All right. Let's get started. Welcome, everyone. This is the Hepatitis B Special Interest Group Program for Liver Meeting 2022, and our session this morning is on Navigating Hep B Treatment and Cure by Starting or Stopping Nucleoside and Nucleotide Analogs. My name is Hannah Lee. I'm at Virginia Commonwealth University in Richmond, Virginia, not too far away from here. And I'm co-moderating with my colleague, Dr. Bob Gish at University of San Diego. And we have an excellent lineup of speakers who are going to share their insights on this topic. And also, lastly, our Q&A session will be at the end when our speakers are all completed. So without further ado, it is delightful to introduce Dr. Carla Coffin, Professor of Medicine at the University of Calgary in Alberta, Canada. And she's going to be talking about what we have gained with long-term nuc therapy. Thank you, Hannah. And thanks to the Hepatitis B Special Interest Group. It's an honor to present here today. And it's great to be here in person. These are my disclosures, sorry, which are mainly related to clinical trials that we conduct through the University of Calgary. Okay. So today my task is to talk about what have we gained from our current antiviral therapy. And I will touch on how the Nucleoside Analogs could be used to advancing a Hepatitis B cure. But other speakers in this session will be reviewing that. So clearly, we still have a major problem with Hepatitis B. According to the WHO, only about 10% of people who deserve or require therapy actually receive a treatment. And the Nucleoside Analogs have been shown to be effective in high-quality data from based on high-quality data to achieve prolonged viral suppression and sustain disease control. It has been shown that it decreases inflammation, reverses fibrosis, and also reduces the risk of liver cancer development. However, the nucs do not achieve a cure. Their mechanism of action is that they are reverse transcriptase inhibitors or polymerase inhibitors and so that they terminate the elongating DNA strand. But they do not directly target HPVCCC DNA or target integrated virus. And thus, there is a residual hepatocellular carcinoma risk. Just as a brief review, for many of you know that the recommended first-line oral antiviral therapies are entecovir or tenofovir. There are some nuances with our treatment selection. In terms of special considerations for people that have had previous exposure or resistance to lamivudine or telbivudine, we would not choose entecovir. If there's a risk of renal or bone toxicity, then we would not choose tenofovir. And then there has been an incremental improvement in tenofovir therapy with the new formulation or tenofovir alaflinamide, which has less plasma bioavailability. So moving on to where we see the benefit of nucleoside analog therapy. As I mentioned, that has been shown from high-quality data that there's a reduced risk of cirrhosis and liver cancer development. In our sickest patients, however, most of the randomized controlled trials would not have included the people with decompensated cirrhosis or people needing a liver transplant. And based on this 10-year observational study that was conducted in Korea, we see that people that have had a maintained biological response show a reduced risk of needing a liver transplant and prolonged survival. Additionally, based on retrospective study done in Taiwan, based on registry data, we see that there's a reduced risk of hepatocellular carcinoma development with long-term therapy compared to those who remained untreated. And similarly, this large meta-analysis that was conducted by the ASLD guidance committee showed that comparing observational studies and outcomes of people that had immune-active infection, comparing treated patients with over 50,000 versus untreated patients, there was a reduced risk of death, hepatocellular carcinoma, and decompensated liver disease. So as I mentioned that the approved first-line antiviral therapies are Intekivir or Tenofovir, but there are still some regions in which the second-line or the older generation nucleoside analogs, meaning lamivudine, are still in use. This is based on the evolved real-world data in China, which showed that in a long-term prospective follow-up of over 3,000 patients, when you compare patients who had received versus the second-line nucleoside analogs, those that had received Intekivir had a lower risk of hepatitis B-related disease progression, viral breakthrough, as well as resistance. And with the evolving first-line regimens, as I mentioned with Tenofovir, there is Tenofovir eleflinamide, which has less plasma bioavailability, and data shown from a U.S. large registry study had shown that there is a switch over time from Intekivir and TDF to Tenofovir eleflinamide. And those that had switched to TAF had shown a higher frequency of ALT normalization, as well as suppression of HPV DNA. And potentially, this could lead to reduced risk of HCC and fibrosis progression. So I've already reviewed the benefits that we have well-recognized from long-term nucleoside analog therapy in terms of treatment according to our guidelines with immune-active disease or those with cirrhosis or advanced disease, but what about expanding our treatment criteria? And this is where there is some controversy in the literature or with the experts. So this study, which was conducted in California, looked at five clinics in patients that would never meet standard treatment criteria based on the ASLD 2018 guidelines, and what they found is that these individuals that were never treated, because they would never have met the criteria, had nearly twice the risk of developing cirrhosis under liver cancer when compared to those that were eligible and those that had received treatment. Am I getting some help? Crew is working on it. Crew is working on it right now. Sorry. Just when I was getting to the good part. Okay, yeah, okay, so then what about expanding treatment to people that we would consider to be so-called immune-tolerant in our old definition, or the high replicate of non-inflammatory state, normal liver enzymes, high viral load. In this study conducted in eight, it was based on a large multi-site study done in Korea, looked at treated versus untreated patients that fit within this definition. And even though the baseline liver tests were better in the control group, using statistical analysis and propensity score matching, they showed that antiviral therapy significantly reduced the risk of liver cancer in cirrhosis in those that were treated. And additionally, there had this discussion about what about people in the so-called indeterminate phase and that we're not quite clear whether that they are so-called inactive carriers or phase one or phase two. This is a large retrospective multinational consortium study, including patients in Europe, Asia, and in the United States, and found that treatment of patients within this phase was associated with substantial reduction in the risk of HCC. And interestingly, this was also found in a subgroup analysis of people with even lower viral load and a younger age. And then finally, what about benefits in the so-called inactive phase? There's less data looking at this question, but in the two studies that I've shown here on the slide, one was a retrospective study of 120 patients in Asia, and what they found was that treatment of these patients with normal ALT was beneficial in terms of declining in liver stiffness measurement as well as viral suppression. In another study, there was no real signal that there was beneficial treatment for people with inactive disease, only in those that have cirrhosis, which is what we would expect to see. And then finally, what about the cost-effectiveness of antiviral therapy? This is a study that was done in Korea, which has a high diagnosis rate for hepatitis B, and what they found was that using their modeling of lowering the threshold for treatment based on viral load, ALT, or e-antigen restrictions, that treatment subsequent in various models showed that it was life-saving as well as cost-effective. And so finally, I would like to just mention briefly about advancing a hepatitis B cure and how the nucleoside analogs may be used for this goal. So our current treatments are very dismal, as you all know, with less than 10% of people, probably even less, on short-term therapy, achieving hepatitis B surface antigen loss. The reasons why a cure is difficult is due to an impaired host immune response, which will certainly be mentioned by other speakers in the session, due to the high antigen burden, to the intolerogenic liver environment, and suppression of the adaptive and innate immune responses. However, one study has shown that treatment with a nucleoside analog can actually restore antiviral T-cell responses. And in this study showing that ex vivo expansion of peripheral blood mononuclear cells from patients from different phases of infection, including those that were surface antigen positive versus those that achieved surface antigen loss, you see enhanced HPV-specific immune responses to the hepatitis B core or to the polymerase. And what about advancing a sterilizing cure or eradication of HPVCCC DNA? Most of the studies have said that nukes do not directly target HPVCCC DNA. In this study, looking at patients from the registration studies that had serial liver biopsies, we see over time that there is a slow decline in HPVCCC DNA based on liver biopsies. And there's a hypothetical model done by Thomas Tu from Australia showing that over time, with mitosis of infected liver cells, that their daughter cells are clearing HPVCCC DNA, and hence with cell turnover as well as nuke suppressive therapy, we can advance the sterilizing cure. Finally, there is new nucleoside combinations and new nucleosides which are in the pipeline, including one which has been shown to show prolonged DNA suppression and absence of ALT flares. This is a clevidine prodrug which was actually canceled or not used in the last decade because of mitochondrial myopathy. And in our future cure regimens, the nukes will certainly be a backbone in many of our therapies. This is a sobering study showing that in one particular patient enrolled in a clinical trial, that stopping therapy led to devastating clinical consequences, as you can see here with an ALT flare requiring an urgent liver transplant. And in the other new drugs that are in the pipeline, patients with their nukes suppressed or on antiviral therapy, there may be a greater suppression of HPVCC DNA. So in summary, the current treatment algorithms for hepatitis B therapy probably need to be expanded. The potent nucleoside analogs are safe, they suppress viral replication, they're lifesaving. When we expand treatment, we need to consider patient preference, cost, adherence, and they will certainly be integrable to the future hepatitis B cure regimens. And so what have we gained from long-term nukes? They have significant clinical benefit. They've been the standard of care for decades. They'll likely benefit those outside of guidelines, however they rarely achieve surface antigen loss or a functional cure, and currently do not achieve a sterilizing cure, but certainly will remain integral to our new combination regimens. So I would like to acknowledge my colleagues within the UFC Liver Unit, my research group, collaborators and people within the Canadian Hepatitis B Network. Thank you. Thank you. I don't know how much time I've gone over. That's great. Awesome. All right, our next speaker is Dr. Anna Locke from the University of Michigan, previous president of AASLD and a super leader in the hepatitis B space. She'll be discussing selecting different nuke for special populations. Thank you, Anna. All right. Thank you. So let's hope that everything goes smoothly. All right. So as you all know, there are separate nukes, and I was specifically asked to talk about specific populations. So these are my disclosures. Okay, so when we talk about specific populations, what do we mean? I'll touch upon children. Oh, now? Okay, can we go back? Okay, so we talk about children, pregnant women, oh, I guess there must be, it's still Halloween, there are some ghosts here. So and we'll talk about patients of HIV co-infection, decompensated cirrhosis, liver transplantation, those at risk of having impaired renal function or bone problems, and patients with prior exposure to other news. So when we make decisions, what are the things that we need to consider? Obviously we need to consider advocacy, we need to consider safety, possibility of drug interactions, and cost. This is an international audience, obviously cost varies depending on which part of the world you're in, and therefore I won't actually dwell on the last part. In terms of advocacy, we all know that we basically, when we talk about selecting news, it's no longer about lamivtin or dafavir, it's really the choice between antacavir, tenofovir, disoproxafumarate, or TDF, and tenofovir elefantamide, TAF. In terms of virus suppression, I think that they're very comparable, even though there are no direct comparison trial between antacavir and tenofovir. In terms of drug resistance, they're also very similar. All of these three first-line drugs have very minimal drug resistance, if any, unless they have prior exposure to news, in which case antacavir is not the drug of choice. There's been a lot of controversy about the risk of liver cancer in patients who receive antacavir versus tenofovir, and most of that difference has been from studies in Asian countries, but there are major differences in the use of these drugs in Asian countries because tenofovir did not become available until much later. So this is one study in which they look at patients globally, from 19 different studies. In the top left, where you can see that—I'm not sure that there's a pointer that I can use—but in the top left, you can see that there's a difference in studies coming from Asia, which reported that antacavir was associated with a higher risk of liver cancer. But if you look at some studies from the U.S., there wasn't a difference. And in the right-hand side, when you look at propensity-matched patients, there was no difference. And similarly, studies from Europe, which included only European patients, found there was no difference in the subgroup with cirrhosis as well as in the subgroup without cirrhosis. And finally, a more recent study that included an even larger number of patients found that when they look at individual patient-level data, regardless of how you slice and dice, there was either no difference or over a five-year follow-up period, you can find a difference in the XCC occurrence rate that differed by less than three weeks. So three weeks within a five-year period of time, we'll consider that as really not a major difference. So what about the side effects? Most of you are very familiar with all those black box warnings, lactate exodosis, potential of exacerbation of hepatitis. That's actually true across all the news. Even though we think that lactate exodosis is really extremely rare, and we're not sure that the current news truly causes lactate exodosis. The major difference is really in renal function, which we all know that TDF has a bigger problem and TEF minimizes that risk. Same thing with bone mineral density. What is actually less clear is the impact on weight gain as well as on lipid level, which is now being reported in several studies on TEF in HIV patient population. It hasn't really been a major issue with hepatitis B, but that's being introduced to hepatitis B patient population in a much later stage, certainly something that we'll be watching out for. In terms of drug interactions, both TDF and TEF have some drug interactions. They're not major issues. We just need to be aware of it when we're using these drugs. As I've mentioned, one of the reasons why we are moving more towards using TEF is because of the reduction in bone mineral density as well as the renal side effects. But bear in mind that this is actually right from the FDA package insert. Even with TEF, with 96 weeks of treatment, there's very minimal changes in renal function and bone, but in the absence of a control group that didn't get treated, we don't know whether this is the same in the placebo patient population or not. So let's come back to those special populations. The first group will be children. And here, we don't have direct comparison trial across the news. This is one study comparing Entacovir with placebo. Not surprisingly, Entacovir works in suppressing the virus and in normalizing the liver enzymes, but loss of surface antigen was extremely rare, even though these children did have active disease. Well, what about tenofovir-DF? There was also a randomized trial in children. For only 48 weeks, some placebo versus some TDF, and then all the children received open label TDF up to 192 weeks. Now in adults, we look at the effect of TDF on decreasing bone mineral density. But in children, we're actually looking at the impact on bone growth. So if there's an impact on bone, the children might not be growing their bones as well. And here, the group that received TDF compared to those that received placebo during the period when they were randomized certainly weren't growing their bones as well as the children receiving placebo. And as a result, even though TDF is approved for younger children, for HIV, for hepatitis B, the FDA approval is 12 years and up, but not for very young children because of concerns about the bone growth and development. The second group of patients I'll talk about would be pregnant women. When we talk about pregnant women, it's really safety to the fetus and the newborn baby that is of greatest concern. All of you are aware of the antiretroviral pregnancy registry, which was initially set up for HIV drugs, but because many of the hep B drugs are also for HIV. So we have a lot of data on teratogenicity and congenital birth defects. And all of these drugs are actually safe except for antacovir because it's not used for HIV. So they're very limited data and it's really not recommended. For all these drugs compared to infants that were not exposed to these drugs, there was no increase in congenital birth defects. Majority of the studies looking at giving pregnant women with high viremia antiviral to further reduce the risk of mother to child transmission was conducted using TDF. But bearing in mind that TAF may have less side effect, so more recent studies have looked at TAF as well. And it's clearly shown in, this is just one example, but there have been several studies now, that both advocacy as well as safety for the mother as well as for the infant appear to be the same for TAF versus TDF. So my take is that for pregnant women, if they're currently on a nuke and they're on antacovir because of unknown safety data, I would prefer to switch them over to TDF. For prevention of mother to child transmission, if the mother has high levels of viremia, even though TAF data appears to be strong, but we have more data on TDF, so currently I would prefer to use some TDF, but the TAF data is accumulating. The miftin and telmiftin also have been shown to be safe and effective, but we prefer not to use those because these mothers have high viremia and there's a risk of drug resistance. Well, what if the mother choose to breastfeed? TDF can be excreted into breast milk, but the concentration in breast milk is so low that majority of the experts would consider that as not consequential. Well, let's move on to the next group, which would be the patients with HIV co-infection. Here I will be very brief because it's fairly straightforward. TDF and TAF are included in most antiviral combinations and they have similar efficacy. Whether you use some TDF or TAF, they have very similar efficacy. In general, TAF is preferred because of the lower risk of renal as well as bone cell effect, but as I've mentioned, increasing data suggests that we also need to pay attention to lipid levels as well as to weight gain. And entegavir, importantly, is not recommended unless the HIV is already well-controlled because otherwise there is a potential risk of selecting for drug-resistant HIV. Well, here I'm just sharing you a couple of slides on weight changes. These are HIV patients. We don't have data on hepatitis B. When they were switched over from TDF to TAF, the patients actually had more of a weight gain. This is a short period of time. It's not massive weight gain, but some of these patients that were normal weight then subsequently became overweight, obese, something to watch out for. Similarly, the patients who were switched over from TDF to TAF, there's a tendency for increase in cholesterol level, particularly with LDL as well as triglyceride. Well next up would be the patients with decompensated cirrhosis and liver transplant. I think here the major concern is these patients are already at risk of renal impairment and also safety of these drugs in those patient population. And multiple studies have shown that entegavir and tenofovir are safe to use in decompensated cirrhosis patients. They're renally excreted. They're not liver metabolized and secreted, and therefore we don't need to worry about dose adjustment with child species cirrhosis or post-liver transplant. This is a data study from Taiwan where they look at a lot of these patients with decompensated cirrhosis and similar advocacy in preventing liver-related death as well as in XCC. Now of course, there is a somewhat higher risk of renal impairment in post-transplant patients who, because of the fact that they're on calcineurin inhibitor, already are predisposed to renal impairment, and TDF does increase that risk. What about TEF then? There are so far very limited data on TEF in liver transplant population. This is a very small study. You can see that it's only 20-odd patients comparing TEF versus TDF, and both in terms of looking at renal function as well as looking at bone mineral density, TEF appears to be just as good or better than TDF. So I think we can safely consider the use of TEF for both decompensated cirrhosis patients as well as liver transplant patients. Well, lastly, I'm going to talk about patients with prior exposure to nukes with antiviral drug resistance. We know that TDF would work for both lamivitin resistance, adafovir resistance, as well as antacovir resistance, and this is some data from a Korean study where some of these patients actually had multiple drug resistance. For patients who initially had adafovir resistance, particularly if they have double drug resistance mutation, the initial suppression of DNA is a little slower, but over time it does catch up, and certainly TDF works very well, even for patients with multi-drug resistance. Well, does TEF work just as well? Well, there's no reason why not. And here, this is a study, again, from Korea, where they had some patients with previous nuke resistance. They were receiving TDF, but because of concerns about drug toxicity, they would switch from TDF to TEF, and you can see that the majority of these patients remain with suppressed DNA and normalized liver enzyme, so certainly TEF would work just as well for drug resistance. So let me now wrap up. This is based on the FDA package insert in terms of guidance of which patient population to use which drugs. Antacovir is approved for children as young as two years old, whereas TDF is 12 years and up, and TEF is 18 years and up, largely because of limitation in data in children. Pregnancy, TDF is category B, whereas antacovir is category C. Renal impairment, we need to do dose adjustments for antacovir and TDF. For TEF, we don't need to do dose adjustment until the GFR drops below 15. For decompensated liver disease, a higher dose is being recommended for antacovir. For TDF and TEF, the FDA is sort of somewhat mute in terms of that based on limited data. And for HIV co-infection, as I've mentioned, antacovir is not recommended. So this is really my sort of take in terms of one being the preferred drug, and two and three are really the second and third-time runners. And there's certainly certain patient population in which some of these news should not be used. For example, not use antacovir for pregnancy, for patients with prior exposure to other news, and for patients with HIV co-infection, whereas TDF and TEF are very similar. In many regards. Thank you. Thank you, Anna. Thank you, Anna, for that excellent talk. Our next speaker is Dr. Harry Janssen, and he is the Chief of Hepatology at Erasmus University in Rotterdam, Netherlands. He was at University of Toronto and went back home, and he will talk about golden outcomes of withdrawing long-term new therapy. Thank you very much, Dr. Lee, for this introduction. I'm most happy and honored to be here and to talk with you about a pretty controversial issue, which is the withdrawing nucleoside analogs. Does it work? How dangerous is it? I will mainly touch on the efficacy of this, of withdrawing, and Pietro Lampertico will talk more on the flares and the potential detrimental effects of nucleoside analog withdrawal. Here are my disclosures. So I kind of show this slide in most of the talks that I give, because it very nicely depicts what's happening and what we're trying to do with stopping nucleoside analogs and hoping for a good response. In fact, what's happening is that in the vast majority of patients, you'll see that the HPV DNA will go up, more than 90% likely, and also the ALT will go up. And then you let that go for a while, and you hope that eventually the patient will move into some sort of immune control situation. So in fact, what you're doing is in the setting of a chronic hepatitis, trying to initiate a kind of an acute hepatitis. It's not an acute hepatitis, obviously, and these patients have been exposed to viral antigens for a long time. But anyway, that's kind of the gist of it. And you would hope for S antigen loss, and also you might have patients who move into a sustained virological response, that they do not have to be treated anymore. And then there's patients that really need to be retreated. I would say that the numbers on the right side, the 20% of S loss, is somewhat optimistic, as I'll show you in a minute. So what about patients who really want to stop therapy? So what are the pros and what are the cons? The pros are definitely that you increase the rate of S antigen loss, because as Carla Coffin just has shown, it's very, very low if you just continue nukes. And by that, you'll lose stigma of HPV infection. It's easier if you want to become pregnant, and you don't need to be treated anymore. You won't have any adherence problems. There will be no long-term side effects, and potentially cost savings. And I put a question mark there. And then the cons is that nukes are just very, very effective. They're well-tolerated. One pill a day keeps the hepatitis away. You improve long-term outcomes, and they've been around for decades now. There's less risk of dangerous flares. And a con is that intensive monitoring is needed if you would stop nucleoside analogs. And the drugs are very, very cheap nowadays. They cost $30, $50 on a yearly basis in countries like China. And it's actually much more expensive now to monitor these patients with HPV DNA and other virological tests. The other thing is that as HPV causes cancer, patients must remain or would be better off likely to have a very, very low viral load. The lower, the better likely. And there are yet limited predictors to identify patients who can stop therapy. So what are the current guidelines? And they vary a bit from continent to continent, but they're kind of similar. So for patients who are at initiation of the nucleoside analog E antigen positive, you obviously first require an E antigen seroconversion. We don't stop patients who are E antigen positive. Be aware of that. We also don't stop patients with cirrhosis. And once these patients have had an E seroconversion, most of the guidelines opt for a so-called consolidation treatment period where you continue treatment for about a year or a bit longer. And obviously DNA should be negative, and then you can try to stop or you can consider to stop. So this is not what has to be done, but what can be considered. A lot of people don't read the guidelines very carefully, but the guidelines are pretty cautious about that. If you're E antigen negative at the start of treatment, then with the European guidelines, you could consider stopping therapy after three years viral suppression. The American guidelines are more conservative, and they don't do that only after S antigen loss, and the APOZO guidelines are kind of in between. So all guidelines recommend stopping after or consider to stop after HBS loss and 12 months consolidation therapy. So does this work from an immunological perspective? And there are now studies ongoing also to look in the liver with finital aspiration biopsies. And this is an earlier study where, indeed, once you stop treatment, you see that there's an increase of cytokines four to eight weeks after treatment withdrawal. there's an induction of CD4, CD8, so HPV-specific T cell responses, as well as the induction of NK cell responses. So there really seems to be happening something immunologically, which you would expect with the flares, obviously, but it is confirmed here. So let's look at some of the data. And I first want to touch upon the randomized controlled trial. And this is the first one from Thomas Berig's group in Germany. In Leipzig, it's a very small study, but it's an interesting study because what you see, particularly on the left side, is what happens to the viral load, the S-level and the ALT. On the right side, you see the patients who continue treatment where nothing is happening. Everything is flat, S is flat, DNA, ALT, nothing happens. And if you discontinue treatment, you're really shaking the tree and you get S antigen going down, HPV DNA going up in many patients and flares. And this smaller study, four patients, so almost 20% of the patients were HBS antigen negative, mainly Caucasian patients. This was followed by a study from my own group in Toronto, where we did a similar study, a bit larger study. And again, on the left side, the stopped treatment, and on the right side, the patients who continued. But it's better to look at the bottom of this slide where you see the response rates, which were pretty disappointing in our hands, that HBS antigen loss in the stop group was only 2%, only one patient. And in the continuation group, it was only also one patient. So it was very similar, and there didn't seem to be a benefit of stopping nucleoside analog. And this was mainly an Asian population of 92% of the patients. Then the largest randomized control trial thus far, 160 patients, again, E negative at stopping treatment, and reports an HBS antigen loss after two years of roughly 10%, was also 10% of the patients needing re-treatment. And most of these trials, obviously these trials, you don't start re-treating very quickly. You let, first of all, the transaminases go up and the HPV DNA go up, and then you see what happened. And only if the ALT becomes too high or the period is too long, then you restart treatment. And that's also the problem with this, that you have to allow a certain amount of inflammation, if it is happening, likely, but not too much. So it's a very delicate balance on what to do here. Here, a trial from the Hepatitis B Research Network, a big American consortium, where patients were treated for four years, either with tenofovir alone or also with tenofovir, but with a lead-in combination with pacinterferon together with tenofovir. And then the patients were stopped. All of the patients were stopped according to certain criteria, which are depicted there. And this is about to be published by Jordan Feld. And also in this particular study, there was the HBS antigen loss rate was rather low. Again, a largely Asian population, 4% of the patients became HBS antigen negative. S antigen decline over time did not really differ by the treatment group that patients had been allocated to, neither by the E antigen status at baseline. And ALT flares were really not indicative of S antigen decline or S antigen loss in this particular study. And they could be predicted, particularly by HPV DNA, which is moving up rather quickly. And I think that Pietro will talk on that. There's a lot of cohort studies published, mostly retrospective from different parts of the world. The response rate of S loss, which are depicted on the right side, really vary a lot. And it also depends, obviously, on your retreatment criteria, on the population that you're looking at. So it is very difficult to judge. And really, the S loss rate moved from around 60% to almost zero. So what we did is to initiate a consortium and approach most of these sites who had been published with very solid databases around the globe and get all these databases together into one, basically. It took my PhD students two years to get that done. But then again, you have 1,500 patients which are really well followed and with pretty solid data. Obviously, it's still retrospective, so it's not ideal, but it's better what we have. And it has also sufficient power to look at things a bit more carefully. So here is the first study that we've published thus far. And I would like to invite you to maybe look at the right part of this slide, where you see that after four years, 13% of the patients had HBS antigen loss. And that in particular, patients who were white had a much better response than Asian patients, six times higher. And also, the patients with a low HBS antigen level at the time of stop therapy had a much higher rate of S antigen loss, 22 times higher as if below or above 100. And the E antigen state is also here at treatment discontinuation, didn't really have any influence on S antigen loss rate. So this led to this kind of, how do you say it, algorithm that if your patient is white and the S antigen level is less than 1,000, you would have a 41% chance of S antigen loss once you stop therapy. And it's only 5% if that S level is higher than 1,000. For the Asian patients who respond less well, the cutoff is at 100, where less than 100 gives you a 33% S loss chance after stopping therapy. And it's much lower if the S antigen level is above 100. This kind of response prediction has been refined by Milan Sonneveld, who looked not only at the S levels, but also at correlated antigen. And in his studies, it's a large series, if your S level is less than 10, you have a very high chance of S loss. But then again, there are very few patients in our clinic who have an S level less than 10. And correlated antigen particularly helps in the intermediate group between 10 and 100 S level at stopping therapy where correlated antigen level above or below two can really help you to, I would say, better predict whether these patients will move into S antigen loss. This is a study from Spain. It's a smaller study, but the nice thing is that they looked very carefully, intrahepatically, as well as in the blood, to viral and immunological parameters. These are 27 patients, and about a third of them had HBS antigen loss, around eight patients. And they showed that a decreased CCCDNA transcription and low S levels were associated with S loss, and also that the presence of functional HPV-specific T cell reactivation at baseline, so at stopping therapy, was associated with particularly a viral control, not so much with S loss, but with, let's say, viral remission over time post-withdrawal. What about relapse? Most of the patients relapse, and there are also patients who don't do very well. This is, again, data from the RETRACT where we had 14 patients that died, and it's 1%, most of them from HCC, but also patients who had a flare. And you have to be very careful what you're doing, and I'll leave this to Pietro to touch upon that. The other thing that we were able to do is to look at tenofovir versus entecovir, because there have been studies published that show, that suggest that there is a difference in relapse rate with these two compounds. So during a median off-treatment follow-up of 18 months, compared with entecovir, tenofovir was associated with a higher rate of HBS antigen loss. However, over time, the associate was no longer after statistical adjustment. And tenofovir was significantly associated with higher clinical relapse rate throughout. The virological relapse rate was also higher, but kind of leveled out over time. So our conclusion was that tenofovir and entecovir have a differential relapse pattern, but are associated with similar rates of S loss over time and retreatment following discontinuation. So there's not a lot of difference, we think. The last thing that we looked at, and which was presented here a year ago by Grishma, he wrote, is that if you don't lose S, what is it worthwhile to stop treatment? So what we did, we looked at patients one year beyond stopping treatment. And we excluded patients at that time who had an S loss in the first year, were retreated, or had hepatic decompensation, or ECO reversion. And so basically what you do is you let the flare come, you let the HPV DNA go up, and then you let it burn out. And then after one year, you start looking what happens to these patients with a so-called sustained remission. And it's actually not very sustained, because if you look at the sustained remission as defined by an HPV DNA less than 2,000 and an ALT less than 1.5, and again, with continuation of nukes, you would even get lower numbers, there was only 30% of the patients who remained in sustained remission after four years of nukes, and it moved down further, so the curve didn't stop there. So most remaining off therapy developed relapses, and may have benefited from earlier treatment, retreatment. So in my personal view, if you don't get an S antigen loss after, let's say, a couple of years, it's not worthwhile to, I think many patients should be retreated, and we should have a lower threshold, because if you compare the level of sustained response to nucleoside analogs, where you have no virus, where ALT is completely normal in most of the patients, I think most patients would be better off. What about if you stop nukes, if it's combined with the new agents, the siRNA and the CAMs, and on the right side, you see that patients treated with just the nukes, and the gray bar, once it's stopped, this is from the Reef 2, where all of the patients were stopped, you see a much more, I would say, vivid or profound increase in HPV DNA, than if these patients are also treated with these newer compounds. And even more so, if you look at the ALT over time, there are hardly any flares anymore in the setting of this combination treatment versus those patients treated with nucleoside analogs alone. So we'll have to see where that go, but it is very important for industry, for all of these companies designing these new regimens, trying to cure hepatitis B, how to deal with stopping nucleoside analog, and in the RETRACT study, we're trying now to do a second phase of data acquisition to get specifically data to give us answer how to deal with stopping nucleoside analogs in the setting of curative treatment for hepatitis B with new agents. So if you look at an algorithm on when to stop, and I typically mostly stop patients who really ask for it themselves, so I'm not very, I hardly ever propose it myself because there are definitely risks, as will be said in the next talk. E loss, three years of consolidation therapy, E negative at the start, at least three years of HPV DNA undetectability. No, the patient should not have advanced fibrosis and definitely not cirrhosis, should be highly motivated to come back to the hospital and be monitored, otherwise it's a completely no-go, and then I would particularly propose it if their S levels are on the lower side, and then thousands for Caucasians and less than 100 for Asian patients, and then I would consider the patient to be stopped if he asks for it, basically. So what is new on nucleoside analog withdrawal at this particular meeting, at this Deliver meeting here in Washington? I just picked out two abstracts, which I think are interesting. One really has the conclusion that lower pretreatment, the HPV DNA levels are associated with a lower risk of clinical relapse and a higher chance of S loss after cessation of new therapy, and this is independent of end of treatment viral antigen levels, so if you look back at what level the HPV DNA was at the beginning of treatment, it seems to be predictive. Another abstract, another poster, is one from India, where they basically stopped nucleoside analogs and waited for a flare, and then came in with, on top of that, with pack interferon treatment, which is immunologically interesting, but might not be completely without risks, but in any case, the HBS engine loss in that particular population was 27%, so that's rather high. So what are the future directions for stopping therapy, and where do we need to have a better understanding? First of all, it's very important that we look into viral and host factors and how they are involved in chronic hepatitis B in general. We need to identify novel biomarkers and predictors of response after nucleoside analog withdrawal. We're still looking at the black box and the S level and the genetic and the ethnic background of the patients are rather rough variables, obviously, in that sense. We need to deal with the off-treatment flares and manage them, which is going to be a challenge, and I think if we want to move on to cure, also with new agents, we'll have to deal with flares. It's no doubt about it that the immune system should be tiggled to get that done. We need to standardize standardization of stopping and re-treatment criteria and monitoring frequency and nucleoside analog withdrawals, not without risk, and we may need more solid data and randomized controlled trials to move forward into general practice. So, in conclusion, ladies and gentlemen, so if we withdraw nucleoside analog, I think you could likely achieve an HPS engine loss of roughly 10, 15% four years after follow-up. Predictors of S loss are Caucasian race and low S levels at withdrawal. Nucleoside analog stopping very frequently results in a virological and biochemical relapse so that it's almost all patients, and it shouldn't be a reason to immediately restart treatment. Many patients who remain HPS antigen positive and are not re-treated have mildly or have active disease not encountered in those who are on nucleoside analog and therefore HPS engine loss should, in my view, be the goal for stopping therapy. And there's strict follow-up after discontinuation needed, and for safe and effective outcome of nucleoside analog discontinuation, re-treatment should be initiated timely enough to prevent harm, but likely HPV DNA and ALT elevations should be tolerated to some extent to achieve HPS antigen loss. Thank you very much for your attention. Thank you, Harry. That was fantastic. Working with the Hepatitis B Foundation, we know that about 40% of the patients that we survey, which is a little over 10,000 per year, self-discontinue their nukes. So this stopping issue is huge because it's already happening in the community. And then we're gonna hear from Dr. Pietro Lamperdico now about flares and what those risks are. Pietro's from University of Milan, and he's gonna talk about the risk of flares from University of Milan, a leader in Hepatitis B, and also in Delta infection with Hepatitis B. Pietro, we need your guidance. Well, Bob, thank you very much. Hannah, thank you very much. And thanks to the organizer for this kind invitation. And also thanks, Harry, for making my job much easier. Indeed. So these are my disclosures. My topic is basically the safety counterpart of what Harry told you in two different clinical settings. One, nuke discontinuation before S antigen loss. The second will be new therapeutics regimen. So in terms of nuke discontinuation, there are two stopping rules. One stopping rule is the standard one, stop a nuke after you achieve S antigen loss and or seroconversion. I will not cover this topic. The second situation is what we are discussing today. So nuke discontinuation before S antigen loss, and I will cover this topic, but I will specifically refer to patients without any evidence of cirrhosis before they stop nuke. So Harry already alluded, there are some pros and cons of stopping therapy before S antigen loss. On the left side, you see all the disadvantages, potential disadvantages of stopping. Actually, these patients on long-term oral therapy, they are doing very well. Very well from the virological, biochemical, histological, clinical. We were able to show improved survival by long-term nuke therapy. And monitoring is easy, one pill a day. Overall, the cost is very limited. But, you know, we can agree that there are some issues or arguments on the right-hand side in favor of stopping therapy before S antigen loss, you know, about concerns about lifelong therapy, maybe financial concerns, maybe safety issues, and more recently, the possibility to use this strategy to actually increase or achieve S antigen loss. Again, this is the scheme we generated a few years ago together with Thomas Berg. I think it's an easy summary, a good summary of what is going on. Three different phases. The first phase from the left, you are on therapy, your patients are on therapy, everything is easy, stable, no DNA, normal LT, S antigen positivity. And then you enter in a sort of, in a second phase, which is the middle, where you stop nukes before S antigen loss and the situation would become definitely unstable, virological rebound, LT flares, different kinetics, different frequency, different duration. And then after, let's say, one or two years, right inside the third phase, where you will, again, probably enter in a stable phase, could be S antigen loss in few patients, maybe inactive carrier profile, maybe retreatment. But my topic today is really about ALT flares. And I like to start with this study from Greece. This is a nice study published a few years ago in Hepatology. On the left side, you see the probability of virological rebound. And you see highlighted in red, after two years of therapy, again, all patients discontinued before this antigen loss, 90% of the patients had a viremia above 200. So basically, all patients had a virological rebound. On the right-hand side, you see the panel, the table looking at the ALT elevations according to the virological rebound. Well, the very important point from this study, if you look at the number, only 55% after two years of therapy had abnormality. Only 25% had more than two times the upper limit of normal for more than three occasions. So not so bad, really. And that's another very important point from the study. There is no direct correlation of a virological rebound with ALT flare. You need a virological rebound to have a flare, but not all patients with a virological rebound, even significant, will end up with a significant flare. A very similar message is from this study. Again, on the left side, you see the multicenter German study. On the right-hand side, the Toronto study that Harry already presented to you. In the lower part, you see the ALT flares. Of course, again, if you stop therapy, you will see ALT flares in both studies. But the impression is that in the German study, you had ALT flares very early, but not much after the first, let's say, 24 weeks. On the right-hand side, you see the Toronto study, and my impression is that the kinetics extent of these ALT flares were different in this study, highlighting the issue that maybe Asian patients will behave in a different way compared to Caucasian, maybe genotype D patients. So that's an important variable that you have to consider. Well, we classify ALT flares in a different way. On the left side, you can have on-treatment flares. When they are early, they are generally related to immunostimulation, for example, during interferon or antigen-positive patients. You might have a late flare on therapy, on nuke. This now is very rare, but could be related to the generation of resistance. On the lower part left, you see off-treatment flares. This is the most relevant issue today for my presentation. On the right part of the slide, you see that there are also another possible classification of ALT flares in general, but specifically for my lecture, off-therapy. Well, you might have beneficial flares on the left part, and so-called bad flares or deprimental flares on the right-hand side. Well, this is a very fancy and potentially very useful differentiation, but be careful. The differential diagnosis between these two flares, good ones and bad ones, relies only on the S antigen levels at the peak and after the peak. If you have S antigen levels going down after the peak, this is a good flare. If these S antigen levels go up or stable after the peak of ALT, that's a bad flare. Well, I'd like to challenge you how you will be able to do in clinical practice this differentiation. I think it's almost impossible. Well, sometimes things go wrong, go wrong even in a best possible place for liver disease, like disease management like UK, or even the best possible setting, like a randomized controlled trial. This is a nice case being recently published by Kosh Agarwal on J-HAB. On the left side, you see the features of this case. 54-year-old male from Hong Kong, probably genotype B or C. He had a knee antigen-negative chronic hepatitis, has been on therapy or new TDF for many years with very low fibroscan levels, low DNA, lowest antigen levels, normal LT levels. He was randomized to a RIFD study, and he was randomized to no active therapy. So basically, in the right side of the slide, you see he was randomized to continue TDF for one year. He had normal LT levels, lowest antigen levels, undetectable DNA, then he stopped per protocol. He was followed very, very every two weeks. At the beginning, no issues, normal LT levels, normal or lowest antigen levels, but already a week eight, very high DNA levels. But because of the protocol of that time, rescue was not started. Then after a couple of weeks, LT increased, DNA further increased, and then you started to have a problem of synthetic functional deliver. TDF was started, but it was too late. And actually, this guy was saved because of urgent liver transplantation. Well, the message is that sometimes it's not easy to predict these flares, even if you are working in a super access center. And maybe rescue with nuke cannot be even effective in this specific case. Well, then it would be very important to try to define which are the predictors that we have, not to predict S antigen loss. Harry already provided you this data. But do we have predictors of flares? This is a nice study from UK. 23 patients discontinued nuke before S antigen loss. On the right-hand side, you see a table summarizing the predictors of flares, specifically severe flares. Severe means ALT above 10 times the upper limit anemone. Maybe you can see at the last column on the right of the table, four patients had a severe flare. All these patients were core-related antigen positive. High levels before stopping therapy. Almost all were RNA positive. But there were no difference in terms of S antigen levels. So suggesting maybe this new biomarker should be very relevant. Well, but you have another possibility to predict flares. If you're working with Antonio Bertoletti, if you're working with Patrick Kennedy, other people, very good immunologists, while you might be able to look at this study, very nice, while they correlated the absence of ALT flares after nuke discontinuation before S antigen loss to specific immunological recovery before you stop nuke, specifically HPV core and polymerase-specific T cells. So if you can do this, probably you might be able to predict flares. But again, we need prospective validation studies on these biomarkers. What about retreatment? If you stop flare, 40% of the patient will require retreatment in Greece, in Germany, in Canada, and in Taiwan. That's very similar across all studies. Top left, you see the experience from Greece and Taiwan. 40% restarted. But look at the curve. There is no flat curve after one year, two years. This is a progressively continuous decline of the curve of patients remaining off therapy. So maybe the longer the follow-up, more patients will have to start antiviral therapy as a rescue therapy. Well, but there is another issue which is making the story even a little bit more complicated. This is a nice study from Taiwan. A large number of patients stopped nuke therapy before S antigen loss. You see on the left side the probability to achieve S antigen loss according to some different profiles. I'd like you to concentrate only on group A and group B. Group A were patients with a clinical relapse who did not receive early rescue therapy. 0% S antigen loss. Group B, the same patient or similar patient with the same clinical relapse who did not got a rescue therapy early, 18% S antigen loss. So this paper is making the point that timing or re-treatment could be relevant. Not all the studies agree. But that's an important point. Basically, not too early, but not too late. Well, this is kind of complicated strategy. Not too early, not at the first DNA rebound, maybe not even the first flare, but yes, after the second flare. Well, it's very complicated for clinical practice. So how do we manage these patients? On the left side, you see how we manage patients if you want to discontinue before S antigen loss. Either the antigen positive on the left side, the antigen negative right hand side. Well, the management is similar. You follow up your patients very closely. You define whether you have a flare, significant flare, and then you do a rescue. On the right hand side, you see what we define by severe flares, more than 10 times the upper limit of normal, or even lower if you have increased bilirubin or INR. And of course, you have additional potential rescue therapies related to mild to moderate disease in different situations. But let me make a point. The management of therapy is very complicated. This is my personal simulation of one year management on the left side if you continue oral therapy compared to the stop, nuke, before S antigen loss on the right hand side. If you stop therapy before S antigen loss, you have a lot of monitoring, a lot of testing, many visits, and you need a center which is a super expert in the management of these patients. So I don't think this strategy can be used widespread in non-expert centers. What about the new treatments? This is the second part of my presentation. Well, new treatments are aimed to achieve a functional cure on the right hand side, which means S antigen loss of therapy. Of course, negative DNA. Eventually, in some situation, partial cure, which means S antigen positivity of therapy, but DNA negativity. There are many studies, many drugs, many new strategies being used and developed to achieve functional cure. I don't have the time to cover all these strategies. Some drugs never even achieved or were tested in phase 2 because of severe liver toxicity, ALT flares. Some of the studies did not provide any issue with ALT flares, but some of the studies are characterized by ALT flares. Let me start with this study, which is probably one of the best new drugs available now in phase 2, which is GSK836. It's an antisense oligo. Now it's called BP, or BP, that you administer by sub-Q injection every week, 300 milligrams. Look at it. This is a phase 2A study, top part on the left. Four patients were E antigen negative, all new, and received this therapy for only four weeks. And you see three cases had a significant ALT flare. And in all these three cases, the significant ALT flare followed S antigen decline, was short lasting, not very relevant, only 200, 250 units of ALT. It was associated with S antigen negativity. So in three of the four cases, it was a clear, clear ALT flare of therapy, but therapy was only four weeks. In the lower part, you see another case in the same study, but this patient was a naive patient. He received this drug as a monotherapy, a very similar pattern, S antigen decline again, but ALT levels were above 800. So maybe nuke therapy is protecting these patients. On the right-hand side top, there is a clear relationship linking S antigen decline with the extent of ALT flares. And again, in nuke naive patients, flares were much higher compared to the nuke suppressed patients. So I'm making the point that some drugs will lead to significant ALT flares. But there is another study I like to quote. It's this study with this drug. This is siRNA, Vir-2218. On the top left, you see four different strategies. The yellow one is siRNA without PEG interferon, no flares, no S antigen loss, and no flares. The other three strategies were with PEG interferon together. In the lower part left, you see three patients only in the combo therapy, siRNA and PEG interferon, achieved S antigen loss. And you see at the profile, all these three patients achieved had an ALT flare during or after S antigen loss, maybe immunomediated. But the flare was not a major flare. And the explanation, in my view, if you look at the S antigen levels at baseline, were very low, 100 units only, which means the replication space or the number of infected cells was very limited into the liver. Again, another case of ALT flare. But there is another drug which is interesting. In the future, this is ASC-22, which is an anti-PD-L1 antibody. In this study, we showed one case with a very significant ALT flare. Again, the similar profile. S antigen decline in blue, significant ALT flare, I think it's red, but very short-lasting, associated with S antigen decline and negativity. He was on NUCC. NUCC was continued. Then NUCC was stopped. And he remained or she remained, I don't know, negative for S. Again, another example, potentially an immunomediated ALT flare. But sometimes, new drugs may lead to a different pattern. This is an interesting study, a RIF-2 study, a study of randomized control placebo, which means NUCC versus NUCC plus sRNA plus CAM. This study was negative in terms of S antigen negativity. But it was very interesting in terms of DNA profile on the left side and ALT profile on the right-hand side in terms of off therapy. All patients stop therapies, either NUCC monotherapy or NUCC plus sRNA and CAM after one year. And look on the right-hand side. If you stop a NUCC monotherapy, you see a major, major ALT flares as expected. On the right-hand side, last graph on the right, if you stop a NUCC but pretreatment with sRNA and CAM, you don't see flares. That's surprising. That's interesting. That's the first time we see something like this. In the lower part of the slide, the table, 35% of the patients who discontinued NUCC as a monotherapy before this antigen loss had a significant ALT flare. On the right-hand side, only 3% of the patients who discontinued NUCC before this antigen loss but with a sort of pretreatment with sRNA and CAM had a significant ALT flare. So that's something new we have to think about this. So in conclusion, ladies and gentlemen, I have tried to cover and summarize two different clinical situations. NUCC discontinuation before this antigen loss is possible, but in my view, is possible only in very selected patients in very selected centers and may lead to flares, very eventually even significant flares. The incidence of flares is variable, but the severity can be unpredictable. And sometimes, this can be a lie-treatment condition or situation. We do not have robust predictors of severe flares. And in case of ALT flares, off-therapy monitoring is very complicating and very demanding. The second situation, clinical setting, is the one with new therapeutics. Again, even new therapeutics may lead to significant ALT flares either on or off-therapy, mainly on-therapy. This is completely different from the NUCC therapy, where you see off-therapy flares only. In the new therapy strategies, the frequency of flare is different in different drugs, rare with pure antivirals, frequent with immunomodulatory drugs. The mechanism is unclear for NUCC discontinuation is secondary and driven by DNA rebound. For these new drugs, the mechanism is unclear, probably immunomediated. Many of these flares are mainly associated with the ascantogen decline or loss. This is definitely good news. But if significant flares are required to achieve ascantogen loss, this strategy, in my view, will not be widely implemented. Only mild, short-lasting, predictable flares can be managed in clinical practice by non-expert centers and only if they're associated with significant rates of ascantogen loss. Thank you very much for your attention. Thank you. Could we have the rest of our speakers up for our panel discussion? Thanks. Thanks. And if you could, with your questions, come to the microphone and state your name and institution affiliation, that would be great. The lights are pretty bright, so I'm not really seeing. I see Mark, Dr. Ghani. Yes, thank you. Mark Ghani from NIH. First, I wanted to thank all the speakers for really wonderful talks. My question is, there has been a lot of discussion about expanding treatment as well as simplifying the guidelines for patients with chronic hepatitis B. So, I guess the simplest approach is perhaps to adopt the HIV model, and any patient with detectable viremia, you recommend treatment. I wanted to get the panel's view on this approach. The alternative is we continue with guidance, but then perhaps select certain individuals who currently don't meet treatment criteria. But this is a very heterogeneous group, and I wanted to ask the panel, then, who of those patients that currently don't meet treatment criteria would they recommend for treatment? So, two questions. One is, should we move to adopt a treat-all approach based on detectable viremia? If not that approach, then what's the next approach to which patients who currently don't have a treatment recommendation would the panel target for therapy? I guess I should take that question, since that was my presentation. I mean, it's an interesting thought, Mark, when you think about the HIV model with treating all, but I don't think that's feasible in the hepatitis B world. I mean, even though, I mean, we have these very cheap and effective nukes that may be only $30 a year in China, there are many countries where it's not that easily available. Even in a high-income country, such as Canada, the second-generation nukes are not even approved in some provinces, shockingly. And then there's also patient preference and adherence, and whether or not they're going to stay on long-term therapy. I mean, I certainly think we need to expand our treatment criteria, and that the current guidelines are probably too strict, but whether it's feasible to treat everybody who's viremic, I don't think that's going to be possible, and interesting to hear other people's thoughts. When we talk about stopping therapy, and adherence, and the risk of flares, and people that may have undiagnosed cirrhosis, I mean, all of these are considerations. But then the second question is, then who do you? Can I chime in? Because I've been involved in this debate, like, every few months, and so, I mean, I think that hepatitis B and HIV do have some differences. In HIV, once you get into a stable chronic infection, if you don't treat, it's progressive downhill. There's no such thing as spontaneous E antigen loss, spontaneous S antigen loss, you're going to remission. There's no such thing. And therefore, the whole notion that every patient needs to be treated should be balanced, because there's some patients who go into spontaneous remission and stay there for decades. Treatment, I mean, the U.S. is not very drug-friendly either, because even with generic drugs, it's $30 a month with coupons, not a year. And it's not readily accessible for everyone. And compliance is an issue, because Bob Gisham just sort of said it, look at me, these patients come off treatment. It's very dangerous. So, a lot of people think that if I put every patient on treatment, then I don't need to keep monitoring to see when I need to start treatment. But you put them on treatment, you forget about them, and the patients forget about themselves either. And all of a sudden, they stop the treatment, they come back decompensated. Can I make a sort of a European perspective? Well, in the European guidelines, and Harry was in the board of the guidelines, we tried to simplify the starting rules, the rules for starting therapy. And the message was very simple. All patients in phase two E antigen positive chronic hepatitis and all patients in phase four E antigen should be treated. That's very simple. And that's what we are doing in Europe. And that, for us, is a very good condition. The second advantage we have in Europe, in most of the countries, drugs are for free. DNA monitoring is for free. And all the visits are for free. And the compliance is 95% of the patient will continue oral therapy for more than 10 years, which is completely different from probably U.S. So in this situation, we are able to basically eliminate almost all the complications in hepatitis B patients in Europe. So there is not, at least in my view, I don't know about Harry, but there is no need, no urgency to start looking for new treatments in different patient population, although in the EASEL guidelines, we were able to open already to the phase one E antigen positive patients to start therapy, some conditions. Maybe I can just give my perspective. I think we should move towards treatment expansion, particularly for the immune tolerant population, people with very high viral load. I think we should treat them to prevent integration, to decrease the chances of getting liver cancer over time, because a lot of these patients immunologically wake up and will get active disease anyway. In fact, so why starting to quench the fire once the house is burning? I think it's better to prevent that. I think for the E antigen negative inactive population, it's much more subtle, and I don't tend to treat. So I kind of differentiate, and we really need good evidence. It's very unfortunate that we never had a good trial in immune tolerant patients being treated with nukes versus placebo, and we should have done that. It's a big study, a long study, but at least we would have an answer with HCC as an endpoint, and we still could do that type of study. So we need better data as well. But I think with nukes being so safe, so cheap, not getting resistant over time now for decades, I think we're in an era that we should really expand our treatment criteria. So Harry, maybe if I could just ask you about this last point you made about perhaps expanding treatment to the immune tolerant population. Is there any data yet to show that therapy would be beneficial in that group, or is there a subset of patients within that group that you would recommend therapy for? No, there's very little, unfortunately, but there's a lot of substantial evidence that integration, recently a big study from Taiwan published in Gastroenterology that with nukes, you decrease the amount of integration, of clonal expansion, really, which is highly related to HCC development. So with everything else I said, it's for me a reason to start treatment. Thank you. Move on to our next. Microphone 10. Oh, thank you. So I'm Tim Block from, well, nowhere now, I retired, but I guess still the Hepatitis B Foundation and the Blumberg Institute. So first, a comment on the expanded treatment. In my opinion, I think that if medical benefit, if clinical benefit is shown to a treatment, and we're talking about the drugs that are out there now, then that should be the guidance. The compliance and the finances will follow, but if you can show there's a benefit, then obviously that should be offered to the patient. My question is, I guess, going back to Dr. Coffin, and related to these comments. I was struck by, it went by very quickly, the evidence that individuals in the intermediate category, undetermined category, seem to benefit from medical intervention, from the nukes. That surprised me a little bit, and that's very important. And my question is, how significant was that benefit, if you recall, and was there any effort to correlate that with the baseline DNA level? Because that would be a very, very interesting group, because the viremia levels are reasonably low to undetectable in that group, and one wouldn't have thought, a priori, that a polymerase inhibitor or nuke would be beneficial. Yeah, I mean, to your first point, I agree with you that we shouldn't have social or political issues change what our expert recommendations are with needing treatment. Yeah, and in that study, it was five clinics in California, retrospective, and they looked at people that were indeterminate. And what they found was that, in this, I apologize, Tim, I'm actually, I think I'm thinking about the other study that I presented, and those that had the, the study that you're talking about, it's this global study, yeah, right, that multinational consortium, no, they didn't have the information about the actual HPV DNA levels, and so they weren't able to correlate that to the actual outcomes. But what they did say, when they censored people that had transitioned from one phase to another, that it did show a significant benefit. Thank you. Well, actually, I know that study very well, because I used that study in one of my debates. The problem with that study is, if you look carefully, and they did report how often ALT was monitored in that group, it was like, roughly every 18 months, you get one ALT, and roughly every three years, you get one HPV DNA. So the problem is, those patients were not carefully monitored. They probably have transitioned much sooner, and would have been put on treatment much sooner if they were monitored every six or 12 months instead. So this is one of the big issues. You either put everyone on treatment, but you still need to monitor, or if you're not putting everyone on treatment, you also need to monitor. There's no such thing as, forget about the patients. But if, but if you can show, if they're saying, even, even with the kind of changing the rules, if you can show medical benefit in an intermediate group, that's very surprising in a low DNA, with these drugs, and suggest a rationale. I guess her point is that they may not have been the indeterminate group if they did not have serial close ALT monitoring. Right, right. That's the moving target argument I was trying to say. Yeah, and that was the issue with that study, I guess. Yeah. All right, we have two more minutes, so microphone four. Thank you very much. Good morning. Mark Sondra from Cape Town, South Africa. Just perhaps to add to the debate on test and treat, I think an aspect of it that's perhaps lost is, not as much as whether we should be amending guidance, which I think, you know, there should be a relook. It's what are you going to test with, and who are you going to decide to treat? Because at the moment, the benchmark appropriately is HPV DNA. Now the issue in many parts of the world, particularly sub-Saharan Africa, is access and cost of HPV DNA. So perhaps the debate really should be not test and treat, but what do we test with, and what's affordable biomarkers that is available cheap to decide who actually accesses treatment? And I'd love your thoughts on that. Yeah, I can only agree with that. I mean, we're working on point-of-care HPV DNA tests, which are not easy to design, but I think they'll be in development and they'll come, which would be enormously helpful, rather than S antigen positivity. So that would also help countries like South Africa. If I can make a comment on this issue. Well, in specific countries, in specific situations, I don't see any problem to start therapy in everyone without monitoring, as long as they are S antigen positive. So again, different countries might need different strategies because of whatever, local resources or whatever. So I'm not against this, no way. I don't see any major disadvantage of this. Of course, you have to provide the drug for free or very low price. We have just one more minute and two more questions. Three and then 11, that's okay. Okay. Thank you very much for this comprehensive lectures. I'm Fathah Hanouf from Alexandria, Egypt. We have a lot of patients in Egyptian patients suffering from chronic hepatitis B, E antigen negative. And we are following the stopping rules in about some of them. And most of them, in spite of the following, the hepatitis B, E surface antigen level quantitative assay less than 100, most of them does not develop antibody. And at least about 25% of this group developed FLIR. What is your explanation? So they have a low S level below 100? Yes, below 100. Most of them during up to three years, the hepatitis B surface antigen less than 100. Yeah. So I mean, you first like to have the mass antigen negative before they get NTS. But these patients are really in an, I would say in a sustained remission of disease, yet not HPS antigen negative. And likely the S antigen will fade away over time. So in that particular case, I wouldn't do anything to monitor them if they have low ALTs. And over time, what I see is that with age, these people become HPS antigen negative. Actually, I'm monitoring them and measurement the level of antibodies, but does not exceeding two. So if there is impairment in the immune system can be stimulated by another means, for example, giving him some use of vaccination. Yeah, we've tried vaccination in those patients. It doesn't really work. You don't get NTS development, which is sustainable over time. So with new treatments coming along, these patients might be treated, I think, if this is a licensed treatment. But then again, in a setting of someone who has immune control and has low S levels, I would just wait and see. And they'll likely do quite well. Obviously, you might have to monitor still for HCC surveillance. That's good. Actually, I try giving him hepatitis B surface antigen and does not develop antibody. We're going to go ahead and change that. Thank you very much. And people might talk afterwards. 11 and then 2. Stephen Wu from Los Angeles, California. In terms of expanding the treatment, we are talking about in the gray zone. In determining the patient, the DNA actually can fluctuate. When you see at three month, six month follow-up, it fluctuates. How do you determine that at one time it's more than 2,000 that you treat? And the second question is, what tool do we predict the fibrosis? Because I see from the fibroscan, fibroscan has multiple etiology, like in the Asian population, Lynn Nash has contribution to the fibrosis as well. So do we have any other specific tool to predict? Yeah, I can sort of maybe try to address that question. So the first question with the fluctuating viremia, this would be the patient I would actually consider treatment if they're going above 2,000 and then coming down. Quantitative hepatitis B surface antigen may be a helpful predictive tool, although most of the data is done in Asians or genotype B, genotype C population. And then the question about the fibroscan or liver stiffness measurement, I mean, I agree that it can fluctuate depending on other fatty liver disease and certain populations, but maybe it's more important to sort of follow this serially, is to see in the individual patient how this changes over time to inform your treatment decisions. Two response is, number one, if you do the fluctuate on the DNA, then you're talking about to treat AB patient in the gray zone. And then number two for the fibroscan, I do have a fibroscan in my office and I do that and it's fluctuate as well in terms of diabetes, lean fatty liver. So how can you determine the efficacy and the important predictor of fibroscan in a hepatitis B patient? Well, I mean, these are the patients that in my practice I would select for a liver biopsy to help clarify that question. And then the question about the viral load, you know, fluctuating up and down, this is where if you have availability of quantitative hepatitis B surface antigen, it might help that. I do have a check on the surface antigen in the Asian population is usually very high and the DNA is high and the liver enzyme is high, but if the surface antigen is low, usually the liver enzyme is low and the DNA, surprisingly, is still fluctuate. And also genotype C is actually is much more on the patient with higher DNA instead of genotype B in the Asian population. We're going to move to the last question, if that's okay. Yeah. Thank you very much. My name is Jackie Chen. I'm a Hep B patient and I just want to say that I really appreciate this debate session and also tomorrow we have the same experts that will do the debate, the same continued debate. And we, the difference is that we're going to have a patient perspective to input into this session. But I have one scientific question about the stopping treatment that you mentioned, there's a major difference between Asian population and then the Caucasian patient. The Caucasian patient seems to have a very good success rate of functional cure after stopping the nuke, up to 40%. What do you think is the difference? Is it genetic? Is it skin color? Or what is it? What is the difference? Is it because of the, when they were infected, are we, do you have a contamination of those Caucasian patient who were actually been infected when they were adopted? Yeah, you're completely right. There's a lot of confounders towards ethnic background here. There's the genotype, obviously genotype A and D in the Caucasian and genotype B and C in the Asian population. There's the time point of infection, which in Asians is much more frequently at birth. And there is the duration of the infection, which is typically longer in Asian patients as well. But, and it's very difficult to determine the duration of infection because you don't know when someone officially is, I mean, you presume that a lot of patients have been infected at birth. So, you're right. We don't really know what causes this. The most easy variable though parameter to look at is the genetic background, the race of the patient. So in clinical practice, we use it, but you're right. We should really have an in-depth analysis on what causes this. Thank you everybody. And I want to thank Harry Janssen for his two years of leadership in the SIG. So it's been fantastic, Harry, having you and the rest of the members of the SIG making this possible and the speakers. And if you have any questions, maybe you can come up and join us up here at the podium. Thank you very much. Thank you.

Hepatitis B

treatment options

cure options

nucleoside analog therapy

virus suppression

disease control

treatment limitations

expanding treatment criteria

specific patient populations

viral flares

research

panel discussion

personalized treatment