Very good, well thank you very much. It's, I'm delighted to be here. This is actually really a fantastic, exciting area, so I too am looking forward to sort of hearing the discussion. I'm gonna talk about the ACV positive donor and the setting of liver transplantation, and really by way of introduction, I don't think anybody needs to be reminded that the reason that we keep pushing the envelope in terms of donors is due to the significant number of individuals who every year die waiting for an organ transplant, and this is the data for liver transplant patients, in which you can see that 20% of the candidates sort of annually are dying on the list. And you can see there's actually a pretty big disparity as you look across the United States, and I'm sure this happens in other countries as well in terms of kind of organs that are available and the rates at which individuals are dying on the waiting list. So that certainly sets the stage for why we need to do this, and nobody, and we're all very aware that this is a very recent trend, and this is data that recently was compiled looking again at U.S. data, but just the rise in terms of the use of HCV viremic donors in HCV-negative recipients in the United States, and this is by organ, but just to focus on the liver group, you can see that just in a relatively short period of three years, HCV-viremic donors going into HCV-negative recipients increased from seven up to about 179 individuals. Now you might actually be thinking, well, wow, I'm surprised it's not more, but part of the reason is that for, I think for the setting of liver transplantation, we've had lots of hepatitis C-infected individuals on the waiting list, and so the preferred kind of approach has been in the past that we would put an HCV-positive donor into an HCV-negative recipient, and we would just treat them sort of as we would our usual recipient had HCV infection, but two things are happening. One is there's fewer HCV-viremic candidates on the waiting list, because we're now treating very well, and less people come to transplant, and even those that are on the waiting list often get treated while they're on the waiting list, so now we see that there's less of those HCV-positive patients on the transplant list, and so now we think about using more of those HCV-viremic donors in the HCV-negative recipients. So just in a global way, before I was highlighting that we tended to do HCV-positive donors into HCV-positive recipients, and this is just to show that, in fact, that's mainly what was done in the past, and that when we did that, that the results were excellent, and this is really comparing, these are donor-positive into recipient-positive, not what we're talking about, but just to give you the background on sort of where we were, and you can see that this really was the practice up until really 2016-17, so really, this is a very recent change, even for the liver transplant community, to put HCV-viremic donors into an HCV-negative recipient, because in the past, we've always done it into the HCV-positives. I'm gonna try to make the point that livers are very different from all the other organs, where we're talking about kidneys, lungs, hearts, and they're different for a couple of reasons. One is it's very consistently transmits infection, so you'll see data, I'm sure, from other organs where if you give somebody a kidney, they don't always get HCV infection, even if the donor was viremic, whereas in liver, because of the burden of virus that's coming with that donor, generally, you very effectively transmit infection to the recipient, and then, of course, the amount of virus that the individual is getting is also much greater. You've got a liver full of virus as opposed to a small amount that might be transmitted with a kidney that's been on a pump, for example. The second, the third thing that's important is that not only are you transplanting a virus, but you're transplanting the liver organ, and so the status of the disease in the donor needs to be evaluated, so we need to know how much injury to the liver had occurred in that individual while they had their HCV infection, and so that's sort of a major issue, and then the third thing is that once we transplant these organs, if you have a liver that's got a lot of infection in it and it's left untreated for very long, probably the consequences, potentially, for a liver patient might be greater. That's theoretical. Now, just to remind you, we know a lot about what happens to hepatitis C after transplant from all of our years of transplanting patients who have hepatitis C who got recurrent disease, and it's really just to highlight for you that we already know that the course of disease in somebody who acquires hepatitis C, who has hepatitis C, and then gets it again after transplant when they reinfect their new graft, that that is a very accelerated course compared to a non-transplant setting, and so that's shown here where you take a transplanted liver, and within weeks, you have evidence of chronic hepatitis. 5% of patients get the cholestatic variant, which is a severe form of recurrence that can lead to graft loss within a year, and even in those that don't get that severe version, that they just have progressive hepatitis, the timeline to cirrhosis can be as little as a few years, and on average, is about eight to 10 years, so an accelerated course, we have to just be aware of that, and the thing I would highlight is that we don't have really good data at all about is somebody who had hep C gets transplanted with a new organ and gets recurrence the same as somebody who's never seen hep C, and now you're gonna give them hep C through transplantation, de novo infection. Could it be that maybe that would even set up the circumstances where the progression might be even more rapid? That we don't know, and just to say something about the severe cholestatic hepatitis, because I think we should be worried about it, because it can occur very early after transplant, and as I'm gonna show you, we don't always initiate treatment in these recipients of the HCV-positive donors right away, so here's just a nice series looking at sort of just the onset of cholestatic hepatitis post-transplant, and while you can see it's quite variable, anywhere from sort of one to 14 months after transplant, the vast majority are within the first six months, but I do want to highlight that you see a small percentage of patients that get this severe form within a month or two of transplant, so this idea of a window where you could potentially have a patient who gets a very severe form of recurrence really has to be kept in mind. 25% of patients in this series develop cholestatic hepatitis within two months, and then the interesting thing is when you get cholestatic hepatitis, you can treat it, and in fact, in this case, they all were treated, they're all alive, but they still get rapid progression of their fibrosis, even in the context of having been treated, and so in this patient, 25% of the patients had at least F2 fibrosis or higher, even though they'd been successfully treated, so this concept that we got a very narrow window potentially for some patients to intervene before they actually are at risk for getting significant liver injury. So this comes back to the sort of initial comment that in contrast to the other donors you're gonna hear about today, for a liver recipient who's gonna get an HCV positive donor, not only do we need to know is it a viremic donor, but we need to know something about the status of the liver itself, and there was a consensus conference the AST put on in 2017 where this was sort of first being discussed, and their recommendation at that time was that all of the patients who are gonna have a liver from an HCV viremic donor going into an HCV negative recipient should have a biopsy done before an implantation, and the biopsy should have F1 or less fibrosis, and you would say, well, why F1, and the rationale was that in general when they do these biopsies and they're being read in the middle of the night by somebody who may not be an expert, that they often get understayed, so that's the first problem, and there's even inconsistencies on sort of how all of that gets reported, but the second reason that you don't wanna give a patient not only hep C, but a liver that has fibrosis is that they're very likely to get a second hit, and the second hit might be an episode of CMV hepatitis, they might get a biliary complication because their bile duct's an issue, they might gain weight and get steatohepatitis, so you already have a patient who's got fibrosis and now you're going to give them something that can accelerate that course, so I think this idea that liver patients bring the virus and bring a liver that may be already injured is a relevant and important aspect of this transplant. Okay, so what is the actual experience thus far with putting HTV viremic donors into liver transplant recipients? So I'm gonna say it's very limited, I'm gonna show you two studies that have been presented, published, a total of 35 patients, so it's pretty small, but you're gonna see most of the data sets are quite small, and I'm gonna try to highlight sort of some of the aspects of these cases that I think should help to inform us in terms of how we think about transplant for this group. And in particular, I wanna look at sort of the idea of DAA options and when we should consider treating, recognizing that when you do a transplant in somebody with liver disease, very often these patients also have kidney disease these days, we have high male scores, so they go into transplant on dialysis, sometimes their kidneys don't work in the first several weeks after transplant, sometimes the graft doesn't work the first days and they may have very high bilirubins, those things are gonna influence the drugs that we can use to treat their hepatitis C, so we have to be kind of aware of that. And then I'm gonna highlight, I think there's not randomized data here to show that I think that the risk of immunological injury to the graft might be heightened, but indeed I think this is something we should be attentive to. So let me start first with the first published paper that came out in AGT earlier this year, this is from Stanford, so they had 11 patients, and I'll just point out that seven of the 11 were hep C patients that had been previously treated and cured, and then they decided to give them a viremic donor, which is appropriate. All of them tested viremic within the first week after transplant, you can see that it's a very variable group of drugs that were used to treat the patients, because they were all viremic, they had got the genotypes, you can see the genotypes in the recipients was across the range, they were treated in general for what I would call standard or maybe even extended periods of time, so our typical treatment for a treatment-naive patient these days is eight or 12 weeks of treatment, depending on what drug you're using, and in the transplant setting it's typically recommended you use 12 weeks, so you'll see here that they were using 12, sometimes they used 24, sometimes they added ribavirin, so it's a little bit heterogeneous, but all that said, you can see in the graft on the right that every single one of the patients had a great response in terms of having HTV RNA become undetectable by four weeks, and all of the patients achieved SVR. Oh, I missed, okay. Now the one thing that I want to point out just at the bottom there is when they looked at sort of tolerability and how the therapy, whether there were complications related to treatment, there were really none, it was well-tolerated, they didn't have any issues, but there's two things to note. One is that there's quite a bit of variability in terms of when they started treatment, so you'll see sort of reading from the top, some were 84 days till they started treatment, some were 30 days, and the reason for this is that they were accessing the drug through the patient's insurance. So we're gonna come back to this, but this access to drug is really pretty critical, and if you have to go through an insurer, that is a process, and even with lots of expert help to do it, it can take several weeks, and so this is really sort of real life when you're trying to get the drug through a patient's insurer. So there was delays, some starting as early as 17 days, but many of them several weeks to even months after their transplant, so remember that window of what can happen in a month or two. And then the other thing that they commented on in terms of sort of nuances, and we'll come back to it a little bit later in my talk, is that they saw four patients who developed acute rejection, one of whom had antibody-mediated rejection, and four out of 11 is a pretty high number. You know, it's not controlled data, but that, they said in the comments, was somewhat surprising. All right, then the other is the Mayo Clinic experience was just presented at the meeting here, so I'm very grateful for them sharing slides with me. So the Mayo Clinic, across their three sites, has done 24 liver transplant recipients in which they had zero positive donors. 10 of those were actually NAT positive, and 14 are NAT negative, oh, sorry, NAT positive, sorry, the purple should be positive. So 14 patients that I'm gonna really review in detail, but of these 24 donors, you can see that they went into recipients with a median age of 60, male scores were in the 20, the donor age was, on the young site, 39, and they're, interestingly, used it in several patients that needed SLK, and even did it in patients that were retransplant candidates, so a fairly sort of broad range of patients that they put the organs into. Of the 10 recipients who got a HCV NAT negative graft, 100% of them were uninfected, so this is just confirming what we know, is that if you're NAT negative, the likelihood you're gonna get infected is close to zero, and none were infected, but of the 14 patients that got a HCV NAT positive graft, 100% of them were viremic, and they were viremic within five days of transplant. So in this study, they used basically two types of therapy. You can see that GP for 12 weeks, or esophageal adiposphere plus riboflavin for 12 weeks was used in genotypes one, four, five, and six, and for genotype two, three, they used predominantly GP for 12 weeks. The others were options in their protocol, but in the patients that were actually treated, this is the standard treatments they used, which I would say are very typical of what we would use for transplantation today. Here too, you see that the change in the viral load is really quite lovely, meaning that when they start treatment here on, you can see that when they finally do initiate treatment, there's a rapid decline in the HCV viral load. Similar to the Stanford experience, they also were obtaining the drug through insurers. They had a dedicated pharmacist to try to acquire the drug, and so were able to start patients on treatment a median of 27 days after transplant. So most were really in that range, but some as early as six days, some as long as 67 days post-transplant. But once they're on drug, they rapidly become negative, and again, in this series, all of the patients achieved SVR. They also looked at the adverse consequences that they saw in their recipients, and again, these are uncontrolled data. We don't have a comparator group, but they saw 17% incidence of biopsy-proven acute cellular rejection, one of the four cases being severe. One case of ischemic cholangiopathy, but they did use DCD donors, be aware of that. But probably the most interesting of the adverse effects was a case of acute renal failure, and this acute renal failure actually was an HCV-associated glomerulonephritis. So it developed in the patient before the patient had their virus cleared. Patient was effectively treated and cured, but later went on to develop sort of a superimposed acute kidney injury and actually died. So is it directly related? You know, I leave it to you to decide, but really to make this point that with relatively short periods of iremia, serious things can happen. Now, if we look at the sort of U.S. experience, this was recently published, where now it looks at the HCV-positive donor going to HCV-negative recipients that are liver patients. This is a very nice summary of UNOS data, and it's capturing a total of 82 patients, really, on the right there that have undergone the positive to negative transplantation. And this study concluded, as you can show from the graphics, that there's no discernible impact on graft or on short-term graft survival, meaning we really only have data up to one or two years. A few other comments. It's pretty clear in modeling studies that offering a patient an HCV-positive donor versus waiting for an HCV-negative donor gives a life advantage, a gain in life days, life years. And this is shown in a very nice modeling study in which they really characterized that gain. And in this case, based on what the male score of the recipient is, and basically for a recipient with a male score over 22, kind of regardless of what region you are in the United States, there's a benefit in that recipient accepting an HCV-positive donor versus waiting for an HCV-negative. So this idea that we can shorten waiting time and potentially save lives by transplanting people earlier is borne out by these modeling data. So what I've shown you so far is that in terms of thinking about doing HCV viremic donors into the negative liver transplant recipients, certainly these early results are encouraging. We have SVR rates that are essentially 100% in the studies thus far. And graft survival out to one or two years appears similar to HCV-negative donors. And it looks like, especially from the modeling data, that this decreases waiting time and that's gonna be life years gained. The aspects that I think we have to grapple with here is this access to DAAs and the consequences of delays in starting treatment. The risk of DAA treatment failure, which we have not seen here, but I still think remains one that we have to be cognizant of. In some of the studies, they have had to do re-treatment, but they have ultimately led to SVR. And then I'm gonna just review a little bit more this issue of rejection. And I'm gonna just put up front just a concept, and that is when we give a patient HCV as a new virus, when they're maximally immune-suppressed, there's some direct effects, and that's really the concern for cholestatic hepatitis, maybe the concern for cryoglobulinemia-associated renal disease, and then there's also indirect effects, because you kind of rev up their cytokines and other things sort of in response to this virus. And that may have effects that are maybe even more long-lasting, we don't know, such as vasculopathy, diabetes, maybe even lymphoma. And then there's the consequences of actually treating somebody with DAAs. While we consider them safe, going from having a lot of virus and a sort of strong immune environment in the liver to losing virus, is that a situation in which we may actually see more rejection? So I'm gonna just show the patients from the Stanford experience, just to kind of make that point, that the rejection may be related to actually treating with DAAs. And not related, I'm just saying it may be setting up the stage for it. So let's just, if you look to the patient that's on the left, you see their acute rejection occurred, and then they were treated thereafter. So that's not really the consequence. But in other patients, we see they were treated, and then in the context of that post-period is when we see that they actually developed an episode of rejection. And this is, I think, more theoretical than real, but this idea that changing the intra-hepatic environment related to rapid clearance of virus, does that in some way lead to a greater chance of somebody developing rejection? And just to say that this has already been shown in patients who had recurrent hepatitis C, so this is a study, a multi-center study in which these were liver transplant patients with recurrent HTV, and they looked at individuals who got immune graft dysfunction in the context of being treated with DAAs, and showed that indeed it occurred. They had a, it was rare, 3.4%, but indeed it does seem that actually rapid clearance of virus may lead to an immune graft dysfunction. In this case, manifest by plasma cells hepatitis, acute cellular rejection, and even some patients with chronic rejection. So I'm gonna leave you with this sort of idea then that when we treat might be very, very important. And nobody has really done the randomized trial to figure out should we start preemptively, meaning right at the time of transplant, or should we delay, confirm their viremia, make sure they're stable, and then treat. And I just put forward here just a concept, this idea of what are the advantage and disadvantages. So advantages that you, obviously, if you treat preemptively, you can kind of prevent all of that risk in early viremia by getting the virus eradicated very quickly. Whether that can be as successfully done with livers as it is in other organs remains to be seen. But the disadvantages of preemptive therapy is it's just really tricky to use the drugs in sort of sick patients that are just post-op. But I just put that as an option. And then delaying, of course, the advantage here is you confirm viremia, so you have a stable patient. But then what I've tried to highlight with the studies today is there may be both direct effects, risk of cholestatic hepatitis, for example, or a renal disease, or indirect effects. So my conclusion is that use of ACV-positive donors certainly offers benefits. I think it's clear that this is something we're gonna continue to do. The access to DAAs is critical and has to be guaranteed for the patient. Liver quality is very relevant for this particular type of transplant, and that we need to ongoingly investigate and consider both direct and indirect effects of HCV. Thank you.

HCV-positive donors

liver transplantation

organ shortage

HCV-viremic donors

SVR rates

graft survival