Good evening for those who are in India. Good morning from those who have joined us from US and maybe good afternoon to those who are in between. I'm Dr. Ajay Duseja. I'm the Secretary General of Indian National Association for Study of the Liver, INASL. And I welcome you all to this first ever joint webinar between INASL and American Association for Study of Liver Diseases, ASLD. I must tell you that we have had some joint sessions in our physical meetings, but this is for the first time that we are holding this webinar jointly between INASL and ASLD. And what better day? Because we, on Sunday, we just had our World Hepatitis Day, we observed that. And this webinar is happening on the occasion of World Hepatitis Day 2024. And the topic we have chosen is the webinar on viral hepatitis. So for conducting this webinar, I will now hand it over to our two moderators who will be moderating the two talks and followed by a panel discussion. And let me invite both the moderators, Professor SP Singh, who's the president of INASL, and from Klinger Foundation, Katak, India, and Professor Patricia Johns from University of Miami Miller School of Medicine. So they will be both conducting this webinar from now. So hand it over to both of you, Dr. Singh and Dr. Johns, over to you. Thank you. Thank you so much. It's my great pleasure to introduce the speakers today. So first I'm going to introduce Dr. Nora Turow. Dr. Nora Turow is a transplant hepatologist, the Neil Kaplowitz Professor of Medicine and Chief of GI and Liver Diseases Division at the Keck School of Medicine in the University of Southern California in Los Angeles. She's focused her clinical and research activities on viral hepatitis and fatty liver disease with specific focus on patients with cirrhosis and those who've received liver transplant. She's had multiple clinical trials related to preventing and treating chronic hepatitis. And Dr. Turow has been a PI on multiple NIH-funded studies, including the current NIH-supported HPV Clinical Research Network, Non-Alcoholic Hepatitis Clinical Research Network, and Liver Cirrhosis Network. She has authored over 400 peer-reviewed manuscripts, and most importantly, Dr. Turow served as the 2023 ASLD President. I'll also introduce our panelists, Dr. Jennifer Price. Dr. Price is an Associate Professor in the Department of Medicine in the Division of Gastroenterology and Hepatology at the University of California, San Francisco. She's Director of the UCSF Viral Hepatitis Center, and her research examines the contributions of novel and traditional factors associated with liver disease and fibrosis progression in large observational cohorts of individuals living with HIV, with or without viral hepatitis. She's PI of the San Francisco Bay Area site of the Multi-Center AIDS Cohort Study, the Women's Interagency HIV Study, and this integrates two of the largest and longest-running NIH-funded prospective cohorts of persons living with HIV. Dr. Price serves as Co-Chair of the Liver Working Group and Vice Chair of the ASLD HCV SIG. We're so happy to have her here today, and now I'll pass it on to my co-moderator, Dr. Singh, for the other introductions. Thank you, Patricia, and hi, all attendees. It's my proud privilege to introduce the Indian panelists. First, I'd like to introduce Professor P.M. Rao. Professor P.M. Rao would be an eminent panelist for us from NASL. Professor P.M. Rao is a past president of NASL. He's currently holding the position of Director and Chief of Hepatology at the prestigious AIG Hospitals in Hyderabad, India. He was the best outgoing graduate from his medical school, that is, Kanur Medical College, and he did his post-graduation and his gastroenterology training from the prestigious Postgraduate Institute of Medical Education and Research, PGI Chandigarh. Later on, he joined faculty in Usmania Medical College, and then he moved on to NIMS-Nizam Institute, Hyderabad, where he was the head of department when he retired before he joined the Asian Institute of Gastroenterology. He's a founding member of the Coalition for Eradication of Viral Hepatitis in Asia-Pacific. Besides, he's completed a large number of chapters in various books and over 150 publications in international journals. His major interest is NAFL, alcoholic liver disease, and hepatitis B. Next, I would like to introduce Professor Vivek Saraswat. Professor Vivek Saraswat is, again, a past president of Indian National Association for Study of Liver and the Indian Society of Gastroenterology. He's currently professor and head at the Department of Hepatology, Pancreatobiliary Sciences, and Liver Transplantation at the Mahatma Gandhi University of Medical Sciences and Technology, Jaipur in India. Until last year, he was professor and head of gastroenterology at the Sanjay Gandhi Postgraduate Institute of Medical Sciences in Lucknow. He's trained at MAMC, that's the Madanadar Medical College in Delhi, and then he went on to Alliance Institute of Medical Sciences. Following that, he went abroad. He went to Queen Elizabeth Hospital, Birmingham for his training, and later on to King's College Hospital, London. Besides, he also went for a fellowship at Salzburg, Austria. He went to Belgium and Guy's Hospital, London. We shall now begin this webinar with a very important subject, and that is treat all strategy in HIV infection, pros and cons. You all know that following the WHO guidelines, this issue has been a very contentious one, and for this, now I request Professor Vivek Saraswat to please go ahead with his talk lecture. Can you unmute yourself, sir? Yes. Thank you, Professor Singh. I'll now share my slides, and start my presentation on the issue, on the topic, chronic hepatitis B, treat all the pros and cons. It's a great pleasure to be part of the first INAZL-ASLD joint webinar on the occasion of the World Hepatitis Day, and I bring you greetings from Jaipur in India. Now, before we get into the topic, I'd probably recap, I'd like to recapitulate something that you probably all are familiar with, and that is some basics about the natural history, especially the phase transitions that we know happen in hepatitis B infection. So as we all know, following a primary hepatitis B infection, which could result in an acute hepatitis B or fulminant hepatitis, there is a high risk of chronicity, which depends very much on the age at which the infection is acquired. And as per our conventional knowledge, once an infection becomes chronic, it passes through various phases that are shown here, which are conventionally called the immunotolerant phase, the immune clearance phase, the inactive phase, carrier phase, the reactivation phase, and the phase of occult hepatitis B. Now, what we have here is a diagrammatic representation of the important viral biomarkers, the transaminases and the events that are happening in the liver in terms of liver fibrosis shown graphically here in this cartoon, as well as numerically. And the changes that have taken place in the terminology or recently are recapitulated here. We all know that the optimum opportunity or the time to treat chronic hepatitis B is during the phase of phase two and phase four, which is the immune clearance phase and the reactivation phase. And generally conventional wisdom has it that we would withhold treatment during phases one and three, that is the immune tolerant phase and the inactive carrier phase. A variety of milestones mark the transition from one phase to the other. And these are something that we are familiar with for a long time. Now, currently, as of the latest set of guidelines that have been issued by important international bodies like the EASL, the ASLD, the APASL and the national bodies like the ENASL, the currently recommendations for treatment guidelines include the must treat group, which is in the phase two and phase four diseases, as well as in all patients with cirrhosis compensated or otherwise decompensated. We may treat patients who have high viral load and elevated transaminases, or even those who have normal transaminases, but form certain categories like an older age group or the presence of a family history of HCC or cirrhosis or the presence of extra hepatic manifestations. Now, with these restricted guidelines, we are only able to offer treatment currently to approximately one in five individuals who are hepatitis B positive, who according to these guidelines are eligible for treatment. As we all know, very recently, the WHO in June of 2024 has come out with certain recommendations that widen the scope of treatment. Expanded guidelines include treatment of all positive adults and adolescents who have significant fibrosis or cirrhosis of the liver as shown by vibration control transient elastography scores of more than seven for F2 fibrosis, significant fibrosis or 12.5 kilopascals, which indicates established cirrhosis. Again, non-invasive tests like APRI and FIPFO with these cutoffs have been suggested. And these numbers, that is positivity for the viral marker HBSAG and the presence of significant fibrosis or cirrhosis indicate warrant treatment regardless of the HBV DNA, the ALT and the E antigen status. However, this would include some patients who are so-called gray zone chronic hepatitis B individuals which I'll come to in a minute. Additionally, these guidelines have suggested that special categories of people who have co-infections, who have various comorbidities, have a family history of liver cancer and end-stage liver disease or extra hepatic manifestations like polio, arthritis, no-dose or glomerulonephritis should also be offered treatment regardless of their DNA, ALT or E antigen status. A third set of indications that the WHO has come up with is those with viral load of more than 2000 IU per ml and elevated ALT at any level above the upper limit of normal. They should also be candidates for treatment although they might include patients in the phase one and phase three gray zones. In situations or in geographies where DNA testing is difficult to access, even persistently abnormal ALT has been considered according to the 2015 WHO guidelines as an indication for the initiation of treatment. However, this is a rather restricted indication. So this has expanded the indications in which treatment can be offered to an extent that almost 50 to 60% of those who show a chronic hepatitis B infection become eligible for treatment. On the other hand, we also have the Chinese guidelines which came out and have been updated recently in 2023 which can be summarized in these five points that test all adults for chronic hepatitis B with this triple phase marker panel, vaccinate all adults who are negative for markers in these three negative hepatitis B wireless triple panel. If they are positive, check for DNA, check for delta antigen and treat all individuals who are DNA positive which is likely to include patients in the immune tolerant and the inactive carrier phase also. And those who have liver disease that should be staged and surveillance for liver cancer should be instituted. And this is probably one of the guidelines that emphasizes treat all patients with chronic hepatitis B and there have been various proponents for this strategy from different parts of the world, including from India. Now, I'd like to take up some of the implications of these expanded treatment guidelines particularly in the immune tolerant and the inactive carrier phase. It is well established in literature and we all know this fact that those who are truly immune tolerant have a benign natural history and do not benefit from therapy and substantial volume of literature as shown by references shown on this slide established that those who are truly immunotolerant that is that they are persistently normal transaminases, E antigen positive, high viral load with minimal or no hepatic inflammation or fibrosis essentially have a very benign history and less than 5% of them show fibrosis progression on paired biopsies several years apart. And antiviral treatment is a very limited benefit in these people with less than 5% achieving zero conversion less than one in four achieving effective DNA suppression and which promptly rebounds once treatment is withdrawn so that even if you were to offer them treatment they really do not benefit from treatment. This is again borne out by real life data which has shown that in people with in children as well as in adults over a period of time as many as 80 to 85% of these were truly immunotolerant will have E antigen zero conversion and they carry a low cancer risk of as low as below 2%. Also as indicated earlier their response to treatment is rather poor. This meta analysis of 13 studies again substantiates the fairly low 10 year HCC risk below 2% in those who are truly immunotolerant. Nevertheless, in this group there are publications and literature that suggests that there is benefit for treatment and that is more related to the age of the individual and as well as certain reports talk about ALT and DNA. That age is important is clear that is those in the so-called immunotolerant phase with the markers that I've shown earlier as their age advances and crosses 30 the risk of HCC goes up which has been showed in the studies like the reveal study and the others. So it appears that we need to identify those who are apparently immunotolerant phase but may actually be undergoing a phase transition which is not detected by infrequent testing or insensitivity of our testing tools. And those who have significant fibrosis or past history of liver cancer in the family are candidates who should be offered treatment including extra hepatic manifestations. Pregnant women with a high viral load above five log and those who have healthcare workers as well as immunocompromised individuals. So even in the immune tolerant phase there may be those who meet these markers and can be offered treatment and would benefit from treatment. So within the immunotolerant phase one needs to look for these subsets and consider them for treatment. What about inactive carriers? Again, inactive carriers have a persistently normal transaminases, DNA levels that are low, low HBS antigen level, quantitative HBS-AG levels and may or may not have fibrosis depending on which guideline you choose to follow. Now in the inactive carriers there still remains controversy and various bodies like the APAZL suggest that histology and family factors and various clinical factors should be taken into account. The subsets of patients who are in the inactive carrier phase do benefit from treatment while other studies including the reveal and studies from Europe and the US suggest that they may not benefit from treatment. Why do we have this diversity is probably because of this phenomenon of gray zone carriers which was highlighted in a recent paper by Bonacchi et al a few years ago. Now, as we all know, E antigen negative individuals who are anti-HBE positive have a load below 20,000 IU per ml and have ALT levels below 80 would qualify as inactive carriers and those who are true inactive carriers would actually have loads that are lower than 2,000 IU per ml and have normal transaminases. On the other hand, they can be gray zones one, two, and three in which either the DNA is low but the ALT is raised or the DNA is raised but the ALT is normal or groups in which both sets of markers are abnormal. And this is after you've excluded these patients who are shown here in the box here who would be exclusions for consideration as chronic hepatitis B carriers. Now, in these patients what has been shown is that if they are truly inactive carriers as shown by low DNA and low abnormal ALT levels, up to 15% will have HBsAg zero conversion over a period of about eight years. On the other hand, the other gray zone one, two, three sets of carriers will not show this clearance and probably may benefit from treatment and so one needs to be more objective in identifying inactive carriers and categorizing them in this manner. A proposed algorithm is that if those who are chronic hepatitis B antigen negative with persistently normal transaminases and have undetectable DNA only need to be follow-up. On the other hand, if DNA is detectable and they have these risk factors of age more than 30 and a family history of HCC or cirrhosis, active inflammation of fibrosis in the liver or extra hepatic manifestations should be offered antiviral therapy. Those who do not meet these criteria can be further subdivided according to their viral loads and those who have below 2,000 IU per ml and a quantitative HBsAg load of less than 100 IU per ml would be effectively inactive carriers who can be followed up. However, those who have an HBsAg level higher than 100 IU per ml or a load of more than 2,000 IU per ml would again be one of those gray zone carriers that we spoke about. And if they have active inflammation or fibrosis, they would merit treatment and they would indeed benefit from treatment as is shown in some of the studies that are quoted on this slide. So we can have a more, again, what we seem to see is that patients in phase one and phase three increasingly, if you look at them in a more granular way, they do contain subsets of patients who will benefit from treatment and there is indeed scientific objective evidence for widening the expanding the limits of the categories of patients who can be offered treatment. Now so coming to the question that had been posed to me, should we treat all with chronic hepatitis B? Probably yes, other than those who are truly immunotolerant or truly inactive carriers as I've shown in the previous slides. Now what are the points that favor treating all? Well, we all know that we have effective antiviral drugs and can achieve a high sustained virologic suppression in these patients, which will avoid the risk of progression to cirrhosis and stage liver disease and liver cancer, which even in those who are not offered treatment, there is an up to 10% risk of such progression. Similarly by decreasing the by suppressing virus, you will also reduce horizontal transmission and regular monitoring of those who are not treated will be avoided if you offer treatment to all. As I've said, the significant category of phase one, phase three patients and high proportions are not offered treatment and you have to keep monitoring them to see when the phase transition happens and they become eligible for treatment and which involves significant costs and significant dropouts which can be avoided, as can other features like stigmata and loss of self-esteem. As the risk of cancer being increased over 10 years, even in the immunotolerant phase with high viral load was brought out in the reveal study and treatment of these patients is likely to obviate this risk. And with the high genetic barrier agents being available, we do have the tools to treat all. What are the cons or more importantly, what are the challenges which are stopping us from treating all and these are important. First of all, to treat all you better find all and I'll bring out the problems of identifying patients who need treatment, a very large number over 254 million people who are eligible for treatment, you need to find those who you want to treat them and to find them in the global population implies scaling up testing and a substantial cost of screening which has to be borne by someone. If you were to treat all, how do we foot the bill, what is the cost of treating all, what is the cost efficacy analysis and the benefits of treating this all, I'll try and cover in the next few slides. And probably an equally important if not more important handicap is how do you motivate and convince asymptomatic patients who only have some numbers abnormal that you need to continue almost indefinitely if not lifelong on a treatment. And if you're not able to achieve that, you actually risk losing the one or two effective drugs that we have by allowing the emergence of drug resistance to even these three agents that we currently have for treating our patients. Now, in how do we find all these numbers which are recently been put out by the Polaris Observatory show that we have an over 254 million chronic hepatitis B infected population all over the world and which has significant mortality. And the goals that have been set out by the WHO, we are all familiar with them, is reduction in the HBV incidence and reduction in mortality by 65% by the year 2030, which have been revised to decreasing mortality to below 400,000 and HBV incidence to less than 0.1%. Today in 2024, well, we have the latest data is from 2022, where are we? On track with reducing numbers, but still far from reaching the 2030 targets. And why this is so, one of the most important problems has been the challenges in finding the patients. The Polaris Observatory data shows that according to the existing criteria, less than one in three are eligible for treatment. And of the total number of infected patients, 254 million globally, less than 14 or 13% have been diagnosed till date. The remaining 85, 86, 87% patients have yet to be found who can be offered treatment, which and of those who have been identified as being positive, less than 2.5% or 2.6% have actually been linked to treatment and currently are on treatment, which is about 8% of those who have been diagnosed so far to have chronic hepatitis B. And these numbers are supported by the recent WHO 24 guidelines, which shows that only globally, 13.4% of the chronically infected population has been identified till date and only 2.6% linked to treatment, which varies according to the various regions and particularly in the African region, Southeastern Asian and the West Pacific region, which harbor the largest number of chronic hepatitis B. These challenges are particularly daunting because they come in the low, medium and middle income group categories and massive global efforts to identify people in the poorest regions where the challenges are the greatest is required before we find patients who can be offered this strategy of treat-all. Commitments by governments of these countries may have been made, but the actual implementation on the ground level is pretty poor. Now, coming to this important question of cost to treat-all, we have cost-effectiveness study for the treat-all strategy in the high-income groups. Data from the US, Saudi Arabia and Korea have shown that apparently it is cost-effective to treat chronic hepatitis B in these countries, but the cost of the incremental cost-effectiveness ratio per disability adjusted life year that you have averted is as high as about $41,700 in the US, which is cost-effective because the threshold here is higher. This cost-effectiveness threshold basically means 0.5 times the per capita GDP of this country. Even in a country like the UK, cost-effectiveness threshold is not met and the only study which I'll come to in a minute from Africa, from the part of the world which really needs this treat-all strategy. Although the cost of treatment and the ICR per daily averted is relatively low, it is way above the cost-effectiveness threshold and cannot really be considered in this country. So, to look at these data from the Gambia, a modeled cohort of 5,000 young adults modeled according to the treat-B strategy in which only antigen and ALT testing was done and the treat-all strategy in which surface antigen and DNA testing was followed as well as the standard easel and WHO criteria was carried out. And this shows you in cost in thousands of dollars of this strategy for a five-year period and the blue cost is the cost of the drug, the cost of the lab tests and hospital admissions. And what do we find? In the treat-all strategy in Gambia, which is the most effective in terms of the dailies averted, the five-year budget is in this range per annum. For the treat-B strategy, the efficacy is lower, but it is more cost-effective. Yet, this is above the cost-effectiveness threshold for that country. In fact, for willingness-to-pay threshold for Gambia, the cost per daily averted per life year saved is as high as $72,000. And for every year of life saved, it adds to the tune of $110,000 according to this study. Now, these calculations need to be redone for different parts of the world. For example, for South Asia and India, where the cost of per annum treatment of drug is probably going to be less than $100 and not in terms of hundreds of thousands of dollars, the equation is going to be different and it is appropriate to do it differently for different areas depending on the costs in that region. Finally, the risk of emergence of drug resistance. It has been well said that we have only a few drugs available. None are in the pipeline, and we would be wise to use the available drugs cautiously and to avoid the emergence of drug resistance. The usually challenging problem of ensuring high or complete compliance in asymptomatic patients remains, and it remains in parts of the world where facilities and the infrastructure to ensure this compliance rate is rather weak. Stop-start treatment would even allow for drug resistance to emerge in these high genetic barrier drugs. And in fact, a meta-analysis which suggested that up to 75% compliance was ensured in this study of several different parts of the world over a period of five years probably is going to result in even lower compliance rates when our threshold of treatment crosses this five years becomes more prolonged. And already there are reports of emergence of resistance in the TAF and TDF group in case reports and small series, particularly in the HIV co-infected patients. So this is not a threat that can be looked at more casually. We also have this call of action. The WHO also seems to agree with the limitations that have been pointed out and are recapped in this slide. So in conclusion, while there are clear-cut benefits for treating all in terms of reducing the risk of progression of disease, reducing horizontal transmission, reducing costs involved with monitoring at various stages in the course of natural history of hepatitis B virus disease, and we can treat these patients early with the effective drugs that we do have, the major cons or challenges remain, number one, finding all the cases who need this treatment for all strategy, developing an affordable strategy which is feasible in low and middle income group countries based on local calculations of costs in these regions, and ensuring that we can, before we venture to treat all, ensure linkage and retention of people who are offered treatment, compliance with medications in this community, and see how we can think of monitoring drug resistance. So the pros and cons are quite daunting as of now. I'd like to thank my senior colleague, Dr. Anil Anand, for helping the slides and his inputs in this discussion, and I'd like to thank you all in the audience who have had time and patience to listen to this presentation. Thank you very much. Thank you, Dr. Satterthwaite, for that very comprehensive look at the benefits of treating hepatitis B infection. We're going to move quickly to our next speaker. Dr. Nora Turot is going to speak on hepatitis C virus elimination, feasibility, progress, and economic evaluation. So thank you, Patricia, for that introduction, and I'm really excited to be part of this inaugural AASLD and NAWSL webinar, so thanks to the organizers. I'm going to quickly take you through a brief update on where we are with HCV elimination. And as already has been highlighted, the WHO set forward an ambitious goal to eliminate both hepatitis B and C. I'm going to focus here on hepatitis C, and to do so by 2030. They set forth the original goals in 2016, and you can see the goal then was to reduce In 2021, they updated those goals to include actual mortality estimates, so now the goals in terms of HCV are to reduce the incidence to less than or equal to 5 per 100,000 population and to reduce mortality to less than or equal to 2 per 100,000. There's also programmatic goals, and a lot of what I'm going to talk about today is related to that. individuals who are infected with hepatitis C, and ensuring that 80% of those diagnosed get treated. And because we recognize that we do not have a vaccine here to help us in terms of prevention, that much is needed in terms of reducing risk of transmission, so prevention is important, and you can see that there's programmatic goals, and those include identifying 90% of individuals who are infected with hepatitis C and ensuring that 80% of those diagnosed get treated. And you can see that there's prevention goals as well, 0% unsafe injections by 2030, 100% blood safety, and 30 having a distribution of syringes and needles, 300 per person who inject drugs per year. Now, very recently, there was a kind of recap on how we're doing with our global hepatitis response in terms of the elimination. This is the data for hepatitis C, shown on the left, is that it's still estimated that nearly 58 million individuals are infected with, are affected by hepatitis C. That actually is down in terms of where we were at 2016. These are data from 2019. But you can see there's still major gaps. 26% of those that are infected have been diagnosed, so a huge gap in terms of infected versus diagnosed, and of those that have been diagnosed, only 16% have been treated. So we still have a long way to go in terms of meeting our goals for the point of view of diagnosis and treatment. And shown on the right is that there's a lot of geographic differences. And you'll see the leader in terms of treatment initiation is the East Mediterranean region, where over 50% of the patients now have received treatment. That is largely driven by the very effective elimination program in Egypt. You can see that in areas where we are both living and practicing, that we are really much farther behind. Southeast Asia, it's estimated 5.4% have received treatment. In the Americas, 13.8. And one of the major challenges we've come to understand over the last decade is that we're still have this new infections that are really contributing to disease burden. It was estimated in 2019 that 1.5 million new infections occurred, and that's true for Hep B as well. In many countries, including the US, the new infections are actually outpacing the rate of treatment. And so, for example, in the United States, from 2007 to 2019, we had 916,000 new infections and 1.3 million who were cured. And in 2002, we for the first time have had an increase in our prevalence because the new infections are actually outpacing treatment. So this is a real continuing challenge and points towards both thinking about treatment, but also harm reduction and prevention of transmission as important goals. So what I'm going to touch on in terms of how do we get to those 2030 goals, I'm going to touch on these six areas and where we need to go in order to be able to make progress over the next six years. Those include increasing awareness, this focus on decentralized care and integrating care with other health care needs, increasing capacity to test and treat, and of course, simplifying and providing access to diagnostics and treatment. So we led off with viral hepatitis, World Hepatitis Day, having recently been celebrated. And I wanted to just call your attention to the WHO, which always puts out very nice, I think, sort of themes. On the left in 2013, 2023, their theme was one liver, one life. This year's theme was really it's time for action is the theme. And they put out a very nice module around how prevention is really very, very important here. But the focus of the World Hepatitis Day is always about bringing greater public awareness to viral hepatitis. And the theme that really has been focused on is this test, treat, vaccinate as it relates to hepatitis B. So if we're going to increase awareness, really, what are the barriers? And I think one of the major barriers, it remains stigma, both for hepatitis B and C, I'm going to refer to C. And what are the strategies we might think about in terms of trying to reduce stigma? Well, one is really to engage community-based organizations, civil society organizations to raise awareness, to make this something that's just part of liver health, use media campaigns, social media as a means of really normalizing the idea that we should evaluate every individual to see if they have evidence of viral hepatitis. There's a call for increased testing opportunities where individuals can self-test, can test in pharmacies. And this is particularly important in smaller communities or where there's fewer health facilities where patients, persons who may be infected want to remain anonymous, at least until they're diagnosed. There's important need to educate those that are on the front lines in terms of offering treatment so that they can kind of de-stigmatize the presence of infection and educate those who are stepping forward for treatment. And then increasingly, and I'll get to this theme very frequently during my talk, is to bundle health care services so that we're not just calling out hepatitis C as something we're testing for, but doing it as part of a bundle of health care services that might be related to viral hepatitis, STDs, mental health, and overall liver health. I want to focus on really how to kind of move towards this integration and new models of care. And I wanted to highlight one that was done in Delhi and to highlight that this co-localization of care is highly effective. So in this study, they looked at three different models of how to do screening in order to link individuals to getting confirmatory testing and onward to treatment. Model one was where they had hospitals that offered it sort of in one site where they could get the screening, get the butt connection for the confirmatory testing and treating it all in one place. Model two was where they were offered screening, but then they were referred to a linked hospital and model three was around screening camps that did the same thing, screen, but then had to refer them or link them to other hospitals for treatment. And as you can see from this analysis in which the overall number screened was really quite extraordinary, 37,000 individuals were screened across these different models. But what you can see is model one, which is where they co-localized that care, was highly successful in terms of both getting testing done, but then really completing the cascade of care for these patients. So really one excellent example of how co-localization of care yields best results. The WHO has really focused more recently on, and so too are all the guidelines, nationally on simplification. This idea of trying to do more and more test and treat, trying to co-localize that to one provider. Part of instituting that kind of care is the ability to have, in terms of screening, pointed care testing so that you can really in the moment make the diagnosis of hepatitis C. And if you don't have pointed care testing to using reflex testing. So when you test somebody for antibody that there's already a sample collected to do the HCV RNA testing. So again, saves a step so that patients don't have to return to do confirmatory testing. And then increasingly in the mode of pointed care testing, use of hepatitis C for antigen testing as an alternative to HCV RNA is being widely discussed. And then, of course, we want to stage disease because we know that's going to influence what we do with those individuals after cure. And here non-invasive tests, you know, liver biopsy no longer, of course, considered, but really using something very simple such as FIMFOR to do so. And then in terms of treatment, it's a treat all. And to do so using very simplified treatment algorithms with minimal monitoring. And of course, part of that is getting access to low cost DAAs. So I just want to highlight a few countries or programs in which, again, this kind of co-localization, but having access to point-of-care testing and the ability to initiate treatment really can enhance, again, the likelihood of individuals who are being diagnosed actually completing the cascade of care to cure. And what you can see here in this study from Myanmar, where they had two community clinics, one of them serving persons who use drugs, another in chronic liver disease population. And what they did in this study is they offered on-site rapid point-of-care testing, and then general practitioners evaluated if the patient could start DAA therapy immediately or whether they had to see a specialist. And that was basically based on whether they had evidence of cirrhosis or not. And what you can see here is it really reduced the time from getting the diagnosis to starting treatment, three days via this model versus 20 days if they had to invoke or include a specialist. And you can also see, again, in the graphic, that there was really quite excellent completion of both initiation of DAA therapy, completion, and SVR. And this study also highlights that in terms of HTV treatment, we need to recognize that we have to meet patients where they are. If we're going to do a test and treat, we want to be doing it where the patients are. And who are the high-risk groups in terms of those that have high prevalence of hepatitis C? You're all very familiar with those. It would be persons who use drugs. There's a high proportion of incarcerated individuals, those that are unsheltered. Immigrants, and especially with really the large amount of migration that's now going on related to the conflicts in the world, that really that also is a kind of a new demographic. And then in some areas, rural communities, really away from centers is really an important group that doesn't have access and needs a sort of specialized test and treat approach. So shown on the right are the kinds of places where we're going to have to move to, to do a test and treat. So I have to move out of the specialized clinics and into these other settings in order to implement a test and treat. And if we're going to be expanding where testing and treatment is being done, we have to of course increase the capacity of frontline workers to be able to do this. We're specialists and we're very used to being in this space. But our job now becomes part of teams that are going to implement a test and treat model. And shown on this slide are various models that have been highly successful. Many of you are very familiar with Project ECHO, which is a hub and spoke model to support frontline workers in doing HCV care. There's online and remote specialist access that's been used in several countries very, very successfully. Again, I'll highlight that going to where the high prevalence settings are like OST clinics, for example, syringe exchange programs might be really where we want to focus. And then I think very interesting areas also where pharmacists are leading onsite treatment programs with a specialist as backup. So in all of these, a specialist like ourselves would partner with primary care physicians or other frontline workers to expand the number of individuals who are delivering this test and treat approach. Now, of course, there's a big difference across the world in terms of really access to the resources to be able to do elimination. And I wanted to just highlight that public private government partnerships have been highly valuable in advancing an HCV elimination agenda. This is the Clinton Health Access Initiative, in which they partnered with seven countries to really bring on and train and implement HCV testing and testing and treatment. A key aspect of what these partnerships offer and what the Clinton Health Access Initiative focuses on, and they do the help with pricing in terms of negotiation, both for diagnostics and for the DAAs, they focus on policy development, which is important. They try to work on fast tracking the quality assured generics. They try to strengthen service delivery. So they really it's a whole package. It's not just a matter of, you know, giving money, it's really building infrastructure and supporting these initiatives. But very key to any success is the governments have to be partners in the implementation program. And in many cases, these countries are leveraging their HIV infrastructure and financing to overlay HCV, because there certainly is. These are they have shared risk factors. So this is really high, highly effective. And then again, focusing on areas where there's very high prevalence as in doing micro elimination. So in persons who use drugs in those that are incarcerated. And you'll see on this list to the right that India was part of these initiatives. And I just wanted to kind of highlight the total success of that program and then the India experience. So when they published on their success with this initiative in in 2020, at that time, they had trained more than 59,000 health care workers to do test and treat, they'd screened more than 2 million, and then initiated 120,000 plus on treatment. So just to give a sense of how these can be very powerful tools. And in terms of India, the Punjab HCV elimination program, I think is really showing how it can be done and how effective these kinds of partnerships can be. And it emphasizes several things that I've already highlighted in my talk. So this was a partnership, they had strong commitment from the government to execute this expansion of HCV care. They developed a statewide program where they had rapid scale up and then decentralization, again, of these HCV services and shown in this figure is how they started in 2016, where they were focused on the district hospitals and the government medical colleges. And then over time, they've expanded to those areas where there are high prevalence, those that are in prisons, those are receiving antiretroviral therapy, those that are in orbit substitution treatment programs. So where the we know high prevalence is and very successfully expanded their reach with respect to accessing patients who are affected by hepatitis C. And this program has been highly successful. So these are the results that were published in 2030. But what you can see here in terms of the number of individuals both identified, 71% of those identified started treatment, 81% of those on treatment completed it, and they've got SVR data on 62%, with a very high rate of SVR. So all of this is just to say that when that was that support, both at the kind of national level, as well as building the infrastructure and capacity in a state that you can make a real difference. And they emphasize in their publication, the importance of being able to monitor their progress, to be able to make ongoing adjustments to how they're going to develop it and continue to refine it over time. And then I was asked to talk on sort of the finances. And I'm just going to say, really, the economic argument has been made repeatedly, I'm going to show you just one study, this one's actually from the US. But it's where the veterans, which is kind of a health system unto its own, it's a national system. And they did a cost effectiveness analysis among a cohort of 140,000 plus patients. What they showed is using a lifetime horizon, that this the treating every patient with hepatitis C yield the cost savings of seven to 9 billion in this system, if you treated versus you if you didn't treat, and that those cost savings were very rapid, meaning within five years of instituting that program, they could see cost savings that shown in the figure on the right, and then shown on the left is the really impact in terms of lives saved. So you can see significant reductions when you do a treat all approach in terms of cirrhosis, liver cancer, liver related complications. Alright, so to conclude, where we are and where we're going, I think what I've tried to emphasize is the importance of strengthening prevention, and that's largely an HCV around our harm reduction. We need adaptable screening programs that really look at who are we trying to reach and adapt to those, we need a changing accessible diagnostic service delivery, including point of care testing. There has to be an openness to very simplified treatment approaches, flexibility and monitoring and follow up, building on pandemic pandemic gain. So during the pandemic, there was a lot of expansion around workforce service delivery and innovation, we should not lose that. And then the emphasis on really knowing how you're doing is important. So having data and reporting systems that are implemented concurrent with the test and treat models. And with that, I'll close. Thanks so much. Thank you, Nora. That was a great talk. I think you've summarized every aspect of HCV elimination. And now we'll move on to a... So with this, may I... First, I think we'll go to, we have very little time, so we'll go to the question box. We have a question by Mukram Jamat Ali. And he said there are studies which show that most of HBV DNA integration happens in immune tolerant phase. If we treat patients in IT phase, then that will decrease HBV DNA and also result in the integration. So treating these patients will decrease the risk of HCV eventually. Do we have any real world study on this? Vivek, I think... Yeah, I think the point made is valid that HBV integration during the immune tolerant phase does happen. But at least studies targeted to treat the immunotolerant patients and show that there's a reduction in HBV integration during this phase as a result of treatment. I'm not aware that these are published, maybe some of the other panelists might enlighten. Basically, because systematic treatment of the immune tolerant population has not been the rule. It has only recently, some subsets of immune tolerant patients have been offered treatment on the basis of what we discussed earlier. But for this particular target, studies and outcomes are not available to the best of my knowledge. I have a question for you, Vivek. And that is, now, the test which you mentioned to emerge, you know, the gray zone carriers and other things, they are not available in even in a country like India, it's not available in most parts. One, at the same time, today, the cost of treatment has gone down, the government of India is giving free antivirals to all patients. And that too, also at a low and even if patients have to buy where they have to go out and buy, it hardly costs around 100 or $120 per annum. Yes. Yeah, please go ahead. So the strategy that I said in the data that I showed was to elaborate the point that even in what was earlier considered categories who should not be offered treatment, there are six significant subsets who do need treatment and who do benefit from treatment. It was by not a recommendation that this practice of finding and categorizing patients should be followed. It is just to show that the evidence is now emerging, which supports the fact that a wider number of patients in the immune tolerant, larger number in the immune tolerant and the immune inactive clearance carrier state should be offered treatment. Now, what would be the best strategy? I think we have the expanded criteria from WHO, we have some of the guidelines from the Chinese, simply test for surface antigen and DNA. Point of care testing for DNA, HBV DNA is now being developed and being made available, which like I think Professor Terrell just told us that test and treat, you do not have multiple visits and revisits, which results in a dropout is the strategy that is being offered. And better than that is being that is you find those who already have sustained liver damage like F2 fibrosis and they are surface antigen positive without DNA, without the antigen and or serially ELT testing, they can be offered treatment. But again, the problem comes in that finding the fibrosis, either use the NITs, FibroScan is a test, which is becoming more widely but is still not sufficiently widely available to be resorted to regularly on this basis. So, these limitations do remain and the NITs might be a way forward. So, the paradox is that the cost of treatment is less. But I think the challenges I addressed at the latter part of my talk are more important. You just do not know who to offer this to. If there are going to be something like 30 million patients in India, who are these 30 million? We know barely about hundreds of thousands of patients only less than a million have been diagnosed. How do we go about finding these patients, that challenge has to be addressed. Once you have found them, they are going to be asymptomatic who have no interest or being labeled as a person, you know, the stigma associated with it and complying with therapy. So, how do you make them take treatment and eventually, although the cost may be cheaper in India, it is still not negligible. These are the issues. Yeah, thank you. That's a contentious issue. And I think we need much more time for that discussion. And Patricia, could you take the discussion forward? Sure, I know we don't have too much time left. But I actually wanted to hear from Dr. Price, one of our panelists about adapting some of the strategies that we heard discussed by Dr. Turow in multiple settings in terms of co-locating treatment and just to share her experience and how we might adapt that in various practice settings. Yeah, thank you. It's a great question. I really appreciated the presentation and seeing the successful models in India. I think the co-localizing treatment is really critical, especially here in the United States, where we have really decentralized cares, particularly among our most vulnerable populations and people who use drugs, who don't necessarily have regular access to sort of what we would consider traditional health care. So, really trying to find people and meet them where they are to diagnose and then offer treatment at the same site is going to be really important. There's a lot of people doing work to accomplish this in the United States. We're very siloed, right? So, the big challenge is trying to bridge the gaps and to communicate and to share our best practices with one another. We now, as many of you may be aware, have an FDA-approved point-of-care hepatitis C RNA test. So, that's very exciting. But that's just the first step, right, is diagnosing with a point-of-care test. And then the next step is going to be getting people started on treatment at the point of diagnosis. And I think that's our upcoming challenge. Well, I'm going to hand over the mic back to Dr. Juseha, who will take us out and give final parting comments. I think we still have two more minutes for discussion if you want to continue, because we'll finish at 8.30pm. But if there are no more questions in the chat box, or if you know any of the panelists want to make a comment, you can still go ahead before I give the concluding remarks. Dr. Rao, we haven't heard from you. Yes, please. I can see it. No, no, I'm a very simple and a naive person. We haven't agreed upon what is a normal ALT, right? All the three societies differ in their upper limits. And the upper limit of the normal is very confusing. The ULN itself is not being defined. Do we take 13 and then 19, for a male and then female, or irrespective less than 40? And then some upper limits are 50, some are 65, even in USA, some are 50 and then 65. So anyway, that's a different thing, you know, it's a different ballgame altogether. I just wanted to ask the USA panelists one small question. For preventing the post-transfusion hep B, do you do in HbsAZ negative samples, IDNAT or a mini pool NAT or only anti-HbAZ? What is usual practice in the blood banks there? Because we do only HbsAZ, anti-HbAZ, we have to discard many if it is positive, because of the high prevalence. Right. So in the blood banks, they use NAT testing, and they do mini pooled, and then I think the pools are then tested, but they definitely use NAT testing, not relying on surface antigen or antibodies alone. We have cost issues, you know, that's the reason why. Okay. Yeah, I think in India also a lot of blood banks use NAT actually. In my place, we are supposed to be a part of India, the blood banks are using NAT. Yeah, that's right. Most of the corporate private sectors, they are using regular almost. Okay, I think it is time now to close. We are at 8.30. Thank you very much. I must thank first, the ASLD for, you know, giving us this opportunity. And this all started last year for Dr. Nora being there as the president. And then we had a, you know, a joint session last year also, in our annual meeting. And this year also, we have planned two more symposiums, annual meeting coming up next month. But thank you very much, ASLD, as I said, and two very important members of the Education Committee, who actually helped us in planning everything, Dr. Manal, Abdul Malik, and Dr. Bilal, you know, they really helped us in this. And the other members of ASLD who were helping us, like Vander and Sally for all this. And then I go to the on to thank our moderators, Dr. SP Singh, President Inazil and Dr. Patricia Johns, thank you very much for moderating this whole session. And both the speakers, Dr. Nora Terault and Dr. Vivek Saraswat for wonderful talks and taking us through, you know, the treat-all strategy in Hep B and also, you know, the elimination program in hepatitis C. My thanks are also to both the panelists, Dr. Piyan Rao and Dr. Jennifer, for joining us on this weekday evening for us and morning for you meeting. I know this is just a beginning. We've had this wonderful start of, you know, this joint kind of symposium on hepatitis D and more days to come on liver diseases throughout the year, and more webinars, and we'll see more of you together. And thank you very much. And I must thank, you know, all the delegates for joining us, you know, again on a working day in the evening. We had more than 150 registrations, though all could not join us. But then I must tell you that those who have missed it, this, you know, a recorded lecture, recording, sorry, webinar would be available both on Inazil YouTube channel and on the ASLB website. So thank you very much and good night from here and goodbye. Bye-bye.

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