Thank you, my name's Christine Durand, and I'm a transplant infectious diseases specialist. I want to thank the organizers for inviting me to speak about this exciting topic. And I'm going to focus on donors with hepatitis C virus for kidney transplantation. So these are my disclosures. So in the next 15 to 20 minutes, I'll start with just outlining the motivation for doing HCVD plus R minus transplant in kidneys. I'll walk through the outcomes of clinical trials and a few real world practice experiences that have been published to date with a particular focus on the different DAA strategies that have been used and some unique aspects and challenges that we've learned along the way. And then I'll end with some of the remaining questions. So as many of you in this audience are I'm sure aware, in the United States we face a devastating epidemic of opioid abuse and overdose death. And this is tightly linked with an epidemic of hepatitis C infection. Unfortunately, these epidemics in particular are affecting young people. And as you can see in this data from the CDC, among people ages 18 to 29, hepatitis C infection has increased by 400% and opioid injections by over 600%. We know this has also affected the world of organ transplantation. And we did a study to sort of quantify that impact over time on transplantation and donation. You can see in this figure here on the left that with the increase in overdose deaths shown in the black dotted line, there's been a concomitant increase in overdose death donors with an increase of 17% per year. And in the last year we looked in 2016, there were over 1,200 overdose death donors used for transplantation in the United States, accounting for more than one out of every eight donors we use in the US. Amongst these donors, we see quite a high prevalence of hepatitis C, which is also increasing over time. And in the last year we looked, the prevalence was over 30%. In contrast, the incidence of hepatitis C amongst medical death and trauma death donors has remained low and stable. So we hypothesized that with the advent of curative direct acting antiviral therapy, we should see an increase in comfort and confidence in using these organs. And so we looked at changes in utilization over time, picking the year 2014 as sort of the advent of DAAs to see if we saw this change. And amongst HCV positive recipients, we did see a significant increase from 24 to 46% in the percentage of recipients who are accepting HCV D plus organs. However, when we actually looked at the amount of discard, what was surprising to us was that we saw an increased relative rate of discard after the advent of DAAs. And if you compared HCV positive kidneys to comparable HCV negative kidneys, the rate of discard was actually 3.4 folds higher. So we tried to figure out what the cause of this was, and it appears that there's high clustering of use of these organs at certain centers with saturation of HCV positive recipients, which may allow for some centers to be very selective about which of these organs are being used and discard organs that they consider lower quality. I think when you look at the absolute loss potential in terms of the numbers of organs, it's actually quite staggering. So this is data from Peter Reese and David Goldberg who looked at the OPTN national data from 2015 to 2018. They identified over 2,600 transplantable HCV positive kidneys, and only 41% of these kidneys were actually transplanted. About 30% of these kidneys were recovered, which means procured from the donor, but then were not used and discarded, and another 30% were never even recovered. So many of us in the fields felt that this was really a neglected public health resource that could save lives. And back in 2015, this concept of transplanting these hepatitis C positive kidneys into negative recipients was proposed in the New England Journal of Transplant, a New England Journal of Medicine, and shortly thereafter, the first clinical trials were started. So what have been the outcomes of these clinical trials, and what are the different approaches that are being used? So the first trial was out of the University of Pennsylvania. It was the THNKR study, and it looked at 10 of these D plus R minus kidney transplants. They accepted donors who were genotype 1A only, and their approach was to wait and see if there was transmission in the recipient, and if so, they would treat, an approach that I'll refer to as transmit and treat for simplicity. As you can see in the HCV RNA levels in the recipients, all of them became viremic on the first check, which was day three in this study, and they treated them with Grisoprevir-Elbisphere for 12 weeks. All of the patients were cured successfully, and of particular note was the wait time in these patients, which was only 58 days, and this is an area of the country where typically the wait time for a kidney would be three to five years, or even more depending on blood type. At about the same time at Johns Hopkins, we did a similar study of 10 D plus R minus transplants. We accepted donors who had any genotype, and we used a slightly different DAA approach in which we tried to prevent infection in the recipients, and we did this by giving their first dose of DAAs on the way to the OR, and then continued for 12 to 16 weeks thereafter. We used Grisoprevir-Elbisphere, and in cases of genotype 2 or 3 donors, we added sofosbuvir. As you can see, we had very successful virologic outcomes in these recipients. In fact, five of the 10 never had virus detected at any time point, including post-op day one, and in the other five patients, they only had very low levels of viremia in the first week post-transplant, potentially reflecting just donor transfer of viremia rather than a de novo infection of the liver. Again, similar to the THNKR study, we saw very short wait times on the order of just 30 days. So can we, with a prophylaxis approach, cut down the time of treatment that's required? And we think that is possible. So at the liver meeting just yesterday, Brittany Barnaba from our group presented the results of the Rihanna study, and the objective of this study was to see if using a pan-genotypic regimen that's not renally metabolized, called Caprevir-Prebrennisvir, could we shorten the treatment course to four weeks? So this was a single center study with 10 recipients, and again, we gave DAAs as prophylaxis with the first dose on call to the OR, and then treated for just four weeks after transplant with frequent checks for viremia. We had no AEs related to the prophylaxis, no deaths, graft failures, or rejections, and importantly, we had no significant elevations in AST, ALT, or bilirubin. Similar to the expander data, we had very good virologic results as well. Five of 10 recipients never became viremic at any point, and the other five only had low-level viremia in the first week with a peak of 161 IUs per ml. So nine of these 10 patients have been followed long enough to 12 weeks post-prophylaxis, and have had no detectable HCV RNA. So of course, the next question is, how short can we go with this prophylaxis? And I think there are limits to this. So just a couple of weeks ago, in the American Journal of Transplantation, Gupta and colleagues presented their results on what they call ultra-short prophylaxis. They began with just a two-dose prophylaxis approach, where they gave the first dose of soft-val the day of transplant, and then one dose post-transplant. And unfortunately, they had 30% transmission in this first group. So this prompted them to extend the prophylaxis to four doses, with three doses now of soft-val post-transplant. And the transmission rate was lower, but it was still quite significant at 7.5%. Of the six patients who acquired hepatitis C, despite the prophylaxis, it was difficult to eradicate the virus. So only three of six achieved SVR with the first treatment course. And the three patients who required a second DAA course, only two of them achieved SVR. One hypothesis to explain this failure rate is that perhaps the ultra-short prophylaxis actually selected out viral-resistant variants, and when they did resistance testing in four patients, they did find resistance in 100% of them, with the specific mutations listed there. So I think there needs to be some limit on, of course, the duration of prophylaxis, and perhaps larger, carefully-designed studies can find what that basement is. What about outside of clinical trials? Well, we know that this is happening. Mary Grace Bowering and colleagues at Johns Hopkins did a national study using the SRTR data to see what the experience has been using HCV NAT-positive donors. And what they found was really quite impressive. So looking from 2015 to 2018, you can see that the number of HCV viremic donor kidney transplants increased from one per month to now greater than 22 per month. Of the US transplant centers, 70 centers have reported doing at least one of these, but again, if you look at the majority of the transplants, they are still highly clustered with 12 centers reporting most of the transplants. There are some centers who have moved to doing this as their standard of care, and so this is the largest real-world experience we have of HCV D plus R minus kidney transplants reported by the University of Tennessee. They universally adopted this approach, sent letters out to everyone on their wait list, and essentially switched all candidates who were willing to accept HCV-positive organs. They reported outcomes in 53 recipients, and they obtained the DAAs by insurance means. And so similar to what Nora had suggested in the previous talk, there was a much longer time period before DAAs were started with a median of 76 days post-transplant. In terms of major outcomes, they were excellent. There was 100% overall patient and graft survival, and 100% of patients were cured of hepatitis C. However, there was significant transaminitis occurring in about 20% of recipients, and fibrosing cholestatic hepatitis occurred as well. In addition, there were higher-than-expected rates of other complications, including rejection in 8%, development of donor-specific antibodies in 30%, and BK viremia and CMV viremia. So as Nora had suggested in the prior talk, one conceptual framework for explaining some of these other complications that were unexpected is that the HCV replication itself is revving up the immune system, and perhaps leading to indirect effects as well as some direct effects in the liver. I think something else that we've learned about these transplants that is really interesting is that there's unique virology that's going on. So this is a study in the Journal of Clinical Investigation by Dr. Katie Barr and colleagues, and she did a very extensive virologic look at the donors and recipients in the THNKR study. So on the left is a genetic characterization of the hepatitis C infection in a donor. This is a phylogenetic tree, which shows just a very diverse viral population, which is typical in someone with chronic infection. And then on the right, you see the viral landscape in the recipient at day three, which essentially looks identical. Now this is highly unusual for acute hepatitis C infection, which is typically established by a single founder variant and is usually quite genetically homogenous. But in this case, there has been transmission of a very diverse viral population. So what's going on here? It appears that with transplantation of an infected organ, which has probably a larger donor viral inoculum, there is essentially bypassing of this usual genetic bottleneck that we see. And so when you acquire hepatitis C through injection drug use or through sexual exposure, again, you're usually infected by a single founder variant, but perhaps in the case of transplantation with a larger donor viral inoculum, you're being infected with a much more genetically diverse population. Does this matter clinically? I think that remains to be seen, but you could hypothesize that by being infected acutely with a much more genetically diverse population, perhaps you're at higher risk of acquiring a viral variant that carries resistance. So finally, what are some of the remaining questions? I think in the kidney transplantation world, we're highly encouraged by these early results, but there are some things that we still need to decide. And so as you'll hear later in this session, there is a debate over whether this should be research only or if it's ready to be moved into clinical care. In 2017, our American Society of Transplantation put out a consensus report that clearly recommended restricting it to research. However, I think there's certainly different opinions in the field. And last year at our American Transplant Congress, we did debate this. And as you can see, myself as well as many others think that when considering the risk of mortality on the wait list, that it is time to move this into clinical care. I think the other key remaining question which Nora highlighted quite nicely is how to do this. And in the case of non-liver organs, we actually have a chance to prevent infection entirely in our recipients with a prophylactic approach. So the pros of this again are that you would be able to prevent these acute liver injuries and potentially the indirect effects of the hepatitis C. In addition, there would be no risk of the recipients transmitting infection to others. And if you can shorten the course, it would be more cost effective. On the other hand, with a transmit and treat approach, you can wait till you know the recipient can reliably swallow pills in the post-operative period. And of course, we have more information about duration of treatment and known efficacy there. I think many centers have moved to this transmit and treat approach as standard of care primarily because it's just more real world in terms of accessing treatment so they can just apply to payers to get DAAs. On the other hand, what are some of the cons? Well, with prophylaxis, we have limited PK data putting these medications down NG tubes. However, clinically, it is being done and there have not been any reported failures to date. As you saw in the Gupta report, if we go too short, we do risk the development of resistance and harder to treat virus. And then in terms of obtaining DAAs, there's really no guidance from professional societies or payers. So we're not able to reliably obtain the drugs prior to the transplant. I think the cons of the transmit and treat are, again, you're risking the impact of an acute infection in an immunosuppressed host. And recipients do have to take precautions not to transmit the infection to others. In addition, it's more expensive as you are committing yourself to a full treatment course. But I think while we can debate the nuances of how to do this, again, we really need to not lose sight of the forest for the trees and for many of our patients in the setting of a severe organ shortage, they will die before they ever receive an organ offer. I think we have tools to manage these complications such as rejection, CMV, BK, and even resistant HCV. And we're already transmitting non-curable viruses like CMV and hepatitis B as standard of care. Finally, I just want to present the patient perspective as well. We did in-depth interviews with our expander recipients. And while they did acknowledge some of their concerns, both general transplant concerns and some of these HCV-specific concerns, overwhelmingly what we heard were there were many, many reasons to accept an HCV-positive organ. None of them expressed any decisional regret and they really endorsed high satisfaction with the whole process. So in summary, HCVD plus R minus kidney transplantation with DAAs is a strategy to utilize the increasing number of life-saving organs that are being donated after opioid overdose. The outcomes to date are excellent, but there may be complications if DAAs are delayed or if there is ultra-short prophylaxis. And there remains some debate over whether there should be standard of care and when and how the DAAs should be administered. So thank you. Thank you.

kidneys transplantation

hepatitis C virus

direct-acting antiviral therapies

transplant recipients

clinical implementation