for the invitation to speak. Here are my disclosures. On average, 20 people die each day awaiting organ transplantation. One of the questions we're addressing today is whether HCV viremic donors could provide a partial solution to this crisis. At least now, during this period of increased opioid overdose deaths, I think the answer that we're hearing is possibly, and certainly the presentations before have lent a lot of credence to that. But I think we need to step back for a minute and think about whether there are ethical issues that we need to consider. And so I'm going to speak a little about that, and then I'm gonna speak about some of the practical issues that we've encountered at our center and other places as we address this. So I think it's pretty clear from the data that we've seen so far and from what's in the literature that although in small numbers, HCV positive donor organs have expanded the donor pool and decreased wait times, even for organs like heart transplantation. And what's extraordinarily useful about this is not only are these organs helping the individuals who receive them, but it's having an impact on the overall donor pool as these patients then are removed from the waiting lists and other patients are able to be transplanted. Additionally, it appears based on what we know so far that at least the short or slightly longer outcomes appear to be comparable to those individuals who've received negative organs. And I thought Nora would show this slide, but she didn't. But actually, it seems pretty clear that for the right patient, the HCV positive transplant is also cost effective. And so for example, in a liver setting, if the higher your MELD score is, the more likely this is going to be a cost effective transplant for you. So I think if we're going to look at the issue of beneficence, it's pretty clear that these organs play a role for these patients. But what about non-maleficence? Well, I think there's always that story that makes an impact. And this is one that I heard at a recent AST meeting where one of the cardiologists from Columbia, Mary Jane Farr, actually presented a case where they had done a heart transplant and within a year, the patient had severe transplant arteriopathy without having other risk factors for this occurrence. So what is the risk factor for resistance? Well, I'll say up front that it is impossible to really parse this exactly because we have no controlled trials to compare this to. But if you look closely, what we're starting to see is that there may be a rejection signal and certainly the speakers who've talked before me have highlighted this. But one of the things that makes this especially difficult to understand is it doesn't appear to have direct correlates that we can point to that will help us then decide how to best avoid this. Clearly, the start time of the DAA has not had an impact in the preliminary data that we're seeing. Additionally, as we've seen in previous speakers, the timing of the rejection varies and it doesn't appear that rejection correlates specifically with viral load. So where does that leave us? Well, certainly it says that something we need to look more closely at but we don't have an answer for yet. And hopefully, we'll have larger comparative data to let us know if this rejection signal is both real and preventable. But I think there are a lot of other issues that we're starting to see and as more reports come in, we're starting to see evidence of problems including reports of pancreatitis, evidence of immune activation with membranoproliferative glomerulonephritis, FSGS, the cases of fibrosing cholestatic hepatitis, and these very confusing signals of infections including CMV and BK. And at our center, we're still trying to figure out we may even have a hep B reactivation in somebody who had cleared hepatitis B during the period of treatment. So I think we have to say that while we think we're doing a lot of good, we're not sure if there are some people we may be harming as we go ahead with this. What about justice? Are we equitably distributing these HCV-positive organs to our HCV-negative recipients? And what I'm going to speak to now is especially American data, so I don't wanna claim this for any place else. But it's pretty clear in the US that there are already some groups who are disenfranchised, specifically pediatric recip candidates and the HIV-infected, people who might otherwise have potentially benefited if we know how to do this correctly. But the other thing I wanna call to your attention is these early clinical trials have largely been focused on the less severely ill. And so it's not clear to us at this point whether those people, for example, have longer wait times on kidney lists, people who might be more critically ill now awaiting heart or lung transplant might have the same benefit. Additionally, if we actually look at where these organs are going as of now, the organs are not being widely distributed throughout the United States. And you can see, despite the fact that HCV-positive organs have been discovered throughout the US and recovered throughout the US, they're not going throughout the US. And in fact, they're very specific places that are actually taking these kidneys. And they're going to whom? Caucasian males with a median age of 60 and who have higher levels of education. And so I ask you, is that equitable? Probably not. And if we look at hearts, we're actually seeing very similar data in that the organs are not being widely distributed, but primarily being utilized by a very few centers that seem to have a greater comfort level, despite the fact that these organs are coming from throughout the United States. So again, justice, I'm not sure about that yet either. What about autonomy? So I think it's really important to think about how you communicate risk when there are so many unknowns in these patients. Have the populations studied to date been representative of who we normally transplant? I would argue that for cardiothoracic and kidney patients, possibly not, as these individuals have traditionally had less wait time. And certainly in the large study by Ann Woolley and colleagues, those patients were clearly less ill who had been transplanted. We also were not really sure about the impact of viremia and viral load on outcomes. It's really clear from the data that Jordanfeld just presented that we can do things to donors, for example, ex vivo lung perfusion with UV, to actually decrease the viral load. But we know that in all cases, preemptive treatment may not prevent viremia. And interestingly enough, although you would think the high viral loads and duration of viremia may be correlated with outcomes, we actually don't know that yet. And it's not been proven whether that's important. Christine brought up the study from our center where there's actually this discrepancy between the hepatitis C we see in donor-derived hep C and that occurring naturally in the injection drug-using population, where there appears to be, and whether this is verified in greater studies or not, we don't know, there appears to be an absence of a bottleneck. And this viral diversity, we don't have a clinical correlate with. We are able to achieve SVR. But remember, there are all of these unexplained phenomenon, these immune activation syndromes. Could this be a cause of that? Again, unknown. The other thing that I think is important to think about is this is something that's actually been described by David Goldberg from our center and reported also by many others as well. And that is, it appears that during these transplants, there's been a signal of early hepatic injury. And the maximum ALT has actually been higher in these individuals than others getting transplants. And again, we see this, but we actually don't know what it means in terms of long-term outcomes. I also feel as an ID person, I have to bring up the issue of secondary transmission, especially since one thing we're seeing universally in individuals who are not treated rapidly is very high viral loads in well over a million. Now, we all know that hep C is transmitted by blood exposure, especially injection blood exposure. There's been some cases of perinatal transmission. And in this population, we're probably really not all that worried about that because we're potentially controlling these situations. But we also know, especially in the MSM population, that hep C can be a sexually transmitted infection. And recently, there's been some recovery of hep C from other body fluids, including nasal secretions. And so I just pose to you that we may be taking patients who we think have controlled or controllable infection and still potentially exposing others in their midst. Now, in point of fact, no transmissions have been reported associated with these patients. But I just say, at least has a cautionary note that we should be thinking about infection control characteristics when we think about these patients. So that brings us to the issue of how do we consent these patients? If we're talking autonomy, what information can we tell them? What information might we not be able to tell them? And what information do we really have to admit we don't know? So here's what my view is in terms of what I think we know, so-called data-driven elements. I think we can tell them how long we think they're going to wait for an organ in the absence of these donor pools, and that likely use of these organs will get them an organ sooner. I think we can tell them what the likelihood is of survival if they're not transplanted, and the likelihood that we can cure the hep C with DAAs because there's actually good data that shows this is effective in this setting. We also can tell them how long we individually plan to treat them, even if we don't know what the right duration should be. What do we hope we can tell them? Well, we hope we can tell them how the medications are gonna be covered if they're not in a research setting. In the US, I hate to say, still a problem. And we probably can reassure them about the risk of secondary transmission during viremia and appropriate preventive measures. But I think there are a number of things we don't know. We're starting to look at allograft results in the nature of two years or more, but we don't know 10 years down the road what that's going to be. We're still not really sure about what the issue is gonna be in terms of comorbidities, how best to give the DAAs the optimal dose, duration, and when we should start, and whether this is gonna impact their outcomes because of other medication choices we might need to make. And I'm gonna come back to that in the practical aspects. And finally, relapses seem to be vanishingly rare so far, but as we open this up to larger groups of patients, that may change. And I don't think we have enough information now to know about the risk factors for relapse. So I think overall, we still think the benefits outweigh all of this, but it's something to think about as we move forward. So I'm gonna share with you some potential practical concerns, and I'm gonna tell you a little bit about a patient we actually transplanted recently in our center. In our center, we had a clinical trial for using HCV-positive donor hearts, and when the trial fulfilled enrollment, we still had some patients who had consented to this who had gone through a rigorous education process who were still interested in getting these organs. Our hospital made a commitment to give all of the individuals treatment regardless of whether insurance was going to pay, although they did want us to make sure we went to the insurance agents first. So we did that with an individual. We felt confident he'd been consented. We knew he was eligible based on our criteria, and I'm gonna come back to that. And the minute he became viremic, we initiated treatment based on his genotype. But we had some issues to deal with, and I'm going to go into those related to managing drug interactions, how to monitor his hep C, and monitoring for potential other complications, and now we're in the data-free zone. So I want to speak to the issue of consent. Whether your consent is, how you approach consent depends on whether you think this is research, and clearly there are centers in the United States that now consider this standard of care. They've changed the list, and they provide education, but the donor information occurs at the time of the offer, and so they're not necessarily going through this continuous level of information about this. Our center has not transitioned to this because we still are concerned, most of our patients are still being done as research protocols, and so we've been using an education and rigorous consent process. We also, at our center, have decided that it's important to screen non-hepatic candidates for pre-existing liver disease and eligibility for transplant, because in the back of our minds, we worry about that one patient who's going to go on and develop liver disease requiring transplant, and while we don't think it's going to happen, we want to be prepared for that possibility. And so we screen all of our patients, not just for routine hepatitis, but they get fiber scans and echocardiograms to make sure they are liver transplant eligible should that occur. Now, I think everybody's going to have to address when they're going to start the DAA, and we don't know the optimal start time, but it seems earlier makes more sense as an ID person, because you really would like to decrease the risk of anything that occurs with transmission, although I'll admit the data is still out there to definitively say this. In our center, we preemptively hep C genotype the donors because that was actually part of our original clinical trial. But if you're using a pan-genotypic DAA, you may not need to do this, although I will say that what you think you're going to do and what the insurance company thinks you're going to do may not be the same thing, so you have to be aware of what your insurer is going to do. And remember that renal function has been alluded to by Jordan and by Nora is unpredictable, and you may need to consider this as you address this. I'd like to also bring up one other provocative thought. Right now, our donor pool is an injection drug using donor pool. They tend to have genotype ones, but as the United States, depending on where you are, the donor pool becomes more geographically diverse, our hepatitis C genotypes are also going to be more diverse, and that may pose some other issues. I'm happy to say that average retail prices have declined, but even a price of $20,000 is still a lot of money to ask somebody to bear. And notably, not all insurers equally are equally enthusiastic about paying for this, and so it's important to understand where that's going. In this one report by Molnar and colleagues, they actually looked specifically at how hard it was to get insurance approval, and notably, while they got it ultimately on everybody, 21% of their patients actually had to go through an appeals process, further delaying the cost, the onset of treatment. And interestingly enough, even if your center's going to guarantee payment, there may still be issues. For our patient, we started them on Elbospheric Rezeprovir and in the hospital on discharge, so it would be ready on discharge, but then the insurance said we needed to use their mail-order pharmacy, and they wouldn't allow us to manage the co-pay in our pharmacy, and so the patient still got a $7,000 bill, which we're still trying to figure out how to pay. So just be aware of that. Somebody brought up the issue of DAAs being manipulated to give patients unable to swallow pills an opportunity to get drug, and there's almost no data on this, but I will tell you the AUCs that have been measured, for example, with Glucafrovir, Pivrentisvir, have not been equivalent when the pills are crushed, and they're not even equivalent with the two separate components of the drug. Now, they didn't have any relapses, but it's just something to keep track of. And finally, I want to address the issue of drug interactions, and really the things that we worry most about in our cardiothoracic population are amiodarone, which even if it's stopped at the time of transplant is going to be there for a while, and if you're going to start a DAA in the outpatient setting, be aware that you are not easily able to monitor for amiodarone toxicity, especially in people getting cefosfovir-based combinations. Additionally, statins have become a critical part of most post-transplant regimens, and it's important to realize that the statin interactions are actually critical to assess as well, and each statin and each drug has its own independent issues. And finally, gastric acid suppression will affect pH-dependent absorption and actually change the exposure of your drugs. So I think as we think about this, and you're transplanting somebody, you need to think about what are the essential versus the non-essential medications, and how you're going to monitor them for the drug interactions, and whether these drug interactions are going to prevent you from starting your DAA when you think you want to start it. So finally, at this point, we don't actually know how to optimally monitor patients who are not on research trials. Certainly, if you're going to be starting drug as soon as they become viremic, you probably ought to monitor frequently early, because usually most of them are viremic within the first seven days. We know that we should monitor response to treatment, but how often should that occur? On our research trials, we've been doing it very frequently. But in the outpatient setting, it may be harder to do this as often. But certainly, we want to hit at least the basic endpoints of early virologic response, end of treatment, and SVR. We certainly need to be more aware of the possibility for rejection, but we don't know if that means we should do increased DSA monitoring or just how to best do that. And I think finally, we need to be aware of the potential risk for immune complex phenomenon and development of other infections. So where does that leave us? I think hep C viremic donors can augment the donor pool, but we still have a lot to learn about how to safely and effectively use these donors, and shared decision making is really going to be critical. It's important to plan carefully before you take this on, to avoid delays in treatment, determine how you're going to manage the complex drug interactions, and monitor both the safety and efficacy of these transplants. And I will say that at least in our center, it has taken a village to do this and do it right, and I don't think it would happen without all of the people who are on this slide. So with that, I'd like to thank you. Thank you.

organs from HCV viremic donors

organ transplant waiting list

long-term effects

ethical questions

insurance coverage

transplantation