All right. Good morning. We're going to go ahead and get started. So, on behalf of the Hepatitis B-Cig, I'm thrilled to invite you to this morning's session entitled, Hepatitis B, Optimizing Diagnosis and Management to Achieve Elimination. I'm Joe Lim from Yale University. I'm joined by my co-moderator, Dr. Bob Gish. We have an outstanding panel of speakers today that will be addressing key issues in Hepatitis B management, including clinical care, novel biomarkers, and novel therapy. So, I'd like to go ahead and introduce our first speaker today. Dr. Minnie Nguyen from Stanford University will be addressing the topic, Optimizing Hepatitis B Screening and the Cascade of Care. Dr. Nguyen. Good morning. First, I would like to thank the organizers of this meeting for inviting me. And my topic of the lecture today is Optimizing HPV Screening and Care Cascade. So, first, I would like to review briefly the disease burden of Hepatitis B, and then we will review the current care gaps, recent progress, and what other things we could do. So, about 300 million people are living with Hepatitis B globally, and unfortunately, many of the liver complications occur very around the time of the first HPV diagnosis, as shown by the Ontario, Canada provincial data reported from Dr. Jolenfeld and Harry Jensen's group here. And the other thing is that there didn't seem to be significant major changes over the years with this high percentage of pericomplication diagnosis of Hepatitis B. So, we see a pretty high death rate related to both cirrhosis and HCC, as shown in these two maps here, and you could see that the hotspots of the problems here are in the Africa and the Western Pacific regions. Let us also not forget the non-physical burden of Hepatitis B, the stigma and discrimination. And there's complex internal and external factors to this, and it's ranged from the individual person's emotional health to just outright social discriminations by other people at work and with employment, as well as educational opportunities. So, of the 290 or so estimated people with Hepatitis B, only about 10% have been diagnosed according to this estimate, and only 1.6% have received treatment. And again, as a size of the dots, you can see here the really big reservoir in the Western Pacific and the Africa region. Data from the U.S. So, this is from North America, from the U.S., from a cohort of insure, private insure people in the U.S. So, in the U.S., we think that people with private insurance are generally the better insurance, the better coverage. And out of a cohort of 153 million people in this database throughout the U.S., we estimated that there's about 500,000 people with Hepatitis B, and of these, only 18% have been diagnosed. So, we have more than 400,000 people, as of this data in 2014 here, have not been diagnosed yet. And this is fairly consistent with data from our enhanced epidemiology survey of only about 15% of the people confirmed to have Hepatitis B by blood test results are aware that they have a liver disease when we ask them if they are aware of it or not. And even more disturbing is that the people with very advanced disease, with cirrhosis and HCC, for cirrhosis, only about a third have evidence that they received at least one prescription of antiviral medication during the entire study follow-up, and only about half of HCC patients. In regards to HPV screening and diagnosis, we have had some progresses in the recent years. So, about five years ago, we still had a very long laundry list of risk-based screening recommendation criteria, and then we had some data suggesting that maybe we can screen people with a very simple risk-based model, which is demographics, sex and age, and birthplace for U.S. patients. And then last year, we had data suggesting that universal screening for adults in the U.S. would be cost-effective. So, as of March this year, we have universal screening recommended by the U.S. CDC. So, this is a major milestone for us, and in addition to that, the CDC also expanded the testing panel to include core total antibody, and this is important for checking and prevention of HPV reactivation, especially nowadays with so much biologic use in non-oncologic setting as well. And there's also expanded risk base, and with that, anyone who wants to be tested for hepatitis B can be tested, and they don't have to disclose or have any questions that may be stigmatizing. Now, of the people who have been lucky enough, quote-unquote, to be diagnosed, rather than undiagnosed HPV, the patients who actually underwent the basic recommended testing, like ALT, DNA, e-antigen, are very low in the first 12 months of the index hepatitis B diagnosis, especially e-antigen, as shown here. And even though the risk is higher, if the patient saw a GI or ID specialist, it's still quite low, and even in people with cirrhosis, the rate is still low, and it's even worse for long-term monitoring of these tests every 12 months, and you could see that only about 50, 60 percent of the patients had HCC surveillance. So, using another claims database with lab data in the U.S. So, this is the Optum database, and it includes about 60 million U.S. people. So, of that, we identified 12,000 patients with chronic hepatitis B and blood test results, and if we define complete evaluation as ALT, DNA, and e-antigen, only about half had evidence of having at least one set of these tests in the first 12 months, and if we lax it a little bit to exclude to or drop the e-antigen, then about 72 percent, and of this cohort, we determined which one were treatment-eligible by ESL or ASLD criteria, and only about 60 percent of the patients who met treatment criteria by either the ASLD or ESL here initiated treatment. So, we have problem with screening, diagnosis, evaluation, HCC surveillance, monitoring, as well as treatment initiation. And this, the data I just showed you in the last few slides, are from people with commercial private insurance. So, even though financial concerns is still a concern because there's still co-pay, et cetera, for these patients, but it is unlikely to be the major overwhelming reasons, and that is consistent with an earlier study that we did with reviewing the charts and all the physician notes in the San Francisco Bay Area. Now, moving to the people with very advanced disease, HCC. So, currently, there's no limited specific guidance criteria for HCC right now. For Hep B, we have for cirrhosis, if they have decompensated cirrhosis, any level of viremia, they should be treated. But for Hepatitis B, that is less clear. But we have data here from university centers or tertiary care centers from the U.S., Korea, and Taiwan, showing that whether the patient had cirrhosis or not, there was significant improvement in survival for the patient who received antiviral. But for cirrhotic people, only 50 percent had antiviral and non-cirrhotic, only 40 percent. So, it's really suboptimal. And more recently, we focused on a very selected group of people who had curative resection. So, this is very selected people, and these are all tertiary care centers in several places here. And we found that both overall and recurrence-free survival improved with antiviral treatment, especially if the treatment was started early around HCC diagnosis or before, and less so if it was started too much later. But the treatment rates here is far from 100 percent, as you could see on the last three bar graphs. And somehow, it didn't increase with time, but seemed to decrease with time, and we could not really explain this with the data that we have. We wonder if there's some warehousing effect early on, because both Entacavir and Tenofovir came out between 2005 and 2010. So, there may be some of that at that time. Now, moving back to U.S. data. So, the data that I just showed you for HCC are from tertiary care centers. So, this is real-world data from the U.S. So, most of the patients in here are community patients, and academic centers would be included in here, too, but probably the minority. In this, patients can get no treatment or any treatment for HCC, and we found that overall, the overall survival was significantly improved with antiviral treatment. Even though there are some disparities in treatment rate among the different racial, ethnic groups, or by cirrhosis, et cetera, the overall treatment rate is only 36 percent. So, it is lower than what we saw from academic center, which is, you know, understandable. And I also wanted to show this to show you that the data, whatever data that we see from clinical studies, clinical centers, are likely to be an overestimate of what the real world is in the community. So, this is the summary data from the WHO group of 32 studies to determine the treatment eligibility rates for hepatitis B patients, and the study found, you know, as expected, great heterogeneity among the studies because of the different guidelines used, the different study setting, different communities, regions, et cetera. So, the proposed actions that were recommended is that in the future, we need to really stratify the data by patient, region, geographic factors, et cetera. And importantly, implementation of simplified management algorithm. And this is what we kind of have, and this is only four of the maybe more known regional national treatment guidelines. So, I think that all the treatment guidelines are based on pretty similar general principles that we treat high-risk patients, and most people would agree that they would be the immune-active or high-risk immune-tolerant older patients or people with family history. However, it's hard. You can see here that not everybody agree on what is the cutoff for ALT or DNA to define these high-risk patients, and it makes it difficult for practitioners, providers to follow. Now, to add to that, about 40 percent of hepatitis B patients do not fit into any of these well-characterized four clinical phases of hepatitis B. So, in this study, we looked at about 3,300 patients from the U.S. and Taiwan, and our median follow was 12 years, so pretty long, and about half of these indeterminate patients remain indeterminate at 10 years follow-up later. But what we saw is that the HCC risk was clearly higher in indeterminate patients. The first graph show you that these are the data for indeterminate patients at baseline, regardless of where they transition to later. The second graph show you the data for indeterminate patients who remain indeterminate through our follow-up and compare with people who remain inactive through our follow-up, because you all know that hepatitis B patients can transition to different phases. More recently, also using the Real B Consortium, we put together a cohort and balanced baseline characteristics of these patients and found that the 10-year HCC risk was significantly higher, 15 percent in untreated group and 4 percent in the treated group. So, in summary, the vast majority of people with chronic hepatitis B globally as well as in the U.S. have not been diagnosed yet, but we have made a major milestone in that now we have one-time adult universal HPV screening recommended by our CDC as of March this year. But unfortunately, of the people who are diagnosed, a substantial percentage of them do not undergo adequate evaluation for treatment, enter regular lab monitoring or HCC surveillance, and those who meet treatment criteria do not initiate treatment. And the people who have indeterminate phenotype now need more directions on what to do with them as at least a subset of them or most of them may benefit from antiviral treatment, and the same for HCC patients. So, universal adult HPV screening needs to be implemented now that we have made this milestone, so lots of work for many people from physicians, care providers, to patient advocacy group, community groups, and I believe that simpler treatment guidelines and treatment expansion for indeterminate patients and HCC patients should be considered. I would like to acknowledge and thank my wonderful group, both past and current, and the many colleagues I have had the privilege to work with over the years. Thank you for your attention. Thank you. Thank you, Dr. Nguyen, for our fantastic synthesis of the enduring deficits in the care cascade. We're now going to be transitioning to two talks to address how we determine which patients require antiretroviral therapy. At this time, I'll go ahead and introduce our next speaker, Dr. Nora Turow from the University of Southern California and SSLD president. She'll be discussing the topic, how to simplify treatment criteria under the current HPV guidelines. So, first of all, thank you for the invitation, and it's terrific to see such a packed room, and I know they're in the overflow room, so congratulations on organizing an amazing session. I mean, I love this topic because it actually narrows it to what I usually talk about when I talk about sort of the challenges with the guidelines. Here I'm going to really see taking the current AASLD guidelines, and I'm going to be specific here, and how to potentially simplify them based on data that's emerged. So, here are my disclosures, and Mindy did a beautiful job of really laying the groundwork here. So, our current ASLD guidelines really requires you to have three elements to be making treatment decisions, four if you add the fibrosis to HPV. You need to know e-antigen status, HPV DNA level, ALT, and you do need to know whether they have cirrhosis or not. And as was highlighted, our focus has been, and the evidence supports, the need to treat individuals who are at risk for progressive disease. Those are typically those that have immune-active chronic hepatitis B, and then we also put into that group individuals with advanced fibrosis or cirrhosis, and I think part of what's included in the guidance is somebody who has a family history of cancer. I think the very interesting sort of statements made by Mindy about thinking about the cancer group in treatment has not been addressed in the guidelines, and I think that is an area that does need attention for the future. We also in the guidelines have some recommendations around special populations, which I'm not going to go into detail about, those with HIV, those that are embarking upon immune-modulatory therapy, the setting of pregnancy, and in transplantation. I'm going to focus on chronic hepatitis B without those sort of special aspects. So you've heard that there is some complexity that might be viewed in these guidelines, and I think the complexity comes from several different aspects. One is chronic hep B itself is a very dynamic disease, so a decision you make today is not necessarily the right decision for the patient six months later, you know, three months later, three years, three decades. It's going to change. So what that brings in this aspect of monitoring, and I think was highlighted very nicely in the prior talk, is that monitoring is itself something that we don't do that well. And if you're not monitoring well, then you miss the opportunity to potentially intervene at a time when it's appropriate, and you need adherent patients, you need providers that are on board with that and know how to do the monitoring, et cetera. So the monitoring in the absence of somebody on treatment also adds complexity. And then I think the one that's received the kind of greatest play with respect to the guidelines is the challenge in making decisions who fall into the gray zone, and that's where I'll spend most of my time. And then finally, also highlighted by Mindy very nicely, and I acknowledge it as a challenge, is that if you look across guidances, there is differences with respect to what thresholds we use for ALT levels and HPV DNA levels, even to define the groups that we think should be considered for treatment. So that indeed, again, adds to complexity. I think a question where the data is maybe not as strong is, does that complexity per se lead to undertreatment? And does that undertreatment then lead to patient outcomes that are worse? And I think we would assume it does, but I would say that the data around what exactly is leading to undertreatment still needs more work. So if I was going to consider simplifying current guidelines, I think the potential ways to do it is, one is to try to reduce the proportion of patients that fall into the gray zone. The second is, and I'm going to spend some time on this, is really being clearer, I think, than our current guidance about who's an immune-tolerant patient. And then finally, I think we might think about our treatment algorithms where we prioritize HPV DNA level over ALT level, and the reason for that is that we now know that with the widespread prevalence of conditions such as MASLD, that ALTs are up for other reasons. So they become a less helpful marker, perhaps, in making treatment decisions. All right, so here's the current algorithm and the guidelines for somebody who's e-antigen positive. So the first thing I'm going to say up front is that I still think it's useful to consider e-antigen positive versus e-antigen negative. This is the current algorithm. What you can see is shown on the left is the patient who has an elevated HPV DNA level and has normal ALT. That's somebody who falls into the immune-tolerant phase, and we are not recommending treatment for that individual. And then on the far right is your immune-active patient who has an elevated ALT level, elevated HPV DNA level over 20,000, and we recommend treatment. But nicely shown on this slide is there are gray zone patients, and those are in the gray boxes, you know, individuals who don't quite meet those thresholds, and that is what sort of adds to this complexity in treatment decisions. So how common is e-antigen positive gray zone patients? It turns out they're not that common. We have a lot of gray zone patients, but they're mostly e-antigen negative. This is just one study. I could have picked others. They're all quite similar. But when you look at e-antigen positive patients, only 22% of all the gray zone patients are e-antigen positive, and the vast majority of those are individuals who have a normal ALT, but their HPV DNA level is less than six log. So how can we potentially kind of clarify this? Well, I think we should start to pay attention to age. We have some mention of this in the guidance, but I think we should be stronger in terms of using age as a factor in e-antigen positive patients. I think shown nicely here is also this relationship between viral load and your risk for clinical outcomes. What's shown in the figure on the left and then with the associated hazard ratios on the right is that it's really individuals who have HPV DNA levels that are under seven logs that are at risk for the clinically relevant events. If you have an HPV DNA level over seven logs, which is really the range in which immune tolerance should be, if they're immune tolerant, those individuals do not have an increased rate of events. And then there's studies that say, you know, pay attention to other things. This is using FIB4. This looked at FIB4 in individuals that had been defined as being in the immune tolerant phase. Turns out if your FIB4 is elevated even a little bit, that that actually is associated with an increased rate of events. So maybe we should be thinking about bringing in some marker around fibrosis for these individuals when we are in this e-antigen positive phase. And I think that, you know, this study gained a lot of attention. It was a study in which they showed that untreated immune tolerant patients had a higher risk of cancer than treated immune active patients. And it's shown in the figure. But I'm going to just call your attention to the fact that the immune tolerant group here was not only immune tolerant patients. The mean age was 38 years. Twenty six percent of them had an HPV DNA level that was four to six log. If you looked at the platelet distribution, one quarter of them had a platelet count under 167,000. And there were no measures of fibrosis used here. So when you put sort of apples and oranges together and then call them immune tolerant, you're going to see outcomes are going to differ. So how do I think we can simplify e-antigen positives by doing a better job of defining immune tolerant patients? I think the true immune tolerant patients are those that have viral loads over seven log. They're under the age of 40 and their FIB4s are very low. And I would say that if we really do that, a lot of that gray zone e-antigen positive patient will disappear. Now, I will highlight that there has been a lot of talk about, you know, treating patients with high viral loads primarily as a treatment of prevention of transmission approach. We did not address this in the guidelines. I acknowledge that that is something that was omitted and that is something that has to be individualized in terms of decision making. But if we're doing it based on clinically relevant outcomes, I think this is one approach. So the way that I would see a simplified guidelines look would be in the e-antigen positive patients, we'd pay first attention to their age. If they're over the age of 40 and they have viremia over 20,000, treat them. Just treat them because they're older. And they're either transitioning or they're going to transition into the immune active phase anyway. But those under the age of 40, then I think you really want to define that immune tolerant group as I just described. And if they fall into that group, no treatment. If they don't, treat. So that's one way to simplify. So the next I want to talk about is e-antigen negative, which is actually a much, I think, more challenging group. So, again, this is our AASLD guidance. Again, you can see that if you have an individual to e-antigen negative, if their ALT level is below the upper limits of normal and their HPV DNA level is less than 2,000, that's somebody who has inactive chronic hepatitis B, we are not recommending treatment. On the right side, you'll see the individual who has immune active e-antigen negative disease. Their ALT is elevated. Their HPV DNA level is greater than 2,000. You would treat those. But you also see in this figure that there's a lot more gray boxes. There's a lot more gray zone in this where either the ALT level or the HPV DNA level don't meet those thresholds. And this, I think, has really contributed to the greatest challenge with respect to making treatment decisions. And, indeed, it's this group of patients that is actually the most prevalent gray zone patient. Seventy-five percent of the gray zone patients are e-antigen negative. Of those that are in this gray zone, two-thirds of them have a low viral load, under 2,000, but an elevated ALT, making me wonder if they really have ALT elevation related to their hepatitis B. And I think this is highlighted, and I think it's a really important point, is that that indeterminate zone persists. So I think this is one of the things that when we wrote the guidelines initially, we said, if they're in the indeterminate phase, just follow them. They're going to declare themselves. And it turns out they don't. That 75 percent of them remain indeterminate when you follow them even out to five years. So the strategy of monitoring and they're going to declare themselves leaves these patients in that indeterminate zone for too long, I think. And then the other thing I just will highlight about indeterminate B is that it's really important that when we look at indeterminate B, that you understand when we – because HCC is kind of the big concern, is that we realize we have co-factors that are influencing HCC risk. So we need to pay attention to those when we're looking at the role of hep B versus other things. This is just one example where they show that indeterminate patients with hepatitis B in that indeterminate or gray zone, that they had high rates of cancer. But in their multivariate analysis, when they looked at what are the predictors of cancer, it wasn't the HPV DNA level. It was the presence of diabetes. It was their age. It's telling us that these are co-factors that are probably influencing risk. And then you've already seen this study that was presented in which the gray zone patients in this large real-world cohort, of which 21 percent, by the way, are e-antigen positive, but mostly e-antigen negative. You can see their viral load is around four logs. And they excluded patients that have advanced fibrosis. But when they follow these individuals, they were treated or untreated as per the decision of the physician. You can see that the untreated patients had a lower rate of cancer when they looked at the 10-year mark compared to those that had been untreated. And you can see the hazard ratio there suggests there's about a 70 percent risk reduction. But, you know, it's all about this, what happens over those 10 years, and that was highlighted in the prior data. I thought it was very interesting that when this was published, there was a letter to the editor that came out with it saying that it's interesting that the risk doesn't increase until after five years. And they prompted these individuals writing the editorial to say, is it really related to the indeterminate phase, or is it the lack of monitoring and the ability to intervene at an appropriate time that is the issue? And I will state that it's this monitoring that adds to the complexity, but we have to just at least acknowledge that that might be playing a role in these outcomes. And then my final bit of data I want to share with you before I go on to my simplified approach to this group of patients is one in which, again, looking at HPV DNA, I think when the ALT is becoming more complex for us to use as a marker of disease activity, perhaps we have to lean in more to HPV DNA. And here is a study that's looking at patients who are e-antigen negative, and it's just looking at their, again, their risk for clinically relevant outcomes based on HPV DNA level. And what you can see is really where the increase occurs is in those that have viral loads that are four logs or higher. All right, so how do I think about simplification of current guidelines in terms of e-antigen negative? I think first and foremost, I always consider other causes of ALT elevation, especially given the prevalence of MASLD in the population these days, because these things might need our attention just as much as the hepatitis B. The second thing is that I think in contrast to the prior guidelines where it was ALT was sort of the first line in the algorithm, and then you went to HPV DNA, I think we need to flip that and use HPV DNA as our primary driver of decision making. And then finally, I think age here matters as well. So my proposed simplification of the e-antigen negative would look something like this. We still have the ALT here, but you'll see that the HPV DNA level now that we're using, that this has not changed. If it's under 2,000 and the ALT level is normal, no treatment. And then on this side, hang on one second. That's the old. This is my new. So I was like, that's not my new. Okay, so this is the old. Here's the new. So the new is here. So take this picture. Okay, please, please. Okay, so for those that have an HPV DNA level under 2,000, don't treat. Remember to look for other causes of ALT elevation. If their HPV DNA level is over 2,000, treat. If they're in that middle zone, if they are older, if they have significant fibrosis, treat. Otherwise, don't treat. My simplification. So my final words, I'm going to just say what I always say is a guideline is just that. It's a guide. So we really want to try to empower physicians more to be flexible in their tailoring decisions to their individual patients. I do acknowledge that there's a need to harmonize the guidelines. I do see that that creates more difficulty in the field. So that's something that we should strive for in the future. For example, even defining a normal ALT, I think, is something that we need to do. And I think the HPV DNA thresholds even need to be reconsidered. I think many of us can't understand why we're using 2,000 and 20,000, where those numbers came from. And so, again, we might want to shift to using just log values of IU per ml of HPV DNA rather than these numbers going forward. But I was asked to just provide a simplification on what we have. Hopefully I've conveyed that to you. And with that, I'll thank you. Thank you, Dr. Turow, for an outstanding discussion about simplification. We're now going to talk about how we might broaden treatment criteria with ASLD. I'm pleased to introduce our next speaker, Dr. Harry Janssen from Erasmus Medical Center in Rotterdam, who will be discussing the topic, Expanding Treatment Criteria, Do We Need More Evidence or Not? Is it working? There we are. All right. Thanks so much, Dr. Kim, for the introduction. It's my task to take you with me to expanding HPV treatment criteria. Do we need more evidence or not? And there's definitely some overlap with the previous presentations, so I apologize for that. I'll focus mainly on the slides, as you've not seen. I want to give this talk not just from an American perspective, but also from a global perspective, where good monitoring is not always possible. A lot of patients do not always come to the hospital in time, et cetera. So I want to take a little bit of a broader perspective here. So this you have seen, obviously. This is the terminology and the treatment indications attached to that. And I must say, you probably would understand what's happening here. But the average gastroenterologist will have difficulty with this. Definitely the average general practitioner would not know at all what to do with this. So I think it would be good to simplify and move away from these phenotypes that we've been using over time. As already mentioned, if we were to expand our treatment criteria, there will be a huge number of patients being treated, and I don't know if that's what we want. Definitely if we would go to treating all S antigen positive patients, that would be an enormous increase. And I don't think actually we should do that. This one you have seen, no treatment criteria does not mean no risk. I think that's very important to show. This is the, I would say, Asian-American-European co-production under the guidance of Mindy, showing that over time, if you have an indeterminate phenotype, which is outside of the current treatment criteria, that you have a higher risk of getting liver cancer over time as compared to those patients who are truly inactive. Within the multivariate analysis, the indeterminate phase was an independent predictive factor, and the same study group published these data where, with treatment, you definitely can reduce the amount of HCC definitely with the caveats that Nora just mentioned. Another thing is that in a large series with HIV, HPV co-infected patients, there's definitely less HCC if these patients receive TDF-containing antiviral therapy in comparison to those who do not. So if you compare those groups, if you treat patients, even if they're not fully in the treatment criteria, you could reduce cancer most likely. So let's first, I want to touch based on immune-tolerant patients, then on the immune-inactive patients, and then I'll finish off with the indeterminate or the gray zone patients where I have just one or two slides upon. Does treatment work for immune-tolerant patients? And it's in this study, which is done by Henry Chun about 10 years ago, the results were kind of disappointing. These are patients being randomized between tenofovir versus Truvada, which is a combination of tenofovir and emtricitabine, patients being treated for four years. And after those four years, only half of the patients, a little bit more to three-quarters in the combination group, which in itself is actually interesting, had an undetectable HPV DNA. Most of the patients who did have a detectable HPV DNA were just above that level, so most patients that did have low HPV DNAs were just not at the level of undetectability. Even more disappointing, I would say, is the serological endpoints, which is an E-loss of around 5% and no S-loss. And the question is, does this mean that we shouldn't treat these patients? Because this is a short-term treatment if you look at the lifetime of a patient, and there are other studies that might give more benefit. This is another study done by Jordan, and we've done studies with pectin interferon in the past in immune-tolerant patients. And this is a combination of entecovir with a short lead in entecovir, and then a combination of entecovir and pectin interferon for a year, and then another year of post-treatment follow-up. And also here the S-loss is low, which you would expect, obviously, but there's very few patients who reach an undetectable level. So those are the negative studies, so to say. Again, in a lifetime, a short treatment is not doing the job, most likely. And there's also a lot of pros to be treated in immune-tolerant patients. First of all, there's HPV DNA integration, which primarily happens here, and it's shown on the right side in patients with a higher viral load. So there's two ways to get to liver cancer. One is the more conventional way, where there's inflammation, fibrogenesis, and over time cirrhosis and liver cancer. But the HPV DNA integration is a very important and profound pathway as well. As you know, 20% to 30% of our hepatitis B patients develop liver cancer in the absence of cirrhosis. So we have to take that into account that that's happening. And this study from Taiwan indeed shows that with antivirals, you reduce really the viral integrations in dysregulated genes. So this is done by Holden Su. What he did, he randomized patients, and they were treated for three years between tenofovir and placebo, biopsy at the beginning, a biopsy three years afterwards, and there was a clear difference in the number of integrins over time, as shown by all of these plots here. So that's important to realize. This study has been shown already by Nora, which does compare to a certain extent apples to oranges. I agree with that. It does show that indeed patients who are immune-tolerant have a worse outcome towards HCC than patients who are with immune-active disease and who are being treated. And definitely there are patients that move from the immune-tolerant to the immunoactive phase that at a certain time point happens. This study showed that early treatment with HCC in patients with higher viral load to normal ALT indeed reduces the HCC incidence over time. In red you see the untreated patients, and then on the left side there's a 5-8 log viral load, which is already pretty high, and on the right side it's very high, it's more than 8 log. And in both groups you do see that in the untreated patients the HCC incidence is actually higher than in those who are being treated. And what we should do or actually should have done 10 years ago was like a very large 10,000 patient study randomizing towards a nuke on one hand and placebo on the other hand in immune-tolerant patients and take HCC as an outcome because that would really solve our problem on whether we should treat these patients because I still think if we treat them long-term that patients will have a better outcome. So what are the pros and cons for treating immune-tolerant patients? The pro is that we will reduce HPV integration and the HCC risk most likely. IT patients will develop active disease later on anyway in the majority, so why do you want to wait until the house is on fire and not just treat right away before that happens? Reduce the rate of transmission. We'll move much more easily into a simplified treatment strategy. I would say more simplified even than the one that Nora has been showing. We'll reduce stigma of active disease as well. On the con, it's difficult to achieve in a response. Many patients will have an incomplete viral suppression initially. There's limited E and S loss. But what we really want to drive down is the viral load. Over time, that's the most important thing, and that is happening with a nuke. There's, at least in the short term, no or minimal liver disease progression, and in the long term, if you treat a lot of patients, there are adherence problems, particularly younger patients might stop treatment, which we don't want. I think it's most likely that particularly the patients who are transitioning from the immune-tolerant phase into the immune-active phase would be the best candidates to pursue. Let's move to the immune-control patients. I go back to the reveal data. The question really is, is 2,000 or 20,000 a good cutoff point? Here you see, if you look at on the left side the HCC risk and on the right side the cirrhosis risk, that it doesn't really stop at the level of 10,000. Even lower, you do see that there's an increased risk of both HCC and cirrhosis over time. So that 2,000 and 20,000 is totally arbitrary, basically, and the reason that we're using is that the older test, that was basically the cutoff of our older test. We're still stuck with those, I would say, very, very arbitrary cutoffs of treatment, yes or no. Another study showing that treating inactive carriers might be beneficial is this one, and we typically don't do that, obviously, because these patients have a relatively good prognosis. This is a study where a peck interferon and a defavir were given in patients with an ALT, which was normal, and an HPV DNA below 2,000. It enters a negative patient. If you look at treatment in the purple and observation in the red, the HPS antigen clearance was actually surprisingly high in this study, up to 40%, 45%. So, in fact, you could argue that these patients don't really need treatment. On the other hand, it's low-hanging fruit, and it's not just about the outcome. It's also about stigma. It's about keeping your job because your HPV DNA cured. Those things are important as well. So it's interesting to see, and definitely with the new drugs, we will enrich for these patients as well to achieve cure. So treating immune control patients, I would say I'm more hesitant than for patients who are in immune-tolerant phase, for sure. It appears effective, but there's limited evidence, and the challenge is to demonstrate improved prognosis, given the low short-term rates of clinical complications anyway. You have to keep in mind, though, that patients who are in immune control may well switch to other undetermined phenotypes in 50% to 20%, for instance, to the IA phase. And many patients are, well, we hope that they come twice a year to our clinic, or once a year, or three times a year, or whatever, but a lot of them don't. Particularly in resource-limited countries, that's not even possible. So if we really want to simplify, I think we have to make it very, very easy. The other point is that starting nucleoside analog might be like a prelude for new curative treatments which are underway. So lastly, this one, you've seen this slide already. This is on the indeterminate patients, and those are mainly patients with low viral load, as Nora said, below 2,000, but elevated ALTs. You have to exclude other liver disease and the other bigger group, are the moderately high viral loads, 2,000 to 6,000, but normally mildly elevated ALTs, so mostly E-negative patients. And you've seen that this is a substantial number, and that a lot of them remain in that category. If you treat these patients, you would definitely get some reduction of fibrosis. This is a study done by Holden Su, the TORCH study, published in the Lancet Infectious Diseases, which I actually quoted earlier in the study for the integrations. And if you look at the amount of fibrosis reduction on the left side, there's the ESHOC on the right side, there's the NODEL score. And with tenofovir treatment, you see less patients progressing in fibrosis than if you would give placebo. So, ladies and gentlemen, should we treat everyone with nucleoside analog and chronic hepatitis B? I think it's way too early for that, but I definitely think we should increase pushing for treatment to patients who are HPV DNA positive or all patients with an HPV DNA 2,000. The Chinese guidelines are just up to all patients above the age of 30 with detectable HPV DNA to be treated. And you see that over time, our thresholds are getting lower and lower. The rationale, I think, to expand treatment criteria is with generic drugs, likely it's more cost-effective than the current guidelines where you have to have costly visits and diagnostics. And it's actually cheaper to treat a lot of patients. Generic drugs are cheap, they're safe, there's no resistance. So we have a lot of experience with that. The benefits are hard to see in a cohort, but may be clear at the population level. You need a lot of patients to really show that you're doing well here. We would more easily simplify the treatment guidelines. There will be a transmission benefit. There will be destigmatization for sure. And treatment might not be lifelong because we're doing efforts to reach HPV cure, and we have to take that into account. The risk for sure is adherence and stopping therapy. Thank you very much for your attention. Thank you very much for an outstanding discussion, defining the evidence that may be required for further expansion of treatment criteria. We're now going to move to the role of biomarkers. So we're going to introduce our next speaker, Dr. Jordan Feld from the University of Toronto. His talk will be entitled Novel Biomarkers, Can It Simplify Treatment and Predict HPV Cure? Thanks, Joe. Thank you to the organizers for the kind invitation. It's wonderful to be here and a great lineup for discussing different aspects of Hep B. So I've been given the challenging topic of novel biomarkers and whether they can simplify treatment and predict cure. So here are my disclosures again. So what I'm going to go through is first just review the novel biomarkers, what do they measure, and then think about the potential utility in a number of different settings, identify those I'm going to say not to treat more than to treat, and then thinking about how they might be useful for predicting cure, looking at different types of therapy, interferon and nucleoside analogs, and then I think where they're potentially most useful is in the setting of stopping therapy. So let's first look at what are the new HPV or the novel biomarkers. We have our classical biomarkers of surface antigen, e-antigen, and different antibodies and HPV DNA along with our ALT. And if you look at the life cycle of the virus inside the hepatocyte, you can see that the virus goes from CCCDNA through making the RNA intermediates, the pre-genomic RNA going back through reverse transcription to make more CCCDNA, as well as getting translated to make the various viral proteins. And it's using this information and seeing what actually comes out into the bloodstream that you can start to get some other measures of what's going on. So various biomarkers have been used, quantitative surface antigen for the longest, more recently correlated antigen, which is a combination of three different things. So it's the core antigen, the e-antigen, and a truncated form, the P22, which is shown here in the post-translational modification of the HPV core gene product. In addition, very recently, there's been a development of a core antigen and its phosphorylated core antigen, the more specifics looking at only the core antigen. And this hasn't been used very much, so I'm not going to talk about it yet because it's very new, but it's an interesting diagnostic, as well as quantifying antibodies to core antibody, which have also shown some utility. And in terms of the nucleic acid testing, the ability to actually measure encapsulated HPV RNA in the serum, which is produced in fairly high quantity, so you can see that shown here. So is this going to simplify things? Well, we've had a bunch of different things for a long time, and I would say that a few additional biomarkers will simplify HPV, said no one ever. I don't think this is going to simplify things, particularly for how we manage the disease. And I would argue that until we really understand how to use these well, it may actually complicate things further, which, as we've heard from the previous two speakers, is a real challenge with us getting really to our good control at the population level of hepatitis B. So let's first think about what these biomarkers measure and where they're useful. So I'll start with HPV RNA and core-related antigen, which are most commonly compared. And I mentioned that core antigen is probably simpler and maybe more specific than core-related antigen. So the purpose here is that these are a direct measure of CCCDNA transcriptional activity, or at least they should be and can be considered that, and that is potentially useful. When it's positive, that clearly indicates that there's active transcriptional activity. The problem with both of these assays is that sensitivity has been an issue, so that their negative predictive value is not that good. Even when they're undetectable in the blood, that doesn't necessarily mean that there's no CCCDNA being transcribed in the liver. On the other side is quantitative surface antigen, which we've had for a longer time, and this measures two things, and it's important to recognize that there are two things. One is what we want to measure is CCCDNA transcriptional activity with the HPV transcripts coming off of CCCDNA and then making the envelope proteins, the small, medium, and large surface antigen. However, in addition to coming off of CCCDNA, these transcripts can come from integrated HPV DNA, and this is a problem because when we measure surface antigen in the blood, we have no easy way to distinguish the source of that surface antigen, and so we can't really interpret quantitative surface antigen purely as a marker of CCCDNA transcriptional activity. It's a measure of both, and I'll show this in a moment. Let's first start by thinking about where these might be useful in the natural history of the disease, and I think one challenge for us always is when you see someone like this with low or undetectable levels of HPV DNA, normal liver tests, and E antigen negative, is this person someone who is an inactive carrier and is going to remain like that, or are they just in a valley between two peaks of active disease because in one setting we're going to want to follow this patient, in a patient who's going to have active disease, ideally we'd like to treat them. So can these new biomarkers help us identify that? So we have some data that are not new but I think useful. Looking back a number of years ago from this fairly large study in Taiwan of taking E negative patients with HPV DNA less than 2,000 who were followed long-term, and what you can see is that if you looked at patients who had a quantitative surface antigen below or above 1,000 IU per ml, there was a difference in the probability of those patients developing active E negative hepatitis and more importantly the risk of developing cirrhosis over time. And similarly some European data showed the similar cutoff that using surface antigen quantitation at 1,000 at that threshold, again you could identify people with very good accuracy to identify people who were inactive carriers and very good negative predictive value for subsequent active disease. So this is reassuring and potentially identifies a population who are unlikely to have active disease in follow-up, but it is important to highlight and to stress that there was still some risk of both developing negative hepatitis and even of developing cancer. And just as a reminder that this is a dynamic condition that requires lifelong follow-up, even for people who are inactive carriers. So this is a proposed algorithm if you use that model as you start with someone who's got an HPV DNA below 2000, a normal ALT, and then using the surface antigen to potentially decide how frequently you're going to follow them. But importantly, even those who have a low S antigen level, they still need long-term follow-up. Now, an intriguing possibility is that maybe we can distinguish between the types of surface antigen and that might also be helpful. So this study, a German study from a few years ago, looked at the total surface antigen level but then broke it down into their components. And what they saw is that the patients who were inactive carriers had a low level of the large surface antigen. And this does make some sense because this is a longer protein and it needs to have the pre-S1 and pre-S2 added to the small S. And that's a little just by odds less likely to come off of integrated DNA. So it's possible that you're going to get less or even no large surface antigen from integrated DNA and all of it would be coming from CCC DNA. So this is potentially interesting because the patients that have the M and the S may also have only CCC DNA-derived surface antigen. So what about some of these other markers? Well, let's look at correlated antigens. So you can see that across the different phases of HBV, it's not surprising that patients with very high levels of HBV DNA also have high levels of correlated antigen along with expected CCC DNA transcription. And that goes sort of down the cascade to these low replicative people at the other end. And if you look at this, you can see that correlated antigen in most of the phases correlates actually fairly well with quantitative surface antigen. So maybe it's not adding that much. But I think there is potentially some interest here when you look in the inactive carriers where you see this good correlation among people who have detectable correlated antigen. But there's these group of people who have undetectable correlated antigen and are surface antigen positive. And you wonder if this is surface antigen all coming off of integrated DNA, whereas this, which correlates well with correlated antigen, is actually giving you a better measure of CCC DNA transcriptional activity. And if you take it even a step further, maybe some, if not all, of these people have already achieved functional cure, if we think about that as having no active CCC DNA being transcribed, yet they're still surface antigen positive because it's coming off of integrated DNA. And this is an important consideration because if our benchmark for all of our new therapies is surface antigen loss, we're potentially missing these people, which is an important sort of false negative. Now, if you look at correlated antigen on its own, there have been a few studies of this. And I will say that, unfortunately, they don't all agree, which makes this area a little bit confusing. So this is a fairly large study from Europe where they took E negative patients in different phases of E negative chronic hep B, in the classic E negative chronic hep B, the gray zone, and inactive carriers or E negative chronic infection. And you can see that, as you might expect, the patients with most active disease have the highest levels of correlated antigen, as was seen before. And then what they looked at is whether you could classify patients as inactive carriers or as people who had E negative chronic hepatitis B based on either their correlated antigen or their quantitative surface antigen. And what you can see here is that they found quantitative surface antigen didn't perform quite as well. You can see the sensitivity is not great and the area under the receiver operating curve isn't fantastic, whereas they saw for correlated antigen that it looked very good, with high predictive value, good sensitivity and specificity, and a very high AUC here. It was less good for identifying gray zone patients. So from this, you could potentially take that if you had correlated antigen below this threshold, which is around for this assay, the limit of detection, that these patients are more likely to be inactive carriers. However, another study that came out of the hepatitis B research network with North American patients, but most of them were Asian, and I think it may be relevant because the populations are different. They looked at the value of HPV RNA and correlated antigen in different settings, but here just focusing on this group that would likely have stable inactive disease, what they found is that HPV RNA and correlated antigen levels were associated with these outcomes, but they didn't add any value in terms of predictive ability. So they weren't any more predictive than sort of traditional markers, host factors and viral factors. And they actually found that surface antigen levels and E antigen levels were very predictive of both E and surface antigen loss, which as Harry likes to say is more of an announcement than a prediction as things go down, they have to go down before they're lost. So unfortunately, I think we have conflicting data here. These are less predictive in this cohort. It's important to acknowledge the populations are different and actually the way the analyses were done was different. So that's likely quite relevant. It may be true that once we have a more sensitive correlated antigen, the ITACT assay, and some of the improved HPV RNA assays that this may help with prediction. But I think for now, where there's uncertain utility for predicting natural history, and I hate to say in a talk like this that we need more data, but probably if we're going to use these tools for predicting inactive disease and certainly for predicting active disease that we do need more data. So what about looking at treatment outcome? Well, here the best data definitely come with quantitative surface antigen and they come with interferon therapy. So a number of studies, many of them done by Harry's group in the Netherlands, have really shown that you can use this as a very useful tool as a stopping rule. And this is important because you can identify patients who after starting interferon that none of us want to use and they don't want to take. If we can identify people who are unlikely to respond, we can stop treatment early. And this has made it into the guidelines, and you can see that there are different stopping rules for different genotypes and for e-antigen positive and e-antigen negative patients both at 12 and 24 weeks of therapy. And these really are quite useful. Potentially you can add to this a recent paper showing that if you in addition add to quantitative surface antigen also use HPV RNA that you can get better prediction of a sustained off-treatment response. So there may be some benefit over having quantitative surface antigen alone, but I think it's important to recognize that there's not a lot of interferon being used these days for hep B. Now that might change as we get to HPV cure regimens that may include interferon but we'll have to redefine these rules in those settings because many of the therapies are actually directly targeting surface antigen. So interpreting negative predictive value won't really apply. So we'll have to rethink them. For now, I think this has somewhat limited utility. Now what about looking at it in the more common scenario of patients on long-term nuke therapy? And it is true that these are somewhat predictive. So you can take patients that have a significant drop in surface antigen over the first year of therapy or get to a very low level in absolute terms that that does predict surface antigen loss. That's not really very surprising. Unfortunately, that's the small minority of people. So it's really just the lucky few who tend to have this fairly good response to surface antigen. And most people have a very slow or no decline in quantitative surface antigen levels over time. So the reality is this doesn't really help you. It's also important to recognize that at least in the short term, this isn't going to change your management. You're not going to stop based on that initial change. It's just really going to be maybe reassuring to the patient or motivating to them to see that their S levels are going down, and it might be useful for selecting for trials or new therapies. In terms of the correlated antigen and HPV RNA, usually in long-term suppressed patients, these become undetectable, at least with the current assay. So they really provide almost no utility. And so really I think in the context of long-term NA therapy, these are not very useful currently. Where they're probably most useful is in thinking about stopping therapy, which of course has become much more interesting as a therapeutic strategy in the last few years. And this RETRACT-B cohort, which puts together data from Europe, North America, and Asia, with a fairly large group of patients, has shown that you can see that both the background of the patient but also, importantly, the quantitative surface antigen level at the time of stopping therapy is very predictive of subsequent surface antigen loss. You can see that the patients that are below 100 are much more likely to clear surface antigen after stopping therapy. And this led to this proposed very simplified approach that for Caucasian patients, you can see that if they get below 1,000, they have a pretty good chance of clearance. Whereas for Asian patients, they have to get much lower, and it's probably to do with the duration of infection, but they need to get below 100 to have a high likelihood of clearance compared to the probability in patients who are above this threshold. So this gives you some guidance around using quantitative surface antigen for predicting response to stopping therapy. Would the new markers help? Well, there's this paper that came out last year that suggested that correlated antigen might help in a small subset. And this graph makes it a little easier, but it's still complicated to see. If you look at patients who have a surface antigen below 10, they have a very high likelihood of clearance. And if you have groups of patients that have a higher surface antigen level and a correlated antigen level that's high, they have a low likelihood of S loss. So you can see in this relatively small group of patients where the surface antigen is between 10 and 100, so this is still a small group, but it's an important group, you can see here you get some discrimination by using correlated antigen. If it's detectable, they have a lower likelihood of clearance. If it's undetectable, they're more likely to clear S. And so in this particular setting, it might be useful. And similarly, HPV RNA might provide some utility. There have been a few papers that have looked at this. And not really surprisingly, if your HPV RNA is quantifiable at the time you stop therapy and you can combine it with other factors, the probability you're going to have a flare is higher and the probability that you're going to have a sustained off-treatment response is much lower. And this fits with the fact that there's still ongoing transcriptional activity. Now Ed's about to tell us about all of the new exciting therapies coming for HPV cure, and I think it's important to think that there is a strong role for biomarkers in this setting. They confirm target engagement, they clarify the mechanism or mechanisms of action of the new drugs, potentially give us surrogate endpoints, and also may actually be used as clinical endpoints in the future. So we clearly need to collect data for these. So to summarize, the new biomarkers are increasing our role in understanding HPV biology, and at least so far I think that's probably their biggest utility. To date, quantitative surface antigen still has the greatest utility and the most data. With low surface antigen levels in people with low HPV DNA, this gives you some reassurance that they're going to have an active disease over time. And correlated antigen may be helpful, but I think it depends a little bit on how it's used and potentially the assay. On treatment studies, they're very useful for thinking about interferon with stopping rules if you use interferon, but have a pretty limited role in the setting of nuke therapy. For stopping therapy, they definitely give us guidance about risk stratification, certainly quantitative surface antigen, and at least in the subset correlated antigen and HPV RNA. And I would really stress that for the new therapies, they'll be very important for multiple reasons, assessing early responses and potentially even guiding clinical use. And so to date, I would say that I'm not really sure that they've simplified anything quite yet. Thank you very much. Thank you, Jordan, for an outstanding discussion. We're going to close this session with a look into the future of hepatitis B treatment. Our next speaker is Dr. Ed Gein from the University of Auckland. His title of his talk is Emerging Treatment to Achieve HPV Cure. Following this last discussion, we're going to have about 15 minutes for Q&A. We'll be asking the speakers to come up to the front table to take those questions. Thanks, Dr. Lim. Thank you. So today I'm going to give you a very brief look into the future. I'll define functional cure. I'll mention what are the best targets for drug development to achieve that, what successes, more successes we've had to date, and what's hot, what's coming, and a lot of that will be talked about later in the meeting. So what is functional cure? Functional cure, in simplistic terms, is a finite treatment duration. It could be single or combination therapy. And you can cease all treatment and have sustained loss of surface antigen and HPV DNA and inactive disease and no ongoing viral replication. That's what we'll talk about, functional cure rather than partial cure or sterilizing cure. We know the barriers to functional cure, sorry, that should go too quick, are high viral burden in patients with lifelong chronic hepatitis B and a paralyzed or exhausted immune response. And we need to change that paradigm and reduce the viral burden and somehow reboot or restart the HPV-specific immune responses. Better understanding will identify many targets for drug development, and really there are three major approaches to cure. There's inhibiting viral replication, lowering the very high viral antigen burden, and finally boosting the immune response. For inhibiting viral replication, we have, of course, the nukes and the entry inhibitors. Probably the biggest class for development has been capsid assembly modulators, the core inhibitors, and there have been almost 20 of these which have entered clinical development, but most of them have now stopped, either due to toxicity or, more likely, lack of evidence of any reduction in surface antigen, even with up to 76 weeks treatment. But there is currently, and you'll hear more about it at this meeting, one of the first of the next generation CAMs, which I think may well have a role in cure combinations. This is the Elagos 184 CAM, a very potent in vitro and in vivo CAM. And if you look at decline in viral replication in terms of DNA and RNA, it's far more potent than any to date, with almost a seven log reduction in HPV DNA, with no additional benefit of nukes, and around a four log reduction in RNA. And when it's been used for up to a year as monotherapy, there's been no breakthrough. So this seems to be a very potent inhibitor of the first mechanism of action of core assembly modulators. What about the secondary? What about decline in viral replication, in antigen production, in CCC DNA transcription? For the first time here, we are seeing an effect on hepatitis B antigens with use of a capsid assembly modulator. This is in E antigen positive patients receiving a higher dose of 300 milligrams for up to one year. So you can see there's a steady but continued decline in surface antigen, E antigen, and core-related antigen in patients receiving CAMs, but of course no effect with enticovir. So it seems as if this is achieving the secondary mechanism of action. If we now look at lowering the viral antigen burden, the biggest class has been the translation inhibitors, the siRNAs, and the antisense. The siRNAs, a number of them have been developed. The disappointment has been that the effect, although you do see steady decline with repeated dosing, these are subcutaneous every month, it tends to plateau with all the agents at around 24 weeks. And no patients to date have achieved surface antigen loss on siRNAs. So it looks as if if you are going to use those, you're going to have to combine them with other agents. What about BEPI? It looks as though Bepiviracin, the ASO, may be the first drug to be registered for hepatitis B since TAF. So this is now in phase three. We know about this. It's an antisense oligo that targets all the HPV transcripts. The Be Clear study, which is the phase two study, you can see that you were achieving end of treatment surface antigen loss and DNA suppression in up to 28% of patients with the preferred arm, but most patients relapsed in the first 24 weeks post-treatment. Certainly the highest response was in the 300 milligrams for 24 weeks. Responses were associated with ALD flares, which we now think is innate immune activation. And the highest response was seen in patients with a low surface antigen. This is a recurring theme, and I'll come back to this. And if you had a surface antigen level over 3,000, you had a very low chance of establishing a response, and that's really defined the entry criteria into the phase three B-World studies. If we turn now to immune modulators, and I guess this is where most of the development has been over the last few years, there are a number of targets, and I'm not going to talk about all. I'm just going to talk about the three which I think have the most activity and chance of success in the next few years. There's been a lot of interest in reversing the immune exhaustion associated with chronic hepatitis B, and I was involved in this pilot study seven years ago where we gave patients established on nukes a single small dose of a PD-1 inhibitor, nivolumab. And almost every patient had a decline in surface antigen with a mean decline of around half a log. And one patient who remains famous achieved functional cure and remains surface antigen negative almost eight years later. And this led to a huge enthusiasm in looking at checkpoint inhibition as an additional treatment for hepatitis B. And I just think it brings up a need for a word of caution. I talk about this study, which is the most advanced. This is the Ascolexis study, which has two cohorts. Note here they're using repeated dosing, not a single dose, but 12 doses, and they use low dose and high dose in the two cohorts. We saw last year the results of the low dose cohort. It's certainly they were achieving success. Three patients actually lost surface antigen following 12 doses of the low dose, and these were all patients, again, with a low surface antigen at baseline. They recently presented the high dose cohort. Surprisingly, the efficacy or the antiviral effect didn't seem to be any better. In fact, there were no cases of surface antigen loss. But what was to me concerning was a marked increase in thyroid dysfunction, which really is an immune-related adverse event. And I do think there are a number of other studies that are currently using anti-PD-1, anti-PD-L1 in their platforms, and we are starting to see increasing reports of cases of immune-related adverse events with repeated dosing of checkpoint inhibitors. So I think you need—and the HEPI forum talked about this two days ago—you need to look, how are you going to make this safer if you are going to use this? I think you need more liver-targeted approaches to get rid of the extra hepatic manifestations. We know all the monoclonals, given intravenously or subcut, they all have the potential for serious extra hepatic IRs, and they last for a while, because receptor occupancy can last for up to eight weeks, eight to nine weeks. Roche have developed a liver-targeting antisense, which takes out the PD-L1 molecule. That has the advantage that there's really no systemic exposure, and that should reduce extra hepatic side effects, but it does also have a long receptor occupancy. I really think the most successful pathway will be the small molecules, which disrupt PD-L1. Four of those have been in development. They have the advantage of oral dosing. They are very liver-tropic. They are pro-drugs, which are activated in the hepatocyte. There's very little systemic exposure, but the biggest advantage of these is safety. They're tunable. If you stop the drug, the side effects, as well as the EPD, should wear off very quickly. And the one which is the most advanced and is now entering clinical development is the Arbutus AB101. And here, this data was presented at this meeting many years ago, showing internalization of the PD-L1 receptor. This shows, and Emily Thives has shown this data beautifully, excellent target engagement, excellent anti-tumor effect, similar to the monoclonals. And what we wanted to see was, as soon as you stop the drug, the effect wears off. Now, let's talk about therapeutic vaccines. I won't show this slide much more, because I think we are seeing a change in this. But we have had, over 30 years, many of us have worked with many therapeutic vaccines where, really, although they appear to have some improvements in hep-related immunity, the immunogenicity in patients is far less than what we see in healthy subjects. And this very nice summary by Cargill looked at ways we can try and improve therapeutic vaccines. And I think we are seeing a change in landscape, and there are a number of vaccines which you'll hear about at this meeting which look as though they are far more immunogenic in patients, and maybe they will work in combination. The Vaxitech data you've seen here before, this is a prime boost, and they use a single dose of PD-L1. You've seen this data before. You were seeing, with the prime boost strategy, HPV-specific T cell responses, and you were seeing a reduction in surface antigens, again, only in those patients with a low baseline surface antigen theta. But the best results, as I said, in low surface antigen theta, and it looked as though giving the anti-PD-1 at the beginning was not useful. She blunted the response, and you had to give the PD-1 once you've already exposed the patient to the vaccine. So all of these programs have shown that patients with a low baseline surface antigen are more likely to respond. So can we restrict treatment going forward? Can we have a program which only treats patients with low surface antigen? And I thank Dr. Yusuf for this data from GSK. He recorded this presented last year. This is the proportion of your total hep B population according to cutoffs of surface antigen. And you can see the lower the surface antigen criteria, the smaller the population you're going to treat. So I think you have to look at other ways to improve treatments going into the clinic. And one way, which I think is becoming very popular, is looking at lowering surface antigen levels prior to starting immunotherapy. And this is by using lead-ins of siRNAs to lower the surface antigen level artificially. And this certainly works in clinics. You can see here it works when you use this before an anti-PD-1. It works with Ursa Protzer's wonderful study with a vaccine. When you add it to a lead-on of siRNA, you were able to achieve functional cure in all animals. And finally, the last stage of triple therapy showed that it was, in fact, synergistic. If you had a lead-in, suppress surface antigen before you gave the therapeutic vaccine and the anti-PD-1. And Vaxi-Tec actually looking at this with two studies, you'll hear a lot more about later in the study without looking at both approaches. What about anti-HBs? I think we've got some good data here from VIR suggesting that anti-HBs will be an immunomodulator, not just an antiviral. And the March 2 study presented at EASL earlier this year showed that with short duration, this combination appeared to be at least additive. You have profound reductions in surface antigen, 90 percent less than 10 after only a short duration of the therapy. And although patients did rebound, it was a very slow rebound, raising the possibility could we be seeing a vaccinal effect? And you'll see the data from part two later at this meeting. In particular, the three cohorts shown there, and all I want to — this is only end of treatment data I'm showing you here. You'll hear post-treatment data in the meeting. But note that with 20 weeks of VIR-2218, the sRNA, plus the monoclonal, you are seeing surface antigen loss in 15 percent of patients. Compare that to last year with the VIR-2218 pegylated interferon, for 24 weeks you achieved this at only 5.6 percent. So it looks as if you can achieve surface antigen loss, certainly on treatment, without pegylated interferon. And my final part is, what about targeting CCCDNA to bring down surface antigen or as a treatment per se? There are many approaches to targeting CCCDNA, but I think what you'll see at this meeting is a huge increase in interest on gene editing. There are now five companies active in developing gene editing as a pathway for hepatitis B cure. They've been divided into the Caspar CRIS-9, which is a cutting gene editing. They can be talking about base prime editing, where you change a nucleotide, you rewrite the code, and that also regards single DNA cutting, or epigenomic editing without cutting. Will this cure hepatitis B? That's the answer. That's the question. I don't know if you know the answer. But if you look at cutting the CCCDNA, it may work, but it may not. You have to have very specific targeting in order to wipe out CCCDNA in all the cells. You need to know that it gets into the mini chromosome. You need to match perfectly across all genotypes, or you'll get breakthrough and relapse. The cell will repair cut DNA, so we know that CCCDNA will reanneal, and it may remain transcriptionally active. The other risk of CRISPR-Cas9, in particular, is in cutting, doing double-strand breaks of the chromosomes for the integrated sites. You may be at risk for translocation and the long-term results of that. So there's a real interest in epigenetic modification. Mind you, that's not cutting. It's DNA methylation and histone modification to repress the chromatin, repress the cells. So it gives you silenced and durable suppression without cutting, and it targets both integrated and CCCDNA. And it may be a pathway for functional cure, and it may actually reduce the risk of liver cancer. So gene editing, I think we need to confirm that it works. You need to show you can deliver to the site. You need to show that it's conserved. You may need repeated dosing, but most of all, you need to show safety, long-term safety in terms of on-target and off-target editing, and certainly no germline editing. So the regulatory authority is going to say long-term follow-up. My key takeaways from this talk is antiviral approaches. We can profoundly suppress DNA and RNA. With the sRNAs, we can profoundly suppress surface antigen. With the ASOs, we can generate S loss in patients with a low baseline surface antigen. But antiviral approaches alone are unlikely to cure hepatitis B in many patients. We do need immunomodulators. We know that by themselves, they only have a weak in terms of functional cure, and their tolerability is limited by defined toxicities. And CCCDNA targeting approaches, I do think we need to demonstrate efficacy and long-term safety, but it is potentially a one-and-done therapy. So finally, I think for the next few years, our cure arrangements will combine multiple agents from multiple classes of what we already have, and the platform studies will need to quickly determine which classes, when to combine, what duration, and in which patient population. I'd like to stop. Thank you for your attention, and all of those who helped me with this talk. Okay. We'll have all the speakers join us up here. And just to remind everybody to follow in this room is the hepatitis B SIG meeting, and we're encouraging everybody with this great interest in hepatitis B to join the SIG. And while everybody's being seated, could I have a show of hands on who is checking quant S in their patients at baseline, quantitative S, at this time? Some hands? A few hands? Okay. Great. Are you doing it? All right. We only have 10 minutes. We need extremely short questions and short answers. Start microphone A. Hi. David Wong from Toronto. I think we need to – the apples and oranges concept is very important, and we need to remember when we quote studies, we need to distinguish, are we talking apples or oranges? So in Ontario, most of our mortality are people who are not engaged in care. And they come referred as a dying patient, whereas the patients that we actually follow tend to die of old age, even though we don't treat all of them. And I think liberalizing treatment criteria for the people that we follow is not going to help any of them because they're already on treatment. So my question, short, is that there's a mention that treatment decreases stigma. I would like to know if there are any other disease models where putting someone on a pill will decrease stigma because personally, if someone saw that I was on tenofovir or taf in my bathroom, I would be mortified because they might think I have HIV. So comment, please. Very short answers. Yeah. Well, I do think if you have an undetectable viral load, to a certain extent, you're destigmatized. And you might be – I mean, if patients are on treatment and in control of the doctor, that's fine. But a lot of patients fall out of that, basically. So I think we should really expand our treatment criteria for those who are less adherent. Any other comments? Quick comments? Tim? Oh, thank you. Great talks. A quick question. I think I know the answer. Going back to Mindy's slide that showed that treatment of people with diagnosed liver cancer benefit marginally, but benefit from antiviral treatment, I think there could be clues to knowing why that would be if we knew if the people who benefit are more likely to have cancer with cirrhosis or cancer without cirrhosis. Is there any information on that? It kind of opens up that door of thinking. Yeah. Thank you for your question. So we did sub-analyze the cirrhotic and non-cirrhotic, and there was significant association with improved survival for both groups. And I didn't have time to show the data, but we further sub-group analyzed patients by CPTA, BC, and also BCLC, A, B, C, and the association was significant even in people who just had supportive care. So a lot of this is liver function, improvement of liver function, and that's why we did our study that focusing on recurrence, you know, how much of this is for recurrence, how much of this is liver function. So it looks like there was benefit for overall survival, maybe bigger, but there's also benefits with the recurrence-free survival. Thank you. Wendy. Hi. Wendy Lo here. I'm just a happy patient, one of the 290 million people, first time at TLM here. I want to talk about the monitoring, right? When we're just advised to, oh, just monitor, but there's no treatment for you, we fall out of care. We might as well almost be undiagnosed, because for me, to just monitor, do these labs, pay up an ultrasound, but not getting anything, right? And then so when people fall out of care, they're going to seek other treatments, alternative ones, ones that might not be endorsed by this medical society here. And so I really ask the question, if there are three drugs that are in the market that are cost-effective, and we've seen people using it for so long, how is it that we're still holding this restrictive guidelines, or like making sure you meet all these algorithms, when there are people we know, right, that are diagnosed, and the guideline to treat people is so restrictive? So what I'm asking here is, you know, we have a funnel here at the top. I'm asking if we can make the guidelines simpler, where we offer treatment. I'm not talking about necessarily treating, but just offer, and then have the patient be part in consultation with their doctor, and then individualize it in terms of who gets treatment. So if we make the offering bigger, right, those in the room can see my little funnel, okay? We need a bigger, wider top to include people, and just know that's just only 18 percent of the people diagnosed. So my last comment is transmission matters to people who do live with Hep B. We are very concerned about that. Why are there more people like me speaking up here? It's because there is stigma, there is discrimination. So we're kind of playing in this conspiracy of silence, reinforcing the harm. So what I would like to ask is, can we, in planning these guidelines, include a patient perspective and a patient voice? So what activities are we including so that this perspective gets included? So that's my question, but I had a comment. Thank you. Jordan? Jordan, you haven't said anything yet. Your turn. Yeah, well, thanks for the comment. I think it's a really important perspective. I will say that on the ASLB guidelines panel, there are patient representatives, which is important, and I think that's, I think it's the first time, so it's important that that voice has been raised and continues to be raised. And I take your point about the offering treatment. I think it's important to recognize that many people don't want to be treated. And I think sometimes for people that are strong advocates for treatment, which, and it's important that you and many others are, it's important to remember that many of the people we see actually really don't want to go on treatment, even when we advise it. So I think there, I take your point that you're saying to make it available and not insist on it, and I think that's a very good point. But I also think it's important to recognize that in many places, treatment, and it's also that treatment is going to be long-term and that people have to be able to commit to it. I've worked in low and middle-income countries where people go on treatment for three months and then they can't continue it, and that's also a problem. So it's not a, I would say it's not quite as simple as just saying you have hep B, here's treatment for life. But it's also probably not as complicated as we make it. We have one minute left. Okay. Very short. Okay. Bob, two questions. Mindy, Northern California and Southern California looks a little bit different. I mean, practice in the Los Angeles, the data you show is a little bit different from us. We actually cut a lot of patients with hepatitis B, so that's, I wonder whether there's some difference in between the community practice and the tertiary care in the Northern California. Simplify the treatment. That's very important, Nora, that talking about 10-4 luck to 10-7 luck, actually that's from the immune tolerance down to the immune active. So those are the patient, should we immediately treat or should we wait until they into the other direction? So that's the question. And also simplify the ALT. The problem is that we check the ALT how frequently in California. If in the gray zone you check six months or 12 months, of course you are going to see the discrepancy in between. If you check every three months or two, three months, it would be a little bit different. So DNA, that's also the other things. And in the Korea study shows diabetes, NASH, and the limb NASH, also the other things. And the other, last one, the Fibroscan or any other non-invasive to give us fibrosis information to determine the treatment, that would be even more important. Mindy, can you be shorter than that? Okay. All of your points are very well taken. Some of the data I show you, a few of them is just from Northern California, but most of the data are either multi-center global studies or actually whole U.S. population level data. So they are not just restricted to our area. And I totally agree with you about ALT and all that, and that's why we had this session today and all the discussions. And I believe that we will have something more simplified in the very near future. Laura sends her regrets, but I asked her about adding to not treat, but add a checklist under that that included stigma, discrimination, treat to prevent, quality of life, family history, and patient request. If any of those boxes are checked, the patient, I believe, should get treatment. Harry, you're back to the open. Can we open those doors? Well, I hope we can. Yeah, I told my story. I think it's very important that we listen to the patients, and it should make sense, but we have to take into account that in resource-limited countries, people cannot go to the doctor very often, and they just don't have the ability to do that. A lot of patients that we also see in Toronto, I've been practicing in Toronto for 10 years, start coming to our clinic, but then at a certain time point, if they're not treated, they just disappear from follow-up. So yeah, I think we have to do more rather than looking strict at the data in the ideal situation because hepatitis B is not in an ideal situation. Many of our patients are on the lower steps of the social ladder. In the Western world, they don't speak the language very well, and we have to take that into account. Final question. Thank you. Thank you for the chance. When we hold an issue from Taiwan, when we evaluate the risk of complications and the benefit of treatment, the data we have is usually right-sensitive and left-truncated. I mean, we do not follow patients from the time they get infected, and we do not follow them until they die. So we usually talk about five-year, 10-year risk of death, but would that be relevant for a patient who has to live with the disease for their lifetime? So I mean, this is the limitation of the data or evidence that we have. So perhaps we should bring this long-term perspective into consideration when we evaluate the risk and the benefit of treatment. Thank you. Ed Gein, any closing comments? You're the future man. Okay. So sorry. I can't comment on the U.S. guidelines. I think they may change, and I'd be interested to see what people think. If we have a treatment which can clear surface antigen in anyone who's surface antigen positive, then I think we probably would change the guidelines. But there again will come the question of cost-benefit. What is it going to cost, and how are you going to benefit? But I think the guidelines today will not be the guidelines in 10 years' time. And because of people like Ed Gein, we're getting rid of the word lifelong. Just now talking about indefinite or some other hopeful term, that does keep people more engaged. Thank you. All right. Thank you. We're going to move to the SIG meeting. We're running a little bit late. Thanks, everybody. Fantastic speakers, moderators, hosts, chairs. Thank you.

biomarkers

Hepatitis B virus

viral replication

protein expression

antiviral therapy

treatment response

treatment outcomes

patient perspectives

patient-centered approach

stigma reduction

immune modulation therapies

gene editing

personalized treatment strategies