a systematic investigation, testing and evaluation, designed to develop and contribute to generalizable knowledge. And the question that I would ask you today is, do we need more generalizable knowledge to guide our recommendations to our patients? Research is done through vetting, vetting with your IRB, your ethics boards, DSMBs to monitor for safety, third-party review, predetermined monitoring, right? So you can test what's the best way. Well-defined population, do we know which patients will do the best? Do we know how to optimize our approach to this treatment approach via inclusion and exclusion criteria that help us well-define the right populations? And I would say that research ultimately informs best practice. And the question is, do we in this room understand what the best practice is at this point in time? Clinical care, I would argue, applies existing knowledge, generalizable knowledge, to decide what that best practice is so we can have that conversation with our patients. I think our patients assume the care plan is guided by sufficient evidence base and agreed-upon standard of care. Does our medical community at this point in time agree on the appropriate standard of care? So you've already heard about the Molnar et al, and I think this is the largest real-world cohort describing a clinical practice and the approach that this group took to HCV-positive to negative renal transplants. This was a reactive approach. You've already heard that there was delay in access because of the issue of getting access to medications via insurers, which is a major issue. And you've already heard about these outcomes, and I think very well-described by the prior speakers was the issue of the viremias of CMV and BK, et cetera, and really understanding what is this de novo acute infection doing to the immune systems for these patients, and how does that drive outcome? So Dr. Durand actually wrote an editorial to this paper, and I think this figure here really nicely describes the issue, which is generally I think is research, as I mentioned, guiding us to the point that we understand what the best practice is. What she highlights here is that research kind of looks like you see in B, which is a push toward the idea of preemptive treatment, but current clinical real-world cohorts look completely different. And I would argue that you would expect that your best practice would look much more similar to your research, and that is not where we are right now. So do we need more dentalizable knowledge? I would say yes. We've already heard this summarized. The treatment timing, reactive versus preemptive, or prevention, what role does these really exceptionally high hep C viral loads mean? I don't think we really know that, because in chronic infection, they just weren't this high. You heard about the viral diversity, which is very interesting. Treatment length, how long do we treat these patients for, efficacy, failures happening, do we understand what the efficacy is in this patient population? Again, the recipient and the donor selection, do we know what the best donor is for a patient? And do we know the best patients who will have the optimized outcomes based on this? Complications, again, we know this, and I think we need long-term understanding of that. And then ultimately, I do believe that more conclusive findings driven by that data would help us determine the best practice and to justify payer coverage. Then we have a real argument to take to those payers to say, we all agree that this is the best thing to do. And then, oh, one more thing, informed consent, right? This is critically important, and I mean, and we could mean informed consent in research, but what I'm targeting here is in clinical care. When you sit down with that patient and tell them that this is the best thing for them, how confident are you at this point in time that you understand that you can tell them what their risks are that they're assuming? Understanding the element in the room, which is that people die on the wait list, right? I think we understand that there's an issue of public trust, and we should not take that for granted. The AST calls for a multi-step informed consent process, which I think we all agree. In this setting, when it is not crystal clear, needs to be the standard of care. We need to ensure that we provide the patient the ability, as much information as possible to weigh risk and benefit, and really to understand what is clinical care and what is research. Normally, a patient who consents for research understands how that's different than the standard of care. Do we understand that right now? And I would argue that we probably don't. So key takeaways. While there's a clear benefit to the use of ATV viremic to ATV negative organ transplant, there are also risks, and we do not yet have sufficient quantification of what that risk is, in my opinion, to do informed consent. The current data from well-designed studies, not controlled, really, are very limited. But we have a 30-fold increase in the usage of this approach. I think research is critical to gain sufficient generalizable knowledge about this intervention to truly change practice, and I think that we still have a lot to learn. Thank you. Thank you. Thank you, Susanna. Don't go anywhere. Please, if we can have all the speakers come up. We have about 15 minutes left because we haven't had any time for questions or discussion, so if the speakers could all come up and join me at the table. And unfortunately, Greg has to skip out. So I'm gonna try to moderate a little bit of a panel discussion, but also invite people to come up to the microphones to ask questions. And I'll put it away. I'm gonna try to moderate a little bit of a panel discussion, but I'll just put it away. I think there's room for everybody. So before, so if anyone has questions, please feel free to jump up to the microphone. And I'm gonna start by just asking and getting thoughts from the panel on whether we think it's, so we've heard that there's clearly different ways to do this, and there's clearly some uncertainty, and that pushes us in both directions of we know enough, we don't know enough. So is it possible to do a trial to answer this question? What do you think? Can we, do we have enough, is it feasible to do a study with different organs, with finding a specific regimen, and what should we be doing that trial to test? Should the question be preemptive versus reactive, versus a transmit and treat? So Christine, you can jump on. So I think the answer is yes. I think we should absolutely do a randomized control trial, at least in kidney transplant, to see a prevention approach. I like to use that word instead of preemptive, because preemptive in CMV, you wait for a virus, then you treat. So a prevention approach versus transmit and treat. And I think the time, that's the unanswered question, and I think that would be a great trial. And what about in other organs, where it's a little bit more challenging, I would argue, because there's more complications of doing it in other organs, because of the ICU stays, the NG, which regimens we use, and also the consequence. It's also, it's challenging to consent patients for this type of trial, about, because you don't know who's gonna ultimately get these organs. Because one thing that we've certainly given a lot of thought to, is the fact that you have to consent a lot more patients that ultimately end up getting Hep C infected organs, and that's a difficult process. Jordan, I think this is a lot like the conundrum we face with HCV and HCC in the setting of DAAs, where there were multiple ways to approach this, and trying to get people, get a consensus. I think, as you said, you could design the perfect trial, it may be hard to enroll. A solution might be to do a large registry and capture those that believe in a preemptive, those that believe in a reactive approach. It would be great to design a trial that would compare the two across the organs. I'm not sure you would get the transplant centers to all uniformly agree on the approach. It might be probably, in other words, you might wait to enroll a perfect trial. For me, the one thing that I think we really should come out more strongly against is waiting 28 days. I think that while we can talk about preemptive versus do we wait to see viremia and then treat, I think what we want to say is it does not look good when their treatment is delayed. And this waiting until you can get drug approved is just a strategy that we cannot accept, actually, as a transplant community. And so this is what I worry about in terms of making a standard of care. If we're going to make a standard of care, it has to be standard of care where the drug is delivered when you want to give it to the patient, not when the insurer approves it. So I think that while we could do more trials on many things, that's one thing that I think the data already is giving us some glimpses that viremia for weeks or months is where we seem to be seeing some bad outcomes. And I think that's one thing that I think we could probably be stronger about and some advocacy around programs that are going to do this approach is that you have to be prepared to give the drug to the patient. And, Jordan, I would simply add, I mean, I think it may well be, and I think it's pretty clear, that you're not going to have one trial that addresses the question for everyone. But I think the fact that it is complicated in patients who have prolonged ICU or prolonged intubation simply argues you might just have to start a little bit further down in the evidence development to understand PK and that sort of thing, and then you move to the next step. But ultimately, if we think it's too hard to do a trial, what does that mean about how well we do in actually providing care? And I'd like to add, I do think that we need to do it in more than just kidneys, because if you think about the donor pool and the acuity of illness in heart patients, lung patients, liver patients, I don't think we can afford to wait. The one other piece in terms of a clinical trial, though, that I'd like to mention is we need to have a comparator group of control patients who are not getting these organs so that if we're talking about rejection, we know, well, what's the baseline for rejection in the same, in a comparable population? Because that's the one piece of information we don't really have is if you had comparable patients, what would the baseline rejection, what would the baseline CMV rates be, what would the baseline PK, all of these other things. We're saying we think it's higher, but we actually don't know that for those centers and their protocols that it's higher. So I think we need to have that as part of any trial. I mean, in some of the reported single-arm studies that have been done, they've compared the outcomes across to transplants that occurred at the same period of time as the trial. So patients definitely were not randomized, but they were, they did compare it to the outcomes from the same recipients from hep C naive donors. So that certainly gives you at least a flavor for it, but it's definitely, there's some confounding there for sure. It was notable, Nora discussed in our report that we had two episodes of rejection that were significant and both were associated with 48 and 62 days, I believe were the times it took to get the DAAs initiated. Can I also just, in terms of research, and so I'm actually a little bit surprised that, you know, we have a standard therapy for these treatments that we know yields high success, so eight weeks, 12 weeks, why are we so eager to make it three days or one week? Why are we putting the recipient at risk? I don't, I really am kind of trying to understand why we're pushing so hard to make it short when we haven't established that like this length always gives us 100% SVR. So I was just, I'm just curious at how the field is so quickly moving towards ultra short, why would we put the recipient at risk? Don't you think that's insurance? Yes. But people are trying to do, I mean I'm not saying it's right, but I think that's what people are doing. But if we let money drive this, then we're really going to make some bad decisions for patients. But I think there's also some, there is some science here about whether or not you need to treat that long. I mean almost certainly with our current therapies in chronic hep C, we are over treating the vast majority of people and we've made a decision as a collective because our therapies are safe that we will over treat most people so that we don't under treat anyone. And you could make the same argument here, but I suspect that in a recently transmitted infection, the duration that's required is much shorter. Now is it one week? I don't know. It may be that we need to go longer. But I think the idea, I mean maybe it is being driven by financial considerations. But I also think that we, there probably are practical ways to reduce the treatment duration. And when you think about some of these drug interactions, you think about getting treatment finished before a hospital discharge, I think those are some benefits to recipients that need to be weighed against the risks. I think that's fair. Yeah, no, I think the point is well taken. And I think we should think of it more like acute infection rather than sort of chronic. But still, the sort of point is that we should be sort of advancing our approach in a way that's always putting the recipient's best outcome at the forefront. Maybe some comments from the audience. Thank you for the great discussion, panel. A quick question for the time to initiate the treatment compared to liver versus other solid organs. Is there any difference that you can give a thought about? Because the underlying liver disease is not that bad in other solid organ transplants compared to the liver transplantation. So do you think any difference in the time to initiate the treatment is different compared to liver versus other organs? And go ahead. No, I think we can see adverse sequelae quickly, irrespective of whether it's liver or any other organ. In fact, there was a presentation here where there was a very rabid onset of glomerulonephritis. So I think to get them treated expeditiously, irrespective of the organ, is of the highest priority when you're giving a donor-derived infection. Okay, thank you. And the second quick question is, I know we all, does this protocol satisfy, it's not a complete research protocol, but does the IRB, the protocols will satisfy the common ground where we can still work with the patient and try to get this treatment going, so far that we are going. It should be a common ground, I believe that's a common. Thank you. Great. Hi, I just want to support the case for, actually, not necessarily designing a comparative trial, but I think the demonstration of safety of a preemptive approach, I think, convincingly, I think demonstrates to us that we ought to be applying that approach to minimize exposure to viremia for each of our patients. We understand that, certainly, while liver disease might not occur in those first few days, there have been data to support that exposure to viremia may bring about other complications. Certainly, there's a cardiac literature to support the idea that duration or area under the curve of viremia may actually contribute to allograft vasculopathy in that context. So I think that having already demonstrated safety, really, I think, shines a path for us that a preemptive approach is the right way to do it. That said, I think that we do need to establish the minimum effective duration. I think four weeks seems to be repeating itself as an increasingly effective duration. But we need to, I think what's essential is that we collect this data, report it, perhaps in aggregate, update the 2017 statement, because what we need to get out there is a statement to the payers who are actually the tails wagging the dog here. And what we need to do is actually tell them what the right practice is, then have them adapt to that practice, and essentially support a new model, which would say with an approved transplant and that positive donor, you will supply, you would supply DAAs before that transplant occurs. And I think the financing has dictated behavior, and I think right now the outcomes of our patients with intelligently designed regiments really should be dictating the insurance behavior in this case. Dirk van Eeuwen, Dynamics College. Ethical issues were raised. Now, at the horizon is what you want, that as many people get a liver transplant as is possible. And so we bring now in the element of the patient individually that can opt yes or no, an interesting ethical concept. But now I'm envisioning the patient who then declines, two days later deteriorates, the MELD score goes up, and now is on the top of another transplant list. An institution could also decide, this is the total package what you have on offer. Some livers may be better, some may be a little bit less, but all these livers are good enough that we think that you could responsibly transplant, that we could use that. Yeah, and you can have the bad luck that you need to take some extra medication or not. I am not so sure that the individual approach for patients selecting this is the right way to go. I mean, I think that's an interesting issue, and I think clearly there are plenty of people who agree with you because this has become standard of care for some centers without any additional consent. You know, I think part of the problem for us is that we feel, and I mean, this is actually how I believe, I feel that we don't have enough information to at least explain to people what the risks are. I mean, I think we can definitely say your chance of death on the wait list is this, and you could survive with this, but I don't know what you're going to survive to, you know, what the complications are. And I would feel better just knowing what to tell them about it and how best to manage this. You know, I think that I'm most comfortable doing it as research because then they know what they're participating in. But I agree with you that you could look at this in many different ways. You know, there's no question. Last word to Harvey Alter. Well, the answer clearly is yes and no. No, really, you know, we're in this model of the controlled clinical trial, randomized controlled clinical trial, but the issues here are not so major that I think you need a clinical trial of that nature. What you need are numbers. You need a multi-center study where within each center you compare positive donors with negative donors, and you could let the center do whichever procedure they want to do. But if you have enough numbers, you could then sort out what the risks and benefits are in the entire population versus each center of population. And I think you're dealing, you know, 20 patients, 30 patients, you need a lot of patients. The other comment I want to make is that in the blood world, UV light as a viral lethal agent has not worked, but UV light plus sorrelin has worked very effectively. And you could perfuse with sorrelin and then absorb it. You know, UV light and sorrelin absorb the sorrelin, no risk really. So that would be another approach to using that extracorporal. Yeah, we've also thought about using methylene blue, which the concern is that we just don't know about the safety of the, whether there's any effect to the organ. Because the other reason UV is not working is we're not penetrating into the organ, which we knew that was going to be a problem. But I think we're out of time. It's four o'clock. So I just want to thank all of our speakers for really excellent presentations. Thank you.

HIV-infected organs transplantation

research

policies and regulations

de novo HCV transmission

organ transplant risks

randomized control trial