So we've heard a lot of the speakers allude to the issue of whether this should be research or clinical care, and now we're going to have a formal debate about that. And so speaking for the pro, we should move this out of research and into clinical care. We have Paul Kwo, the head of hepatology at Stanford. Thank you very much, and thanks for the invitation to present the pro. HCV donation is no longer researched, and it's ready to move to the standard of care. Here are my disclosures. So we've heard very nicely today about the organ shortage that we have, and again, this is a snapshot of the waiting list, the number of transplants, and the donors, and obviously many more donors. We need to augment the donor pool to address this large waiting list. There's also discrepancy with regard to liver transplant, and this is the median MELD score for adults by deceased donor liver transplant by DSA, and I know these regions are going away over time. But contrast this with the recent map 2017 for drug overdose death rates. While we look at regions, you can see here that this tragic consequence of the opiate epidemic, there are also variations in the opiate death rates here. And again, this potentially presents a solution and maybe some good out of a tragic death that occurs. As Jordan said, we need to be reducing drug overdose as much as we can. The number, this is just a snapshot from UNOS, the OPTN website, which just shows the percent of hepatitis C NAT positive donors and deceased donors is increasing. It's on the bottom row here, and you can see here from 2010, it was about 4% of donors. The snapshot in 2019, it's almost 10% of donors. So these donors are clearly out here for us at least to consider using. And again, we've talked about the discards as well. And again, for a variety of different organs, you can see here particularly kidneys. These are from 2011 to 2019. You can see the number of kidneys that were discarded, as well as livers and heart discards you can see are quite low. Lungs are still in the 20 range in 2018, 2019. And again, not all of these organs may be used successfully. They should at least be considered and recovered and assessed. So we've had a wonderful talk about some of the competing risks of using hCBRNA NAT positive donation. And above all, we wish to do no harm. And we have to contrast the risks of dying on the wait list, or pre-transplant complications, costs, resources, and contrast that with the risk of a donor-derived infection. How does the HCV infection affect the organ quality, the treatments with direct acting antiviral agents, and then the data-free zone, that is, the unknown effects of HCV and DAA exposure on newly transplanted organs. And we don't know the long-term results yet. Though as I'm going to show you, the short-term results are quite good. And again, the ATS consensus conference statement from 2017 said that the transplantation of organs from HCV viremic donors into HCV negative recipients should be conducted only under monitored IRB-approved protocols. So are they effective? Are DAAs effective in post-solid organ transplant? And the answer is yes. These are for liver, but these are our first-line treatment options listed here from our ASLD website here. And again, we have the luxury of two pan-genotypic ribavirin-free options. And they are generally the most commonly used, although Grasoprevir, Elbisphere certainly had advantages with renal metabolism. And so these individuals can receive these pan-genotypic therapies. And we know that the sustained response are very high. We know that we're generally not dealing with any advanced liver disease, so the cirrhosis regimens are not relevant. What about drug-drug interactions? Yes, this was just brought up, and we do have to be concerned with our drug interactions, DAAs with amiodarone, calcineurin inhibitors, and our statins. And it seems like we all think alike here that these are the targets of where we need to be concerned about. But I would argue these are four-to-12-week exposures, and we should be able to manage these. And again, we try to avoid cepasivir and amiodarone, but in a hospital setting where they're closely monitored, this can be used. And of course, glucapovir, preventisvir can be used without amiodarone as well. But there are published reports of using cepasivir with amiodarone, and thus to date, no adverse effects thus far. With the calcineurin inhibitors, really it's the cyclosporine. With the protease inhibitors, there are some limitations there. But these generally can be addressed. There's increasing utilization of HCV-positive donors already, and this just shows you here that this came from Mike Charlton. He published this in Hepatology. And you can see here, this is from the UNOS database from 2008 to 2017, and you can see here that the utilization is increasing, 107 HCV-net-positive-to-negative donors in 2017. And thus far, the survival rates through two years are no different than HCV-negative-to-negative or any of the other permutations. The short-term outcomes thus far are comparable to not using net-positive donors. And again, this very nice paper here looked at the trends in utilization for kidneys. And again, this study here in the center column, there were, between January and March of 2019, 200 HCV-net-positive kidneys went to uninfected recipients, 69 into seropositive, and the GFRs were equivalent. And again, short-term outcomes, but we're not doing any immediate harm to these individuals. Heart transplant, it's very similar. This is the mass general experience with 20 individuals who received eight weeks of Glicapivir, Preventisivir, first dose just going to the OR, and again, all achieved sustained response. And this has been reflected in the heart transplant literature now. And if you look at their utilization rates now in antibody-positive and viremic donor hearts, you can see now not only do they have equivalent risk of post-graft failure and one-year mortality compared to those with HCV-naive donor hearts, but the utilization rates are comparable. And so this has evolved now to essentially be the standard of care. And the liver meeting here, these are just four abstracts that were presented. We heard about some of them already. But again, the preliminary results all suggest that with differing strategies that can be anywhere from a 12-week course to just a seven-day course or four-week course, there are a variety of strategies. The overall sustained response rates are still excellent at this time. And as we already saw very briefly, modeling supports the use of the HCBRNA-positive livers into HCV-negative recipients. This, again, was published with livers. And also the renal literature also suggests that this strategy is less costly and slightly more effective compared to a donor-negative recipient-negative strategy. And as was already pointed out, the costs of the DAAs are now falling. So I have here the therapies here, the DAA therapies, as well as just throwing in hemodialysis and an LVAD cost. And you can see here that if you look at the WACs with now glucapivir-preventisphere and with generic ladipisvir-sifosvir and sifosvir-velpatisvir, four-week costs here are $11,075. The 12-week costs are all on the right side as well as the hemodialysis and LVAD. And you can see here that the costs have come down. And compared to, say, a hospitalization prior to transplant, that I think as the costs continue hopefully to decline, the costs won't become an issue. Resistance and treatment failure, these are concerns. And this is just from the Toronto group here where they had two patients that had treatment failure and had to be retreated. And again, this, when you give a donor-derived infection, is obviously not what we want to see. And I must say that if I had seen a bilirubin of 42, I too would have been concerned. And yet, with- Different units. Huh? Yes, it's different units. Yeah, no, no, no, but still. Right, micromoles. But it's still, yes, good point. But still, it's elevated. Yeah. Liver biopsy findings, cholestatic hepatitis. And the retreatment with soft Velvox was successful in both. There was one treatment failure that occurred that was reported just recently. And I believe that patient got grizoprevir, Elvisvir, followed by Glicaprevir and Preventisphere. So, and so their treatment failures are out there and we're going to have to be prepared to deal with these. So we're going to have to have salvage therapies for these individuals. So, what does not need more research now is the shortage of donors in relationship to the number of individuals who are listed for solid organ transplant. High initial efficacy of DAAs post solid transplant, that's also established. There are excellent short-term outcomes thus far with the use of NAT positive organs. And there are fewer NAT positive recipients for these organs. We've been transplanting NAT positive to NAT positive donor to recipient for quite some time. And we've been giving, as many people have stated, donor-derived infections for decades, that is hepatitis B and cytomegalovirus. And we have experience managing these chronic infections. Once the HCV infection is treated, there's no chronicity to address with regard to the infection. But again, the long-term effects are not yet known. But the risks and benefits of HCV NAT positive donation, the benefits, I think, now outweigh our current risks. And at least using these NAT positive organs should no longer be considered research per se. And I do think, however, we need to implement policies as we move forward with this. And this includes standardized education for patients so that they understand the risks and benefits accepting an HCV RNA positive donor organ. But is this higher risk than an older liver with steatosis? We use, we expand the donor pool now with so-called extended criteria donors. And this is going to be a conundrum that we're going to have until we have the ability to equilibrate the donor and the recipient pool. We have a consent process for high-risk donors already in place, but we need to make sure that patients are adequately educated about the risks and benefits, as well as an explicit plan for coverage for DAAs post-transplant that eliminate barriers and avoid the development of HCV-related complications. We need an effort to enact national policies that guarantee access to DAAs. And I think we should engage CMS to mandate coverage for these. And transplant centers who use HCV RNA NAT positive organs need to be the backstop to provide DAA coverage. And we've gone to our own hospital to try and ensure that we have a supply of these available, when we have delays in initiating therapy. What is the most effective strategy when applied on a large scale? This will have to be a multi-center trial, or we're going to have to use a registry. What is the optimal strategy, await viremia? That seems to be risky. The cases of fibrosing cholestatic hepatitis that are reported give us all great pause. There was a presentation here where glomerulonephritis occurred rapidly without initiation of therapy, and that is of concern. The long-term effects of a brief exposure to viremia and DAAs still needs to be addressed in non-solid organ liver transplant recipients. And again, we are going to need salvage therapies. There are going to be rare adverse outcomes with this strategy. And again, the fibrosing cholestatic hepatitis, this was already reported, it was a great problem a decade ago, it's now gone away in the DAA era. So that I do think that we can say that this is no longer research per se. My own belief is that a preemptive approach seems to be preferred, but I think there are two options here. You can do preemptive treatment with pangenotypic therapy, or immediate treatment of documented post-transplant viremia with monitoring. If you do a preemptive treatment, we will probably treat some individuals who don't actually transmit the virus. You assess for sustained virologic response, and I think we can use this HCV-positive donor pool, again, a tragic consequence of the opiate epidemic, to hopefully augment our ability to get those who require transplants transplanted expeditiously. Thank you.

hepatitis C virus

organ shortage

HCV-positive donors

direct-acting antiviral agents

organ transplant