I'm Dr. John Ward, Director of the Coalition for Global Hepatitis Elimination at the Task Force for Global Health in Atlanta, Georgia. I'm here today to talk about the implementation of all-adult HCV testing around the world and in the United States. We'll be looking at the role of testing in reaching global HCV elimination goals, the recommendations for all-adult HCV testing from WHO, CDC, and the U.S. Preventive Services Task Force, outlining the essential components of effective HCV testing programs, the remaining barriers to scaling up HCV testing in this country and around the world, and some of the ways forward to address those barriers. HCV is a large global health problem. 71 million people living with HCV infection, almost 500,000 deaths. In response, WHO set goals for HCV elimination, 90% reduction in incidents, 65% reduction in HCV mortality by 2030. Those goals inadvert 1.5 million deaths over the next 10 years. To do that, we have to implement some key interventions. Fortunately, those have been successfully reached to reduce transmission in healthcare settings. There's still a great work to be done to provide access to clean injection equipment and drug treatment for people who inject drugs to reduce their prevalence of infection. And the topic for today, the low access to HCV testing and treatment around the world. Indeed, it's estimated that only about one in five people living with hepatitis C are aware of their infection globally, and about 50% are aware of their infection here in the United States. So much more work to be done. And that access to testing is critically important as this model illustrates. By looking, when you bring all those interventions together as I outlined, it's very, very difficult to reach that elimination goal for mortality without large scale HCV testing represented by the red line on the left and its contribution to preventing transmission to helping to reach the elimination goal for incidence reduction as outlined in the graph on the right. So scaling up HCV testing is critical to HCV elimination. So in that regard, WHO has set recommendations for HCV testing, targeting again, populations most affected by HCV, such as people who inject drugs, but also recognizing the value of all adult HCV testing in countries that have a high prevalence of HCV infection defined as greater than 2% or 5% based on a variety of epidemiologic circumstances locally. At this point, it's also important to recognize that the burden of hepatitis C falls on certain low and middle income countries as shown in this bar graph, some of which may be particularly challenged to scale up HCV testing and that linkage to treatment, but yet some programs are underway in some of these countries. One of the most remarkable examples is Egypt, a country 14 years ago, which had a prevalence of HCV infection of about 6%. They set about providing a treatment centers around the country, but wanting to improve diagnosis, began to focus on testing, received catalytic funding from organizations such as US CDC and the World Bank. And then the president of CC committed the country to scaling up testing by targeting large proportions of adults for a one time HCV test. They then set about negotiating very affordable prices for diagnostics as low as 60 cents for a point of care HCV antibody test and a less than a $5 PCR test. And they put a program in place to provide outreach settings for testing such as mobile vans and putting on a very robust health promotion campaign to get the public to respond to the recommendations for treatment. The public response was absolutely remarkable as shown by this line graph and by the table on the right. The country successfully tested over 48 million persons. I found over 1.1 million people living with HCV infection and achieving remarkable proportions of linkages to care and successful completion of treatment and cure. And this is having a remarkable impact on the health of the country and documenting progress toward those HCV elimination goals. We estimated with our colleagues in Egypt and the Institute of Health Metrics and Evaluation at the University of Washington, that those treatment outcomes that I just showed you translates into about a 60% reduction in HCV mortality by 2030. So very much approaching that 65% mortality reduction target which they may yet indeed be achieving because the treatment program has continued since that modeling was conducted about a year ago and at a very favorable cost to the country showing the economic data at the bottom of this slide. Another example of effective program is Punjab State of India in a seroprevalence study that was conducted in collaboration with US CDC. They found a fairly high prevalence of hepatitis C. It then put together a robust HCV testing program that targeted the general population as well as high risk populations. Testing and treatment was made available at no charge and they are doing a very highly effective job in screening and getting those being found chronically infected into testing and successful treatment. This is being seen as a field trial for the programs to be replicated in other parts of the country as the health ministry has recently put in place a national control program aiming to achieve those WHO elimination targets. Another example globally is the country of Rwanda which has very modest economic resources. Yet again, they recognize the high prevalence of hepatitis C infection, began to put in place a variety of prevention measures, a control program, negotiated affordable prices for them for diagnostics as shown there in the table on the left, also affordable prices for therapeutics, began to train the clinical workforce including mid-level providers and set targets for testing, linkage to care, treatment and cure. Bar graph on the right is showing the remarkable progress such as screening over 6 million persons to date and with the numbers in the boxes showing their progress toward their numerical targets. There are barriers that we have to recognize that those example countries that I've showed you successfully managed but not all countries have been able to do that. We continue to be challenged by the two-step process of ACV testing because that adds complications, it adds expense. Some people fall out in that process. What's the right algorithm for testing is a challenge, point of care versus lab-based. We know that there's testing capacity in countries that's not fully utilized because it's cohorted in HIV or TB program and not available with ACV testing. How do you break down those silos? I showed you examples of negotiating affordable prices. All countries haven't been able to do that. How can you help countries achieve those prices that can help them scale up testing and linkage to care? And we always need to be looking for improvements in technology such as the research that could bring about a one test rather than a two-step approach to ACV diagnosis. We also recognize that a large number of countries do not have testing plans in place and those policies need to be there. So one of our technical assistance activities at the coalition is to develop a web-based tool for budget-based planning of ACV testing and treatment. This is being developed with Dr. Jag Chatwal, which had previously developed a tool for states in the United States. We're now modifying that to be applied to countries around the world so they can look at how to overcome those barriers and put together an effective program starting with budget-based planning. Turning to the United States, just this year, there are new recommendations for all-adult ACV testing, first issued by the U.S. Preventive Services Task Force and then quickly followed by CDC, with only very slight differences, such as the CDC recommending the threshold above which routine testing should be put in place. Both recommendations also target pregnant women. These new recommendations recognize a number of different data. Number one, about half the people in the U.S. still are unaware of their status if they're ACV infected. Undiagnosed persons miss the benefits of ACV therapy and reductions in risk of premature mortality. There's been changes in disease burden with large increases in the incidence of ACV infection, particularly among young persons, and a five-fold increase in ACV among pregnant women. And then in looking at the economics, recommending all-adult testing comes out to be a very effective intervention cost-wise for both all-adult testing as well as testing of pregnant women. Also, prevalence has declined in the United States, as has mortality, reflecting, at least in part, the implementation of the previous general population testing guideline targeting all persons born between 1945 and 1965 and their linkage to care and treatment, as well as other persons outside of that birth cohort receiving treatment. But this is welcome news that we are making a difference in reducing prevalence and reducing mortality, which does signify some progress toward the WHO elimination goal. And indeed, when you look at data from large commercial laboratories and patient records, et cetera, you do see an increase in testing of that 1945 to 1965 birth cohort, where it has risen from a 2% to over 6% of that group being tested on an annual basis, and about 24% reported being tested in 2017. This reflects the implementation of programs using a number of strategies which have repeatedly shown to be highly effective, particularly electronic prompts for HCV testing, as well as linkages to treatment, clinical education, performance feedback, so providers know how well they're doing and needs for improvement, patient navigation, and of course, the reduction in barriers to therapy so that testing can be followed by a linkage to treatment. Probably the most notable all-adult testing program in the United States has been the Cherokee Nation HCV Elimination Program, which was started in 2015 with a setting of elimination targets, putting together a variety of strategies, making testing widely available throughout their health system, including dental clinics, patient navigation, providing feedback for quality improvement, finding out ways to pay for both testing and treatment, and resulting in a very robust care cascade shown in the middle of the slide and progress toward their elimination targets, including now testing over half of the adult population in the Cherokee Nation. While we look forward to implementing all-adult testing, we want to continue to prioritize those populations at highest risk, such as people who inject drugs, which represent still three of every four new infections in the country. Those infections can be prevented by a robust combination of access to drug treatment, safe injection equipment, and testing and treatment, yet access to those are very limited, with very poor access to safe injection equipment versus the recommended standard globally, very poor access to HCV testing and drug treatment or general medical settings, which is limiting access to curative HCV therapy, which is just as effective for people who inject drugs as others treated for HCV. And so we really look forward to new test and cure models. And we'll be demonstrating one of those at the late breaker session here at the liver meeting on Monday. And I encourage all of you to tune in to learn more about the HERO study model of care. You know, I've emphasized the importance of national planning in giving you those country examples globally. That's also important for the United States. I was very excited to review the draft of our hepatitis national strategic plan, which is framed as a roadmap to elimination, very exciting development with health outcome goals that align with those WHO elimination goals for reduction in incidence and mortality and a number of performance indicators. However, one that was missing was an HCV testing indicator. And I hope that will be added before the strategy becomes finalized. In closing, we just want to emphasize the essential components of effective hepatitis elimination programs that I hope I've demonstrated to you all over the course of this presentation. The importance of data for planning and monitoring program performance, a plan of action with time limited numerical targets, importance of civil and political support, the capacity to deliver these interventions to the target population, sustainable models for financing, integrating these services throughout health systems to reach those target populations, and then participating in operational research that can improve program performance. I think we can bring all those together. Hepatitis C testing is successfully scaled up and you can greatly advance progress toward elimination goals. And I look forward to doing that here in the United States and globally. Thank you very much. I'm delighted to be here and want to thank the organizers for inviting me to participate in the HCV SIG programming this year. I'll be addressing the topic of novel paradigms of care delivery, treatment beyond the specialty clinic. I'm Nora Thoreau from the University of Southern California, and these are my disclosures. I'm gonna start by providing three strong rationales for why specialty care must move to the background and we need to have primary care and other kinds of providers step forward. And the first is that hepatitis C really is a disease of primary care management with the very highly effective, well-tolerated therapies, simple treatment algorithms, and short courses. Hepatitis C is, I would say, easier to manage than many of the diseases that are managed by primary care now, such as diabetes and hypertension. So we need to encourage this concept and make it real, that hepatitis C belongs in primary care. The second is it's clear that testing and treating in the same space provides optimal throughput in terms of patients and their ability to complete the cascade of care. And that's shown in this study where patients with chronic hepatitis C in five FQHCs in Philadelphia were undergoing universal screening. This was a diverse underserved populations present and they had primary care providers that were of two models of care. One where they tested and treated in the same clinic and the other where they tested and then referred off-site for treatment. And while you can see there are challenges in getting patients through the full cascade of care, there was better outcomes in the setting in which the provider did testing and treatment as opposed to just the testing. And so our goal should be to increasingly align testing and treating into a single setting and I think primary care is well suited for that. And then thirdly is that hepatitis C is becoming increasingly a disease and infection of marginalized populations which require very special approaches that are definitely not in the specialist clinic. Whether it's the underinsured and uninsured, those who are incarcerated, those persons who inject drugs, the unsheltered, the mental health disordered patient. We have many groups that need to get access to testing and treating but very novel ways of getting to those patients providing care is necessary. We cannot expect them to come to a specialist office. Okay so with that as background, what models exist in terms of providing care outside of the specialty clinic? And I'm going to touch on three. One is the hub-and-spoke model of mentoring, tele-mentoring. So specialists training primary care physicians to increase capacity of which Project ECHO is the most well-known. Then I'm going to speak about co-localization of HCV treatment with medication-assisted therapy. I think this in particular holds great promise for providing care to persons who use drugs. And then finally in view of the increasing marginalized populations we may have to think of new ways to deliver care to wherever they are and I'll talk about some of the street medicine programs. So first of all building treatment capacity among PCPs, building capacity. So the Project ECHO which is well known to all of you was started by Sanjeev Arora back more than a decade ago and the concept is instead of a you know one provider who's providing care to one patient, you have a hub of experts. They train frontline workers, primary care providers who then can deliver care to a much larger number of patients and do so in in the medical home of those patients. So very well suited for settings in which there's great distances for patients and and or other barriers that prevent patients from being able to come to specialists. So it was developed to serve the rural communities and it's continued to flourish now really is a global program and it addressed a very critical gap in in bringing especially care to underserved populations. And at UCSF we also, I was late to the to the party in terms of Project ECHO starting mine only five years ago. Many of the HCV programs in the United States have been operating for much longer. But I I'm sharing with you my perspective on having started a recent ECHO. I did so at a time when therapies were becoming increasingly easy to administer and where my enthusiasm for engaging primary care providers was appropriately very high. And indeed we were very successful at reaching out to the northern California communities which really are quite rural and where patients would have to travel hundreds of miles to come to a specialist and so highly effective in reaching those communities and being able to bring care to those patients. But I would acknowledge that it was incredibly challenging to to engage the primary care physicians. There was some word of mouth that helped us out and we had a few in each community that really helped to spread the word and we had some partnerships with Indian Health Services and others. But I would say one of the challenges with ECHO is the model works very well but how do you get the word out? How do you engage initially those primary care physicians to become champions for HCV care in their practice? And that's particularly true because I became very aware of the time constraints these primary care physicians have. They often have very full patient panels and so being able to regularly participate in virtual clinics to learn can be quite difficult. And overall I think the project ECHO has suffers from an inability to have a fundable model in that both the hub and the spokes are doing this as volunteers on their own time as there's not a good mechanism to have this supported in the health systems that we currently have. I do think that digital health solutions are really helping us and will come to rescue many of the connectivity issues that previously existed. And by that I mean when I used to talk to individual primary care doctors about how ECHO worked and that we did these virtual clinics you know twice a month and cases were presented etc. I think they didn't quite kind of get how it would work. But these days with COVID everything is virtual. People learn to do telemedicine, teleconsultation and lots of tele-education. And so I think now it's easier to think about a model in which support for the primary care physicians can be given either as tele-education or as tele-mentoring via a digital health platform. So I do feel like this will advance our ability to work with primary care doctors through ECHO or ECHO-like programs. Now I will point out that there's been recently an expert technology panel which evaluated ECHO and ECHO-like structures in terms of their ability as a technological advance and as something to be potentially reimbursed. And the findings of that panel was that there are numerous knowledge gaps around it and how it actually contributes to outcomes. And so they said there was a lot of enthusiasm for its promise but more work is needed. So I think it's a reminder to us that in studying these mechanisms of engaging and building capacity in primary care providers that we need to publish it as well and to be rigorous in how we undertake this work so that we can actually leverage it to find solutions for this kind of work to be funded. And then I'll just close with just saying that there's a lot of innovations around ECHO and ECHO-like. So ECHO had a very specific structure but I think people are innovating around it. For example, many are offering immersions to sort of jumpstart the education. E-consoles and WhatsApp chats are used to support PCPs in between the so-called ECHO clinics. They're recording the sessions to give more flexibility to the PCPs to participate and there are now online clinical management support tools that allow the primary care doctor to literally know what's step one, what's step two, what's step three and everything being very well delineated in support tools. All of those things go towards making it easier for the primary care doctors to stay engaged once they've made their first step to participate in an HCV education program. And just one example of how that came together, this is the San Francisco Health Net. It's a safety net system and what they did here in terms of building capacity, these are community clinics. They did an in-person training for four hours, kind of immersion and then they used e-referral as the backup consultative service to support the primary care physicians and you can see that with this really very modest investment of time and support, they were able to increase both the total number of patients treated as well as the total number of clinics that were active in treatment. Next I'll discuss co-localization of HCV care with a focus on individuals who can deliver opiate substitution therapy concurrent with HCV care. This is a study that was published in 2019. Dr. Talal developed a model for telemedicine. It's demonstrated in the figure on the left. In this program, individuals who were receiving OAT therapy received on-site patient education sessions about hepatitis C and were encouraged to be tested. Those that were found to be HCV RNA positive were then set up for a patient evaluation with a specialist via telemedicine. Following that patient evaluation, the specialist would then have a discussion with the advanced practitioner, provide documentation in the electronic health record and bill, and then the medications could be delivered to the program. And then of course the ideal situation here is that the patient is then receiving their HCV medications concurrent with their OAT. And the success of this program was highlighted by the fact that of the 62 patients that were evaluated, 45 of them were started on treatment with still some barriers related to insurance in 10 patients. But this offers a very important partnering of specialists with individuals who are on the front lines in OAT therapeutic environments. Another option to having the specialist is to have a pharmacist-led HCV screening and treatment program, again targeting OST clients. And here is a very interesting study from the UK in which they did a pragmatic test-and-treat trial based on community pharmacies in Scotland. 27 pharmacies took on treatment, testing and treatment, and in 28 pharmacies they tested but then referred. So the test-and-treat is in orange, test-and-referred in green, and you can see that there was greater success in obtaining dried blood spot testing, initiating treatment, and completing treatment in those in which the pharmacist did both testing and treatment. And indeed I think the opportunities for pharmacists to take on many aspects of both HCV care but also the prevention of other viruses very common in the population of persons who use drugs and also can play a really important role in harm reduction by not only providing HCV treatment but also overdose prevention and clean syringes. So this is a model I think that could be embraced in many other settings. Finally I'd like to discuss the model of taking care to the street. This is applicable to many of the more most marginalized populations with hepatitis C. The first is a street medicine program in Los Angeles. I think many of the larger urban areas are engaged in providing care to the unsheltered. We have a very large population in Los Angeles and the street medicine team is now offering point-of- care testing and at the moment are working on a linkage with local access to care but with the goal of ultimately bringing treatment to the patients on the street. There are some major issues in terms of bringing HCV treatment to those that are unsheltered and we've learned of their many competing priorities, food and shelter being among the highest ones. There's a lot of misinformation and there's a need for education of individuals who are in this setting. There's a lack of secure location for their medications and for those that need to take medications with food, food insecurity can be making that more difficult. So there's many components to considering a street medicine program but these programs now are underway in several urban areas. The second is having a mobile van. This is a program that was started by my colleague Dr. Jenny Price at UCSF and she began a mobile van to offer screening and there's a portable fiber scan in the van so they could offer fibrosis staging as well and the initial plan was to make it a linkage project so that they could get care with a local provider but it's evolved to be a program in which they offer treatment on site with the physician connecting with the patient in the van via a telehealth visit and where the tell HCV provider provides a recommendation and where they the van actually can provide be a source for providing the medication and a safe location for the medication as well. So a very novel program to bring care to the patient. So the key takeaways in terms of moving away from the specialist office is first and foremost let's advance the concept that HCV is simple and is a primary care disease. Co-locate testing and treatment where whenever possible. We need to continue to build capacity for care with our primary care partners. Recognizing that both the provider and its systems and in clinics there's many barriers so we need to work with them to try to overcome those. The echo and echo like models are good and there's innovations around those models to facilitate and streamline primary care engagement and helping them to very quickly become treaters. Increasingly care is shifting to more marginalized populations and for that reason we need to think about even more models that can bring care to to them wherever they are. The common themes that I have tried to emphasize is that technology is helping us. That as a specialist I think we need to both be advocates but also be available to be the backup. I think it's important if we're asking them to take on care in primary care and increasingly this model of making testing treatment occur where the patients are. Thank you very much. Hello I'm Jordan Feld from the University of Toronto and I'd like to begin by thanking the organizers for giving me the opportunity to speak today about global strategies for HCV elimination. Here are my disclosures and before I go on I would be remiss if I did not acknowledge the unbelievable and really well-deserved but remarkable achievement of these three men Harvey Alter, Michael Houghton and Charlie Rice for their phenomenal achievement of being awarded the Nobel Prize and I would like to first say congratulations and thank you to the three of them because really without their remarkable work and really the giant scientific achievements that they have led this idea of elimination would not even be a possibility. So I think it's important that we really remember that we wouldn't be here today thinking about the possibility of eliminating a public health problem a global infectious disease if it weren't for the efforts of these three and many who have worked with them over the years to tackle and conquer the problem of hep C. So today I'm going to first start by talking about what micro elimination means, talk about whether it's really necessary and if so why, some key components to success and then I'll give some examples to illustrate some points about micro elimination efforts. So when we think about elimination well the WHO kind of set the bar. They told us what we're aiming for to try to eliminate viral hepatitis as a public health problem by 2030 and they gave us some targets to define exactly what that elimination looks like and what it means. Within that in order to achieve those global targets most countries and regions have developed national or regional elimination plans really targeting the WHO goals but then really to actually get there we need to be thinking about micro elimination really working at the very local level and when we think about the big picture it's really definitely important to keep our eye on the prize that's where we're trying to get to we really are trying to get to global elimination but it's important to recognize that that's very far off it's hard to reach it's a bit out of our control I was sort of liken it to you know trying to convince a kid the importance of recycling to affect climate change that it's very you really have to think about acting locally to have effect globally and I think the same applies here that perhaps we need to be focusing a little bit more in the local and tangible areas with micro elimination efforts these are certainly more achievable milestones and I would make the case that they're politically savvy because they really can be deliverables that can then get you to move forward so that's where I would say our focus should be but it's important not to forget where we're trying to get to so is it necessary well some actually don't like the micro elimination approach I've heard people raise concerns that we're missing the long-term goal of total elimination so they're concerned that we're prior type prioritizing efforts where elimination is easily achievable the sort of low-hanging fruit and that when it comes to more challenging populations we don't even actually address them when we think about micro elevation we just say well we're only going to focus where we can be successful and not think about the bigger problem and also there's concern that funding and or interest will run out before we actually reach the final elimination goals and I think those are certainly important concerns they're very valid and we should be mindful of them but I would also argue that just as easel formally adopted the micro elimination approach a couple of years ago I too think it's a good idea because I do believe that incremental success is required along the road if we're gonna eventually get to global elimination but I think it's important to remember that there are some challenges with this approach and the reason I think it's important is because when you think of eradication the only time that's been done is with smallpox for a human disease and I think it's important to remember that in the absence of a vaccine we're not gonna have the smallpox moment of like you see in this photo op of DA Henderson vaccinating one of the last children on the planet who needed smallpox vaccination and it's an incredible triumph but we're gonna be doing it in a much more incremental way where we're gonna be treating and treating and treating and there's never gonna be a day where we suddenly say we've just treated the last person with hep C or at least not likely so it's likely to be a bit anticlimactic and I think we do need to enjoy the journey of getting there so micro elimination sort of allows for that by giving us small successes of achieving elimination, or maybe even you could argue eradication in a local confined area, which will eventually get us to that larger goal. So when we think about approaches to get there, well, you can think about micro elimination in various ways. Some of the ways I've thought about it are thinking about the setting. So the example is a prison or a hospital or dialysis unit, a specific population shown here, HIV, Hep C, co-infected people with blood disorders, a health system like the Veterans Affairs, and perhaps a geographic location. Some might be small like the province of Prince Edward Island in Canada, or fairly isolated like Iceland as a country, or they may actually be quite large and or involve a large number of people sort of like the Nile Delta in Egypt. And you could even take micro elimination to the next step and actually go for national elimination. Whether that's micro or macro is questionable, but certainly needs to be done if we're ultimately to get to global elimination. So I think when we think about this, we should be opportunistic. Success really does beget success and to some degree more funding. So when we're successful with our, even if they're small micro elimination efforts, we should really make sure that we use those successes and make sure that we leverage that to get support for our next, sometimes more challenging goal. And I would even use the example of the Nobel Prize. We should all be using this to raise awareness about Hep C, to talk about elimination, to talk about the remarkable achievement that that initial discovery has allowed us to be able to realize. And so just some successful, very small micro elimination projects, which can still be quite impactful are things like hemophilia and blood disorders. Not so many people, but it can be very impactful to really say that it's truly eliminated in a population. Similarly, with people living with HIV and hepatitis C together, easier to access, they're often already in care for their HIV infection, have a very strong advocacy history and could probably help us in the Hep C field and certainly have, but could help us more. Then sometimes define communities, making a town or even a region Hep C free may actually only require a small commitment in terms of the numbers of treatments, but it really can send a very loud and positive message and can galvanize support within the public and get this idea around reaching elimination together. Some keys to success to any project are listed here and right in the center and highlighted for sure is community involvement. And anyone who works in this field will tell you time and again, that where they've been successful, it's when they had good community engagement from the beginning, community was involved in designing, implementing and evaluating every program. And when things have failed, it's usually because community was not involved. So I would really, really stress that we always keep community at the center of what we're discussing when we're talking about micro elimination. The next biggest box here is stakeholder engagement. We've got to make sure all the stakeholders involved and you've really got to think broadly and make sure you've thought about everybody who might be involved in this discussion when you're developing a program. Funding, a little rigid. We always need to consider it. It's very important. But then other important considerations, make sure the logistics are in place. Make sure that as you're planning, you're thinking about scaling. So don't just do a small pilot project that you can't build up. Make sure you've got the right advocacy behind you so that you can champion your ideas if they're successful. Be realistic about your timelines and your goals, sort of over under promise and over deliver as they say, but I think it's really important with micro elimination. If you fail, people won't give you a second chance. And then also make sure your data systems are there. Make sure you can monitor your progress and that you actually know when you've achieved your success. Because if you can't monitor, then unfortunately you won't even know if you've actually successfully eliminated. So let's look at a few examples. So elimination in a setting. And this is a great example that was led by Joaquin Cabezas in Spain, a joint effort across 71 prisons across the country. And what they did is look at trying to develop a very universal test and street treat strategy. And there's a few things that I'd like to highlight about this going back to 2015. The first thing you see is that the screening rate has stayed flat. It's an impressively high screening rate of 80%, but really this program did not change their screening. They were already doing that. What really changed was that they implemented treatment. So you see in 2015, they weren't treating anyone. 2016, 24%. 2017, 52%. And by 2018, basically treating everybody. And that's when they start to see the real impact where you see the RNA prevalence dropping dramatically from 11% down to 2%. And you start to see incident, new infections in the prisons basically disappearing. And they actually delivered on a decrease in mortality between 2015 and 2018. So very impressive results by this effort of trying to eliminate hepatitis C from the prisons. But an interesting study followed this to say, okay, there's clearly impact in the prison when you do this, but what happens because people are coming in and out of prison. So this nice modeling study looked at what was the effect of the prison elimination system on outside of the prison system. And what they showed is that the scale-up really led to benefits in the community. In fact, about 90% of the benefits of this program were outside of the prison population. This is important because it's important to make sure you track collateral benefits. So first of all, you can report back and recognize them, but also the prison system, they might not know, they also might not care. So that's also important is to remember which stakeholders are going to be interested in which information, but certainly the government who might be paying for the prison system healthcare and for the national healthcare is definitely going to care that there were benefits that were seen beyond the prison system. So important example. What about elimination in a population? So this is an example from Tayside, Scotland, where John Dillon and his group have really done a great job working with a population with a pretty high prevalence of injection drug use and of hepatitis C. And what they have really aimed to do is try to eliminate hepatitis C in the HIV-Hep C co-infected population. And what they've really done here is set up multiple ways to do this. So there's multiple ways people can come into the system to access testing, multiple ways that they can access treatment. It really is truly multidisciplinary wraparound care. Lots of examples of this. This is just one that's been done well, and they were able to show that people living with HIV, 96% have been tested for Hep C and treatment rates have really dramatically increased and they're really on track for elimination. What about a health system? Well, the Veterans Affairs is a very large, huge system of healthcare in the United States, and not always touted for the best delivery of care in all areas, but Hep C has really been an area where they've been extremely successful. Now, I should say they didn't start that way. In fact, they initially blocked access to Hep C treatment because of the cost, but it's really now their pride and joy because of all the successes that they've had. They've also seen ancillary benefits where people have accessed the system for Hep C care, and they're getting other care that they need to control their diabetes, their hypertension, and other medical problems that they have. The real keys to success was they had very well coordinated leadership. They had these hepatitis innovation teams, and this is what they were able to monitor. For example, you see that table showing testing, and they had their goals. They looked at whether they achieved them year over year, and part of that was because they have excellent data systems to be able to track progress, identify successes and failures, and they did this iterative process to lead to improvements and have really done a remarkable job and will truly eliminate hepatitis C in this very large health system. Now, what about a geographic region? Well, I'm going to go to Egypt because they really are leading the world in this effort, and this was a paper published this year in the Journal of Hepatology highlighting a project that's been going on for a number of years now treating it in villages in the Nile Delta. What you see here is that of this huge population of over 300,000 people, 92% of the population that was targeted for testing was tested, and you can see that about 16% had hepatitis C antibodies, so pretty high prevalence as you'd expect in this country. Now, it's important. I like to put the bars go back to the top because it shouldn't look like 85% of the people didn't do something. We really only expect the rest of the cascade to occur in those who have hepatitis C antibody, and you can see that even without reflex testing, remarkably, all 33,839 folks went on to get RNA testing, so really remarkable. Of those, about half were positive, and again, we go right back up to the top because that's who we care about, and you see that 91% were treated, 98% SVR like we'd expect, so 83% of that overall RNA positive group are cured. Quite remarkable. Some key components to this, community mobilization, really critical. They had free testing, free linkage to care, free treatment, but really important education campaign to get people motivated and involved in this program, and effectively, this is multiple micro-elimination projects through these different villages to lead to fairly macro-elimination. Now, it's important to remember that we want to do things as well as possible, but perfection can be the enemy of very, very good, and I actually give an example that we've struggled with in northwestern Ontario with working with indigenous communities where there's a high burden of hepatitis C, very challenging to access the area. It's very remote and rural, and working with chief and council, we've had some success in getting the community behind a screening and really an elimination program, but there's been this feeling that things have to be perfect before we can move forward, and it's been a bit frustrating, and actually, it stalls, so I think it's an important example where you can run into challenges. I want to highlight this example in Uzbekistan where Homi Razavi and the Centers for Disease Analysis have piloted this interesting program of using economics to drive elimination where they have about 80% of people in green pay for their treatment for hepatitis C and B, 20% receive free treatment because they pay a little more than the cost, and then they get a catalytic investment, a little bit of, and they get some discounts, and they're able to actually deliver care and potentially deliver elimination of both hep C and B together. Quite remarkable if this actually pans out. They've run into some unexpected challenges, primary care folks not really treating, data challenges, the private system competing and bringing down prices, but still an innovative approach to the problem. Of course, COVID-19 has derailed things a little bit. Is that going to be a problem for all of us? Well, it might be, and you can imagine that there's lots of places in the cascade of care, I'm not going to spend too much time talking about it, where COVID-19 could really impact our elimination efforts all the way from reduced harm reduction, decreased testing, decreased treatment, and decreased follow-up care after treatment, but it also presents some opportunities. So if you can think that a public health approach has been recognized, at least in most places, as an appropriate way to deal with this infectious disease, which could help us with hep C, where we struggled to get that, we've had some coordinated responses put into place pretty quickly, and they've worked fairly well. We've advanced telemedicine dramatically, which is perfect now that we have very simplified treatment, and even testing opportunities, because we've increased our capacity in central labs, which we can now use for hepatitis C testing, and in truth, we might even be able to do co-testing, because people want to know their COVID antibody status. It might allow us to test for hep C, especially given the overlap of the populations. Certainly challenges, but we need to be planning now to regain momentum towards micro and ultimately macro elimination. So to summarize, micro elimination is key to reaching WHO elimination goals. There's lots of potential possibilities, settings, populations, health systems, geographies, but key, absolutely critical, is to have community involvement at every step of the way, and micro will ultimately lead to macro elimination. I think COVID-19 certainly will have created some challenges, but also some opportunities, and I'm confident that we're going to get there. Thank you very much. Hello. Welcome to the HCV SIG, Treatment as Prevention, Addressing HCV in Persons Who Inject Drugs. My name is Dr. Stacey Truskin. I am the Chief Medical Officer and Director of Viral Hepatitis Programs at Philadelphia FITE Community Health Centers, and I also am a faculty member at the Perlman School of Medicine at the University of Pennsylvania. I oversee C-CHANGE, which is Philadelphia's plan to eliminate HCV among people who inject drugs. These are my disclosures. So I'd like to begin with showing you all the estimated prevalence of injection drug use by country, and what you can see here is there is great variability. In some parts of the world, injection drug use is more common than others. It is difficult to get a real understanding of what's happening in real time, since injection drug use is often criminalized and stigmatized. Things like opioid overdose deaths, though, do give us a window into what may be happening in our communities. It is important to note, however, that opioid use is not always via injection drug use, but it does give us some sense as to what the rates are, and what you can see here is that the rates have been steadily increasing. So opioid deaths related to commonly prescribed opioids has been steadily on the rise over the last decade. There was a rise in heroin-related overdose deaths that started around 2010, and then more recently, there's been a rise in synthetic opioid overdose deaths that has really skyrocketed. So things like fentanyl have really been causing a lot of overdoses in our communities, and again, not all of these are injection drug use related, but we certainly see the impact of what has been a very well-described opioid epidemic in the United States. If we look nationally, we see this also reflected in our hepatitis C numbers, and so what you can see here is that age group of 20 to 29 years old has had the most steady and stark incline compared to other age groups, followed closely by those 30 to 39 years of age, and if we come to my hometown in Philadelphia, you can see that this has been reflected in the newly reported cases of chronic infection that have been reported to our Department of Health. In 2007, ours was primarily an epidemic of baby boomers, and then over the decade that followed, we have developed a bimodal distribution, so a whole new generation being impacted by hepatitis C, and if I showed you today's epidemiologic curve, you would see that the numbers that are reported among younger individuals now far exceeds that among those who are in that baby boomer birth cohort. This is not just an issue, though, in urban communities like Philadelphia. In fact, this is disproportionately impacting, in the United States, our rural communities, and here you can see national data of the incidence of acute hepatitis C among young individuals in the U.S. I want you to keep in mind that these are acute cases, and so this is the tip of the iceberg. As you all know, acute cases are often missed, not diagnosed, people are asymptomatic, and they don't come into care, so what we are seeing is just a small fraction of what's happening in our communities. What we do know is that we are doing a pretty poor job of engaging this subset of the population in HCV care. Among people who inject drugs, only a fraction of individuals have been seen by a specialist, and even fewer have been treated, and it is not because the medication doesn't work in this subpopulation. DAA therapy is, in fact, effective among people who inject drugs. There was a really nice meta-analysis that was done that demonstrated that individuals who are on medication-assisted treatment have cure rates greater than 90 percent, and those who have recently injected drugs are very close as well. There was a sub-analysis that was done which did demonstrate higher rates of cure in people who inject drugs who were treated in clinical trials versus those who were treated in observational studies. However, this difference was largely due to follow-up and difficulty in getting individuals to come back for SVR checks, not to virologic failure. We know that adherence rates are very good in this population as are cure rates, so there is no challenge around efficacy in people who inject drugs. As a result, last year, the ASLD and IDSA guidance was updated to reflect this information. Annual testing is now recommended for people who inject drugs that have not had prior testing or past negative testing and subsequent injection drug use. Depending on the level of risk, more frequent testing may be indicated. Certainly, this is true in the population that I take care of. We end up testing individuals who are actively using drugs anywhere from every three to six months, but we want to do this at least annually. I'll also note that the general testing recommendations for the general population in the U.S. and many other guideline panels abroad are now recommending universal screening for individuals 18 and older recognizing that there is a whole new population, a younger cohort that are at risk for developing hepatitis C but may not feel comfortable disclosing to their provider that they do, in fact, inject drugs. I think the most important thing to note here is this last statement that active or recent drug use or concern for reinfection is not a contraindication to treatment. Also important to note is that the guidance panel now recommends treatment of acute hepatitis C, whereas in the interferon era, we used to wait for individuals to clear virus on their own, we now are recommending the treatment of individuals with acute infection. The reason we do this is that, clearly, treatment is much more simple now. It's well-tolerated, but part of the issue is that individuals who are acutely infected are engaging in higher risk activity. As a result, they themselves will be able to pass along their infection to other people within their injection and sexual network. If we cure them, they can't give it to somebody else. You can't give somebody what you yourself do not have. they have demonstrated this very well in Australia and other places where they have aggressively been treating people who inject drugs. This slide is courtesy of Greg Doerr and his group. The work they have done is just extraordinary. So you can see that they have made a concerted effort to treat people who inject drugs. This is data from their needle and syringe program survey. They have now treated nearly 60% in 2018. It's probably more now. Individuals within that access those community-based services. And then you can see they've had a commensurate decline in HCV RNA positivity. We see similar evidence out of Iceland where they began their Trap C program in 2016. And they've seen a precipitous drop among the prevalence of HCV viremia in this community as soon as they started aggressively treating individuals for hepatitis C. And the idea here is really that if you scale up and treat a critical mass of individuals, the likelihood of reinfection will precipitously drop. The idea being that if somebody then continues to inject, if their community members have also been cured, they will be less likely to encounter somebody else who can lead to their own reinfection. But in order to get to this sort of decrease in rates of reinfection, in addition to scaling up and treating a large number of individuals, we must also scale up our harm reduction measures. So the concept of harm reduction is really based in meeting people where they are. Acknowledging that not everybody is ready to stop engaging in behavior that may lead to harm or higher risk. And we do this every day in our own lives. Many of us do not drive the speed limit even though that would be better for our health and for other people on the road. But instead we put on our seatbelts. That is a mechanism of harm reduction. And in people who inject drugs, there are lots of different opportunities for harm reduction, including medication assisted treatment, syringe service programs, which give out clean syringes and other works used to prepare drugs for injection, increased support for some patients like directly observed therapy or other support services, patient education and counseling. And in order to get a decrease in reinfection rates, we also must be able to increase the HCV treater workforce so we can get to that critical mass of patients that require treatment in order to decrease community viral load and decrease the likelihood that somebody will inject with somebody else who is infected. We have a long way to go in the United States. Other countries are doing really well in this area. Obviously, Australia, places in Europe and Scandinavia are doing well when it comes to harm reduction services. But this study speaks volumes. It surveyed about twenty nine thousand people with HCV. Eighty percent of them lived more than ten miles from a syringe service program, with the median distance being thirty seven miles. And you can see here each red dot represents one HCV case. There are folks that have a long way to drive to get to those little triangles that represent the syringe service program. And in fact, the Polaris Observatory takes a look at how the US is doing and where we're falling the most behind is access to syringes and treatment for people who inject drugs. So until we are able or other countries are able to scale up appropriately, we are going to have a lot more work to do. This is something that we just simply can't treat our way out of. We need to be preventing reinfection as well. And if we do that, we can actually eliminate hepatitis C in our communities. There are other barriers to care that exist as well. And so for those of you who are practicing in the United States, I'd encourage you to take a look at these maps. If you have patients that are on state Medicaid programs or even prior pay private payers, you may be familiar with some of these restrictions. So the first is a fibrosis restriction. And the reason I'm bringing up the fibrosis restriction in a talk that is specifically about people who inject drugs is we've already established that this disproportionately impacts the younger birth cohort. And if you're younger, you will have had hepatitis C likely for a shorter period of time, and you will not have advanced fibrosis. So to have a restriction in place that requires somebody to have advanced fibrosis, in order to access hepatitis C treatment, we are limiting our ability to treat individuals who are driving our current hepatitis C epidemic. The data overwhelmingly suggests that if we treat earlier, it's better because we can prevent long-term sequelae from occurring. The guidance and the evidence overwhelmingly tells us to do this. Yet there are payers that are getting in the way and not allowing us to follow the standard of care. Then, of course, the sobriety or substance use restriction. So there are payers that are requiring individuals to demonstrate sobriety. And given the fact that individuals with hepatitis C who happen to inject drugs can cure at just as high rates as individuals who do not inject drugs, requiring individuals to abstain from treat, I'm sorry, abstain from drug use in order to access treatment is discriminatory. We should be treating individuals with hepatitis C who inject drugs aggressively, not just because it will benefit the patient, but it will also benefit the public's health. And then the prescriber type restriction, making it so individuals can only treat if they are a hepatologist, GI doc, or infectious disease provider, really limits individuals access to treatment, particularly those who are in rural communities and may not have a lot of access to subspecialty care. So until we have a situation where we can implement a test and treat model, and move away from these restrictions and move away from cumbersome prior authorizations, we're going to continue to have a problem with implementing models that support treatment as prevention. But there are some key takeaway here is that I want to remind you all of, as you move away from this lecture, the first is that the treatment guidance supports the testing and the treatment of acute and chronic HCV in people who inject drugs. And I encourage you to go with the evidence here. We all carry implicit bias when we see patients, but please look at the science and let that rain, support the patient and support the public's health and treat people who inject drugs. We know that DA treatment for HCV in people who inject drugs is effective. And I think we need to accept that reinfection will happen until it doesn't. And it won't happen when we have treated a critical mass and scale up our harm reduction services. Treatment is prevention benefits the patient, and it benefits the community. And if you happen to be a provider that runs into barriers impeding your ability to provide treatment to the patient and to the community, I encourage you to advocate and use your voice. Please take a look at NVHR.org backslash voices for HEP and join our community of providers who are willing to advocate on behalf of healthier patients and healthier communities. Thank you so much for your time. Thank you very much to the organizers for giving me this opportunity to talk with you about the future of hepatitis C virus vaccine development. I have no conflicts of interest relevant to this presentation. The World Health Organization has set 2030 targets for viral hepatitis control globally. A number of studies have assessed whether we are on target to meet these WHO goals. A 2019 study by Homi Razavi and colleagues assess the progress made in 45 high income countries and territories towards meeting the 2030 HCV elimination targets set by the WHO for incidence, mortality, treatment and diagnosis of hepatitis C. The results are that 80% of those high income countries are not on track for elimination by 2030 and 67% of the high income countries could not achieve hepatitis C virus elimination if given until 2050 to do so. Shown on this map in color are the 45 high income countries with countries on track for elimination by 2030 in green by 2040 in yellow by 2050 in orange and those that will fail to achieve elimination by 2050 are shown in red. The four WHO targets for HCV elimination include incidence, mortality, treatment and diagnosis. And of these, the largest number of countries failed in the category of reduction of incidence. 34 of the 45 high income countries failed to meet incidence target goals for reduction of infection by 2030. Epidemiologic data extracted for 210 countries for 2016 by Andrew Hill and colleagues showed that only 91 of those countries had data to even analyze a sustained virologic response, HCV related deaths and new infections which are required to determine if there is control over hepatitis C virus infection. 54 of those 91 countries had more new hepatitis C virus infections than cure in 2016. If we don't cure more people than we have newly infected, we will simply not gain control over this epidemic. In fact, the net HCV in 91 countries only dropped by 0.7% if we extrapolate the data of to the total number of countries across the globe, the projected global net change is essentially from 70 million to 70 million, a 0.4% reduction. So effectively, we're really not because of new infections gaining control over hepatitis C, even when we're curing people. In order to talk about the future of hepatitis C virus vaccine development, I think it's important to talk a little bit about where we've been and what we've learned. There are a number of different strategies that have been tested in rodents and a subset of those have been advanced to testing in macaques and chimps, with chimps the only animals infectable by hepatitis C. Of those, protein strategies, meaning the injection of proteins, particularly envelope proteins that induce neutralizing antibodies to hepatitis C with adjuvant, as well as viral vectors or strategies that have been employed in humans at low risk of hepatitis C virus infection. I'll talk more about viral vectors because that is in fact the only strategy that has been employed in people at high risk for hepatitis C virus infection. So what is a vectored vaccine? Genes that usually encode the antigen of antigens from pathogenic organisms are inserted into the genome of a non-pathogenic organism that triggers the immune response. Antigens are subsequently expressed and can elicit an immune response. An Ebola vaccine has been developed that is an excellent example of a vectored vaccine. The glycoprotein that induces neutralizing antibodies from the Ebola genome has been inserted into the vesticular stomatitis virus genome so that the vesticular stomatitis virus expresses actually the Ebola surface glycoprotein instead of its own. The vesticular stomatitis virus triggers all the immune responses normally triggered by viral infection but the immune response generated targets not just VSV but also the Ebola glycoprotein and this has proven to be a highly effective strategy in creating a vaccine against Ebola. The same strategy of to design a prophylactic vaccine against hepatitis C has been employed with the idea that you could encode antigens that generate robust T cell immunity. The vectors used are for a prime a low seroprevalence meaning there aren't a lot of pre-existing antibodies in the general population to this adenovirus that is replication defective and is normally an adenovirus that infects chimpanzees called chimpanzee adenovirus 3 or chad 3. The boost is with modified vaccinia unkara an attenuated stream that is non replicating in mammalian cells and both the prime and the boost viruses are engineered were engineered to encode a hepatitis C virus antigen that was the non-structural proteins of genotype 1b HCV not the envelope protein which are again the targets of neutralizing antibodies. The construct was also mutated to further limit the chances that productive production of hepatitis C could occur. The vaccine strategy was tested at Oxford by Ellie Barnes and Paul Klenerman and Leo Swadling and was found to be immunogenic and well tolerated and advanced therefore to testing in people at risk of infection. That trial was called vaccine is prevention or VIP. It was a double-blind randomized placebo controlled phase 1-2 trial at Johns Hopkins the University of California San Francisco and the University of New Mexico. The population of people enrolled was 18 to 45 year old people who inject drugs or pee woods who are actively injecting and at risk for but not already infected with hepatitis C at screening that was by antibody and HCV RNA testing they were negative. They were counseled and referred to drug treatment and needle and syringe service programs as well as extensively counseled on other mechanisms of harm reduction. They were stratified by gender and IL-28B status both known to affect the outcome of hep C infection upon exposure and they were randomized one-to-one to receive placebo or the prime boost vaccine regimen. 548 individuals were enrolled and the goal was to assess the safety immunogenicity and efficacy of the vaccine combination in preventing chronic HCV infection. Because there was no envelope it was not thought to be able to reduce the incidence of infection. Chronic infection was defined as the persistence of the same viral infection at six months as the primary endpoint. Why was this defined as the same infection? When sequencing was performed to determine this because of this this is an individual who is infected not in the vaccine trial but in another cohort of hep C infected individuals we follow and you can see when you look at the HCV RNA levels over time in this individual that this person has four distinct infections indicated by the different colored bars so with periods of a viremia in between and four distinct infections including two different 3a infections a 2b and a 1a infection this is classic infection control reinfection control and then reinfection again so this individual who repeatedly controls hep C then goes on to have a period of many years of high risk behavior without any periods of viremia we need to study these individuals to understand what they're doing against diverse genotypes and subtypes of hepatitis C because this looks like immunity that protects individuals from chronic infection but you can also see that simply measuring HCV RNA does not determine if someone is chronically infected because there are many time points at this at which this person is positive for HCV RNA but not chronically infected. The vaccine is prevention trial design included two injections administered at zero and eight weeks there were 455 participants who received both doses of the vaccine or placebo immune responses were assessed over time as shown below and HCV RNA was tested monthly for 20 months or nine months after infection. What were the results of this trial? Fortunately there were no problematic safety signals. The vaccine was also immunogenic and induced T cell responses but much less so than healthy volunteers in the Oxford trials. Why was immunogenicity reduced in this patient population? One possibility is the existence of antibodies against CHAD3. Antibodies against adenoviral vectors have been shown with other adenoviruses to reduce immunogenicity. It's also been shown in studies of individuals receiving HIV vaccines that people who inject drugs respond less well to vaccine. It's not clear if that's because of the drug use or nutritional status but for some reason people who inject drugs seem to have impaired immune responses compared to those who don't as demonstrated in published studies of HIV vaccines. It's also possible that repeated low level exposure to HCV blunts immunity upon acute infection as has been shown in chimpanzees by Barbara Rehrman's group. No matter what the reason is the lower immunogenicity of the vaccines in peeweeds argues for universal vaccination in other words vaccination of adolescents who have not yet begun to inject drugs because they're less likely to have adenovirus antibodies and they're also less likely to experience some of the difficulties that peeweeds have with immunogenicity. In addition to the safety and immunogenicity we also looked at what happened upon infection to determine what the levels of virus were and whether we observed chronic infection. The vaccine suppressed virus transiently as I will show you but there are unfortunately no significant differences in the rates of chronic infection between vaccine and placebo recipients. So what you see here is the geometric mean HCV RNA level over time for those who received placebo shown in black and those who received in vaccines shown in gray. The peak of HCV RNA geometric mean peak HCV RNA is at incident infection in those vaccinated and in the placebo recipients is at month one and you can see there is a significant difference in the peak HCV RNA levels in those who are vaccinated compared to placebo. By month three, there is no difference in GMP HCV RNA, and unfortunately again, there was no difference in the rates of chronic infection in the two groups. The vaccine did not prevent chronic infection despite blunting initial viremia. What other lessons have we learned from this vaccine that neutralizing antibodies may be necessary not just to prevent incident infection, but to provide additional pressure in addition to T cells for control after infection? Studies in highly at-risk individuals are important because this is the most at-risk population, but they're complex and slow. The trial I just outlined took six years to complete. So this raises the question, should we consider controlled human infection models or CHIM? And we have outlined in great detail some of the ethical and practical issues associated with the possibilities of doing CHIM with hepatitis C. On the plus, you can treat someone who is infected. One question is how long you would let them remain infected before treating them to determine if your vaccine prevented chronic infection. Another aspect is that individuals also are at risk of transmission to others while viremic, and some individuals do poorly in the acute phase of HCV infection. There are many things to consider. In conclusion, I would say the need for a hepatitis C vaccine remains high to interrupt transmission, achieve WHO goals, and prevent liver cancer. Investigation of strategies to enhance immunogenicity are needed, but consider universal vaccination to allow good immunogenicity in young, healthy people. We may also need an envelope protein, and there are multiple design strategies being employed right now to find the right envelope to induce good neutralizing antibodies and the right adjuvants. It may be that the best-in-class neutralizing antibody vaccine should be combined with the best-in-class T cell vaccine. Testing will be simpler with vaccines designed to prevent incidents. You just have to look to see if the person becomes viremic, but may underrepresent vaccine effects in that the vaccine that may not prevent incident infection could prevent chronic infection and that might be missed if you only looked at incident viremia. If controlled human infection models are planned, we'll need experts in hepatology, infectious diseases, virology, immunology, and ethics to design them appropriately. And lastly, I would like to say that we've only just begun to develop vaccines against hepatitis C, and I hope we don't give up the fight. I think it's an important tool in the tool chest for the fight against hepatitis C. With that, I'll acknowledge the individuals primarily study subjects who participated in the first vaccine trial of a preventative hep C vaccine, as well as the teams at the University of New Mexico, Johns Hopkins, University of California, San Francisco. The vaccine trial was funded by the National Institutes of Health, specifically the Division of Microbial and Infectious Diseases. Thank you very much for your time. I want to thank the organizers for giving me the opportunity to give this talk, Use of Hepatitis C Positive Organs in Transplantation. I do have relevant financial disclosures. I will be discussing research funded by several investigator-initiated grants. I did receive research funding for a grant paid to the University of Pennsylvania to evaluate hepatitis C screening rates, and I have received funding for a multi-center trial funded by the NIH. So the objectives of this talk are to discuss the background data that led to developing trials of transplanting organs from hepatitis C-infected donors into hepatitis C-negative recipients, review published data from recent studies and case series, exploring transplanting of organs from hepatitis C-infected donors into hepatitis C-negative recipients, and discuss the barriers to making this practice standard of care. It's important to discuss what we mean by hepatitis C positivity in organ donors. Pre-2014, hepatitis C NAT, or RNA testing, was not mandatory in deceased donors in the U.S. and was variable. And donor hepatitis C positivity was largely defined solely by an antibody. We know that one-third of previously infected patients will be without disease because they will spontaneously clear this, and this is the same phenomenon we see in donors. The antibody positivity alone does not equal active hepatitis C infection. In the setting of donation, the antibody can be a red herring. It could be a false positive. It could be evidence of prior infection that's either spontaneously cleared or treated or related to chronic infection with a fluctuating viral load, which is a rare occurrence but does occur. The antibody alone does not mean that there's an increased risk of transmission of hepatitis C. All of the published data on antibody-positive NAT-negative transmissions occurred in the setting of increased risk donors in the window period, i.e., a donor with intravenous drug use who's checked shortly after admission to the hospital. And some of this series, they've rechecked the pre-donation sample, and the donors have had detectable NAT. Studies using OPT and UNOS data prior to 2015, when these data were collected, are based solely on antibody positivity. So for this talk, hepatitis C positive equals hepatitis C viremic. Now, the reason why this is becoming a bigger thing is due to important and unfortunate changes to the donor pool. We see that drug use, either active drug use with a different mechanism of death or active drug use where the mechanism of death is categorized as drug intoxication, has rapidly risen over the last four years. And this has become an issue because we see that more and more donors either die as the mechanism is coded as drug use, or they die of another mechanism, but they have active drug use. And this has obviously been associated with a corresponding increase in the number of hepatitis C NAT-positive donors, which in 2019 was almost 800, and likely in 2020 might approach 1,000 donors. So what about the use of hepatitis C viremic organs prior to 2016? So liver, there was a high utilization because it was a large pool of recipients that had hepatitis C and were viremic. Kidney, there was limited utilization for hepatitis C positive recipients, and many centers would restrict those recipients who could receive these organs. Specifically, if a recipient had genotype 2 or 3 hepatitis C, they would not want to give them a hepatitis C-positive organ because of the differences in treatment response from interferon and the concern of genotype switching. We know that interferon and ribavirin post-transplant were very challenging. There was increased utilization in 2014 and 2015 for hepatitis C-infected recipients due to the advent of sevastavir-based regimens. Lung and heart were rarely used. Hepatitis C was seen as a comorbidity in recipients, and there were worse outcomes in those that were transplanted with a hepatitis C-positive donor or when the recipient had hepatitis C. So why were the hepatitis C viremic organs discarded? Well, there were challenges in terms of treating hepatitis C post-transplant, especially in the interferon era. There were medication toxicities, there were drug-drug interactions, and on top of all of that, there was a limited efficacy. These organs were thought of as lower quality. So in kidney transplantation, the kidney donor profile index, which is a measure of graft quality, assigns extra points simply if a donor is hepatitis C-positive. And there was a higher risk of graft failure in heart recipients, thought in part to be due to an increased risk of coronary arterial vasculopathy. So the first pilot trials of hepatitis C donor-positive recipient negative kidney transplants used Grisoprevir and Elbisvir. Now of course, there were a series of centers doing this beforehand, but these were the two published trials where recipients were infected knowingly with hepatitis C with the intent to cure. The first published trial was the THNKR trial at Penn, and this was a study that what we did is that it required real-time donor genotyping because Grisoprevir and Elbisvir could only be used in genotype 1 in four recipients. This did have a layer of added complexity as we had to get donor blood to genotype them prior to accepting the organ. This led to organ refusals because it was unable to get a specimen in the middle of the night, or we typed the donor and they were the wrong genotype, and about a third of the time, the genotype was type 3, and thus we couldn't use the donors. The way we did this is that we treated on day three, and our initial experience, we had 10 out of 10 get SVR12 or a cure. We expanded this and published data on 40 recipients, and 39 of the first 40 were cured with first-line therapy. One patient did fail Grisoprevir, Elbisvir, and then we had a retreat with Cifosavir and Ribavirin, and that patient was treated and cured. The expander trial from Hopkins took a slightly different approach. They used Grisoprevir, Elbisvir as the background, but if after transplantation, the recipient was found to have genotype 2 or 3, they added Cifosavir. They started therapy on call to the OR, and 10 out of 10 were cured, but 7 out of 10 never had detectable hep C starting to be checked on the day post-transplant. Give a selection of other published studies of hepatitis C donor-positive recipient negative transplants, first abdominal, and again, this is just a subset of the published studies. The Cleveland Clinic published their study in Hepatology, their real-world experience of kidneys and livers. At the time of publication, they had done 64 kidney transplants, 41 achieved SVR, that's just a 12, 10 had an end of treatment response, and 7 were still on treatment at the time of publication. Methodist in Tennessee had a standard of care approach where they did 53 transplants. They started treatment, interestingly, 1 to 3 months post-transplant, and all 53 were cured. Stanford had a non-trial experience of livers that they published back in 2018, where they did 10 donor-positive recipient negative liver transplants, and all 10 had SVR12. So you see here, very good treatment responses and high cure rates. In the thoracic world, there have been several studies in several different groups taking a different approach. So Vanderbilt has first published their smaller experience and then has published a larger series where they had a standard of care approach, meaning that it wasn't a research trial, but there was special consent required for recipients. They published data on 70 recipients of a heart from a hepatitis C NAT-positive donor. Interestingly, and sort of impressively, the median time from activation to transplant, meaning activation and eligible for a hep C viremic heart to transplant, was four days. They had a one-year survival of 90%, which is actually typical of a heart transplantation, and all of those that survived to the SVR12 mark had cure. They obviously did have some one-year mortality, but it was unrelated to hepatitis C. Brigham and Women's published their data in the New England Journal of Medicine. This is a formal clinical trial where they did heart and lung transplants from hepatitis C viremic donors, and they did short course of EFKLUSA, or cepasivir velpatisvir, within a few hours of post-transplant. So anywhere from two to five, six hours post-transplant. They did 36 lungs and eight hearts, and their cure rate was 100%. And Toronto General Hospital has published several different series. One of their first ones was a protocol where they did EVLP, so ex vivo lung perfusion, sort of pumping the lungs, and then they actually had a perfuse that they flushed the lungs with that was hit with a UV light to try and inactivate virus. What they interestingly found is when they did this, it led to lower viral loads, and two of the 11 never actually developed hepatitis C, but still nine out of 11 did. Now, what are some of the novel treatment approaches? So I mentioned the Toronto group, who I think has really been cutting edge with this. They published a study recently where they did short course of GP plus ezetimibe for seven days. This was started six to 12 hours pre-transplant. And the reason why they use ezetimibe is that there's some experimental data that it may serve to block hepatitis C entry into the cells. They published that they had 30 transplants, 13 lung, 10 kidney, six heart, and one kidney pancreas, and they had 30 out of 30 SVR12. Interestingly, two of the patients had end of treatment viremia, but still developed SVR12 or cure. The group at VCU took a very bold approach of an ultra short duration with some adaptivity to it. So what they did is there were several different groups, and they did this adaptive over time. All groups received one dose of medication that usually includes on-call to the OR. The first group got one dose on-call to the OR and one day post-transplant. Three out of 10 developed viremia. So they did an adaptive approach where they then did longer treatment post-transplant, where they gave two days post-transplant. And in that, three out of 40 developed viremia. Interestingly, in this approach, you know, we see that six out of 50 did not develop viremia and needed a full course of therapy. But of those six, three of them were cured with first-line therapy. Two of them failed first line and had to be cured with the second line. And one of the six patients that required full course failed first and second line, and based on published data, is likely now incurable. They have published a number of studies that have shown that they have published more recent data giving a longer duration post-transplant with even lower rates of viremia in recipients. And then the Hopkins group published a recent study where they did four weeks of GP post-kidney transplant, where they started on-call to the OR and 10 out of 10 were cured. So what is the current landscape of hepatitis C donor positive recipient negative transplants? So some centers are offering this as standard of care. There's no IRB approval for doing this except for data collection. There's a variable consent process in terms of the timing of it, the amount of data that's given. Now, most of the time, there's a plan to apply for insurance approval afterwards. Some health systems agree to pay for the therapy if insurance declines. Some do require that the patient be responsible, and this obviously limits the potential pool of patients. There is variable information provided to patients based on reviewing some of the data from different centers that are provided to patients. There are, though, emerging publications of potential unanticipated risks. Methodists in their series had an increased risk of BK and CMV. Methodists in Cleveland Clinic both reported cases of fibrosin cholestatic hepatitis C. VCU, as I mentioned earlier, the multiple treatment failures. Toronto did have relapse rates in their lung recipients of 10% that required a second course of therapy. Mayo Jacksonville published a case report of someone who got a hep C viremic liver. There were delays with the insurance approval, and they developed a glomerulonephritis thought to be related to hepatitis C, which led to renal failure requiring dialysis. And then there are insurance denials at Ohio State where they published 35% of their kidney recipients and 10% of their liver had refusals and denials and delays in care. And lastly, something that we have just had accepted for publication, is there has been a disturbing early pattern of disparities in utilization of kidneys from hep C viremic donors where there is decreased use in racial and ethnic minorities, women, and those with less education. And this, I think, is obviously a very concerning thing as to whether centers are consciously or subconsciously selecting certain patients for these organs. So how to implement the practice of hep C donor positive recipient negative transplants? My personal opinion is that it should be an IRB approved research protocol vetted for safety and informed consent. I think we should always evaluate for higher risk features of liver disease in non-liver recipients, especially those with kidney disease and diabetes who may be at higher risk of NASH and even have fibrosis. There are unknowns. While the data are encouraging, we don't have a narrow confidence in the confidence interval for cure rates from a large study. The survival benefit and risk of accepting these organs, the CMV and BK, again, there are concerns from some early studies, including Methodist and long-term graft outcome. I think a reasonable alternative is a formal education and informed consent process that does not disproportionately leave out one group of patients. I personally think there should be pre-transplant assessment of liver disease and guaranteed drug coverage. I think it's unethical to do these transplants and not have the health system say, we will cover this if insurance denies it. And I think the treatment regimen should be a Cluser or Maveritt. And I personally think it should be full course because I would argue that the cost savings of a shorter course are not worth the risk of potential treatment failures. There are logistical barriers. So insurance approval is not universal. Medicaid programs may have fibrosis restrictions. DAAs are not FDA approved for acute hepatitis C. And as we saw from the group at Ohio State, denials and delays are common. Timing of treatment initiation, the ASLD guidance document did say earlier the better. But if we were to do perioperative treatment, this would either require insurance approval prior to infection, prior to transplant. And you get authorization for your entire list. Will insurance approve it without documentation of hepatitis C in the donor or recipient based on a theoretical transplant? Or health systems will eat the cost. But then what if you start therapy early and the recipient doesn't have detectable viremia? Will insurance approve based on donor viremia? So key takeaways are transplanting organs from hepatitis C positive donors into hepatitis C negative patients is an important mechanism to save more lives, increase the number of transplants, and improve utilization of a scarce resource. Highly potent DAAs should change how we view hepatitis C in the setting of transplantation. But informed consent is critical. And we need to define operational factors for broader utilization, including insurers, optimal and ethical and equitable patient selection, and unexpected risks. Thank you very much.

Hepatitis C Virus

HCV

global aim

elimination

testing

community involvement

micro-elimination

stakeholder engagement

funding

data systems

COVID-19 challenges

organ transplants

direct-acting antivirals