Well, good morning, good afternoon, or good evening, depending on what part of the world you're signed in from. I am Mark Ganney from the Liver Diseases Branch, NIDDK-NIH, and on behalf of my co-moderator Dr. Yaochun Shi from Ida Hospital, Aishu University, Taiwan, I would like to warmly welcome you to this ASLD webinar sponsored by the Hepatitis B Virus Special Interest Group to Stop or Not Stop the Practice of Finite Nucleoside Nucleotide Analog Therapy. As this audience is very aware, chronic hepatitis B cannot be cured due to the lack of effective nucleoside analogs on covalently closed circular DNA, as well as integrated HPV DNA. Guidelines recommend to discontinue nucleoside analog therapy only after surface antigen loss is achieved. As this occurs rarely, in practice, treatment is continued long-term, if not indefinitely. However, interest in stopping antiviral therapy was rekindled after a landmark publication from Greece reported a high rate of surface antigen loss, 39%, after stopping continuous antiviral therapy. Since then, there have been numerous retrospective and a few prospective studies that have examined the outcome of stopping antiviral therapy in patients with chronic hepatitis B. Interpretation of the data has been muddied by inclusion of heterogeneous populations, such as Asians only versus Caucasians, cirrhosis versus no cirrhosis, varying durations of follow-up, as well as different definitions of relapse and criteria for restarting nucleoside analog therapy. So, here today to make sense of it all are two experts on this topic, Drs. Rachel Jiang and Harry Janssen. And we've asked each speaker to take the opposing viewpoints and to present evidence-based data supporting their position. Dr. Jiang will provide data supporting finite therapy and Dr. Janssen will argue against stopping therapy. A few words regarding the format. Both speakers will give their presentations and will have 15 to 20 minutes at the end for Q&A. We kindly ask the attendees to post their questions using the Q&A tab, which you can find at the bottom of the screen. We'll try to address as many questions as we can. And at the end, Dr. Xi will summarize the key findings and take-home points. So I would encourage everyone to stay until the end. So now I'll turn the podium over to Dr. Xi, who will introduce our first speaker. Hello, everyone. Good morning or good afternoon or good evening, please take the one that suits you best. It is my great pleasure to introduce Dr. Rachel Winrye Jiang to you. Dr. Jiang is currently an associate professor of clinical medicine at Chang'an University in Taiwan. She is a mentee of Professor Yunfan Liao. And with the mentorship from Professor Liao, Dr. Jiang focuses her research on the management of chronic hepatitis B, particularly the use of antiviral treatment. She has published several seminar works on the clinical course, relapse patterns, and the risk prediction after discontinuation of oral antiviral treatment in patients with chronic hepatitis B. As an expert in the practice of finite nucleoside or nucleotide analog therapy, she is going to tell us why she endorsed the finite strategy and how she practices it. Dr. Jiang, please. Hi, ladies and gentlemen. I'm Dr. Rachel Jiang and very honored to be invited by the ASLD to discuss the topic entitled To Stop or Not to Stop, the Practice of Finite Nucleotide Analog Therapy, an Argument for Finite Treatment. I have no conflict of interest to disclose. As all we know that the antiviral therapy improved the adverse outcome in chronic hepatitis B patients, such as cirrhosis, hepatic decompensation, and liver-related mortality. This is an important finding from the Hong Kong with large database of 20,000 anticovular or tenofovir treated patients. The accumulated incidence of hepatocytic carcinoma was decreased in the patients with complete viral suppression compared to those without viral suppression. However, the lowest cumulative incidence of HCC belonged to the group who has HBS antigen loss over the eight years of follow-up. This is also called the functional cure, the optimal endpoint for antiviral treatment across three major liver association guidelines. When we talk about when to stop antiviral therapy in E-positive patients, all three major guidelines agree that stoppage of nucleoside or nucleotide analog can be considered if the patient have achieved HB antigen seroconversion combined with undetectable HBV DNA longer than one year. However, when it comes to E-inactive patients, there are no consensus across the three major guidelines. ESO is the first association proposed that stoppage can be considered since 2008. That they suggest that this continuation may be considered if the patient has undetectable HBV DNA longer than one year and total treatment duration longer than two years. The updated ESO guidelines suggest that stoppage can be considered in non-serotic patients, especially after viral suppression longer than three years. The ASLD guideline is the most conservative one that suggests no stoppage unless there are compelling rationale such as adherence, willingness, or cost. Otherwise, the endpoint should be S antigen loss. Now, why finite therapy should be considered nowadays? First, in real-world practice, we'll face the issue of patient's willingness, adherence, and loss to follow-up, especially when the patient started treatment at their very young age. Second, nowadays, we still don't have the drug safety data for the potent nukes such as Lanhevivir or Tonevivir beyond the 10 years of treatment. Third, all we know that HBs antigen decline is very slow during the nucleoside or nucleotide analog treatment. The annual incidence for HBs antigen loss is only 0.15% to 0.33%. The estimated time to reach functional cure takes 50 years. It's really called the lifelong. And last, the medication cost for lifelong treatment is a concern, especially in countries where HBV is endemic. Take Taiwanese patients for example. Our government needs to pay for more than $2,200 for per patient annually. But here we have 2 million of chronic hepatitis B patients. When longer treatment duration or lifelong treatment is desired, the compliance issues emerge. In a recent systemic review and meta-analysis of 23,800 patients who are mostly treated with Anticovir, the adherence rate was only 75%, and it has no relationship with income settings. The WHO report in 2001 reported that the average adherence rate among the chronic disease patients in well-developed countries is only 50%. And another Singapore questionnaire study reported that only 44% of the patients would agree to lifelong treatment. And the rate will decrease to 25% if the patient needs to self-pay for a $10 per day. As we talk about lifelong therapy, human nature must be considered. How poor adherence will impact the health? This is an important study composed of 894 treatment-naive chronic hepatitis B patients receiving 10 years of Anticovir treatment. From this figure, the HCC incidence, serotic complications, and the risk of chronic disease The HCC incidence, serotic complications, and liver-related mortality all increase in the patients whose adherence rate is lower than 90%. The hazard ratio of these adverse events increases, especially when the patient's adherence rate is lower than 70%. And most important of all, if the patient does not want to take the medication himself or herself, and dare not tell the doctor, and just discontinue the medication themselves and lost to follow-up, severe flare and hepatic decompensation may occur without any notice, which leads to liver-related mortality. Self-discontinuation or loss to follow-up occurred about 7% to 9% during 5 to 10 years of Anticovir treatment. In a recent study of 631 patients during the post-clinical trial follow-up, during the 10 years of tenofovir treatment, the loss of follow-up rate increased along with the longer treatment duration. This is why final therapy should be considered and feasible and safe. From the systemic review of 1,700 inactive patients, although the biological relapse rate occurred in less than 70%, the clinical relapse rate occurred in less than half. The retreatment decision was necessary in less than 40%. Hepatic decompensation occurred in one of the 165 serotic patients. In another systemic review of 1,700 both antigen-positive inactive patients, hepatic decompensation occurred in two of the 243 serotic patients. This is a summary slide comparing the hepatic decompensation in serotic patients among those who stopped NUCC, those under long-term treatment, and those without any treatment. The hepatic decompensation rate from the OFNUCC studies are not higher than that in the long-term treatment cohort. And the Red Square Markdov study, which composed both the OFNUCC arm and the long-term treatment arm, and the OFNUCC decompensation rate is not higher than that in the long-term treatment cohort. As for the liver-related mortality, it's not higher in the OFNUCC studies comparing to that reported in the long-term treatment cohort and both lower than the untreated natural history. When we move to the HGCC incidence, there are two independent cohort studies using the propane score matching to adjust the baseline characteristic difference. Both studies support that the HGCC incidence is not higher in the OFNUCC arm compared to that in the long-term treatment arm over five to eight years of follow-up. And most interestingly is the S antigen decline show more prominently in the patient who stopped NUCC compared to the long-term treatment group. The study also used their propane score matching to adjust the two groups' difference. From the right-hand side, the cumulative incidence of the HBs antigen loss increased in the STOP-NU arms comparing to that in the long-term treatment arm over eight years of anticoagulant treatment. This is the summary slide, including two randomized control trials, PROSPETI cohort, Asian cohort, and the Global LARGE cohort. These studies compose different ethnicity and different kind of NUCC, but all suggest that the HBs antigen loss rate increased after stoppage and increased along with the follow-up duration, maybe as high as 33% over the five years of follow-up, which is much more increased compared to that reported as 2.6 to 4% over 10 years of anticoagulant or tenofovir treatment. And this is why the Asian PROSPETI suggests that finite new therapy in inactive patients may be considered. To move from the lifelong to the finite therapy, the concerns such as cost, willingness, non-adherence, or loss to follow-up will decrease. And the probability for functional cure will increase. Such idea is not restricted in the Asian PROSPETI only. In the recent past HPV-SIG symposium discussed by Professor Tyrell, she also talked about we now need to think about our curing strategy as long-term viral suppression, to how to increase the probability for functional cure. From the short-run strategy as undetectable DNA and ALT normalization by nucleoside or nucleotide analog treatment, to think about how to increase the apneic sustained response with the subsequent S antigen loss. As nearly half of the patients will encounter clinical relapse, this is a summary slide comparing the S antigen loss rate between the patients with clinical relapse and retreat and those stay off therapy during the follow-up. The S antigen loss rate in the retreatment group is much lower than that in the sustained response or off-treatment. Two of the studies include the variable S retreatment as a predictor for the off-therapy functional cure and both suggest that retreatment is an unfavorable factor for subsequent S antigen loss. However, retreatment decision is crucial because not too late for patient safety sake, but also not too early to halt the HPS antigen decline or loss. Since there are no consensus for which is the best timing for retreatment, this is a summary slide to compare the retreatment criteria from the four prospective studies. All of these studies suggest that retreatment should be considered if the patient's ALT is greater than 10 times ARPA limit on normal for one or two visits, or greater than five times ARPA limit on normal for two visits or longer than four weeks, or if there is hepatic decompensation concern such as increasing buropine or RNA level. However, among these retreatment criteria and suggestions, it should be mentioned that the follow-up interval with four-weekly is too loose since the hepatitis B flare may be abruptly increased and severe flare or hepatitis decompensation may occur within these four weeks. In such circumstances, we will suggest that weekly or biweekly follow-up is better for the patient's safety. When we move to the topic about hepatitis flare, it's a result of the interaction between host and virus, and not all the flares are bad. On the left-hand side, if the S antigen quantification increase along with the ALT surge, it stands for an infected immunoclearance, which we also call the virus-dominating flare or bad flare. On the right-hand side, if the S antigen decline along with the ALT surge, it stands for infected immunoclearance, or we call it host-dominating flare or good flare. In such population, retreatment may be postponed or even no need. This is the figure illustrating how the good flare be in the real-world practice. The S antigen decline along with the ALT surge. If these patients are left untreated, there are 21% of the patients will achieve S antigen loss over three years of follow-up. However, on the right-hand side, if retreatment apply in such population, then one-third of the patient will be observed with the HBS antigen rebound and minimal decline in the S antigen during the retreatment, and none of these patients will reach functional cure over the three years. And this, on the left-hand side, is the untreated history, untreated course of the bad flare. The S antigen increase along with the ALT surge. If these patients are left untreated, another episode of clinical relapse or flare will occur within a short interval. However, if retreatment are applied in such population, 70% of the patient will have rapid HBS antigen decline, which defined as greater than 0.5 log within six months or greater than one log within one year. And 32% of the patient can achieve surface antigen lower than 100 international unit per milliliter by three years, which also a sentinel marker, favorable marker to predict the therapy loss. Before the end of my talk, I would like to summarize the follow-up strategy according to the Apostle Stopping Rule. That monthly monitoring with the ALT in the first three months, and thereafter, ALT combined with the HPV DNA every three months within the first year, and afterward, every three to six month interval. Once the patient was detected with the virological relapse, which we define as HPV DNA greater than 2,000 international unit per milliliter, then monthly or 1.5-month follow-up with ALT is necessary to detect the clinical relapse or hepatitis flare. If the patients have increased ALT or ALT greater than five times our preliminary normal, weekly or biweekly follow-up with ALT, bureaubin, and INR is necessary to secure the patient's safety and also for the retreatment decision. And this is why I propose the finite therapy to be possible. In inactive patients, each course of finite therapy will have 50% of the patient with sustained response, and HBS antigen loss rate may be as high as 33% during the five years of follow-up. Since HBS antigen loss is an optimal endpoint, it seems to be an achievable goal for finite therapy comparing to lifelong expectation. Self-discontinuation or loss to follow-up is more dangerous than scheduled stringent monitoring. We need to consider human nature and safety. Finite therapy is feasible and should be considered, especially when stoppage with monitoring schedule can be offered. Not all hepatitis flare is bad. By use of combination of HBS antigen and ALT, it will help the physician to differentiate the nature of flare. In patients with virus-dominating flare, they will benefit most from retreatment, while patients with host-dominating flare deserve a wait-and-watch strategy, which may lead to subsequent S antigen loss. Among these, safety first. Thank you for attention. Okay, thank you, Rachel. We will leave the questions at the third part of the discussion, so we should move on to the next presentations. Dr. Gany, please. Yes, thank you, Dr. Yang, for a wonderful presentation. It's now my pleasure and honor to introduce our next speaker, who really needs no introduction. Harry Janssen is Professor of Medicine at the University of Toronto, Ontario, Canada, where he holds the Francis Family Chair in Hepatology. Dr. Janssen is Chief of Hepatology and Director of the Toronto Centre for Liver Disease. Dr. Janssen is an internationally recognized expert on viral hepatitis. He has coordinated numerous global multi-centre studies on the natural history and treatment of chronic viral hepatitis. Particularly relevant to today's talk, Dr. Janssen has conducted one of the largest randomized trials of stopping antiviral therapy in patients with chronic hepatitis B. He has authored over 500 peer-reviewed publications and is a member of the ESL Guideline Committee for both hepatitis B and vascular liver disease. He currently serves as the Head of the Division of Experimental Therapeutics at Toronto General Hospital and is Vice-Chair of the ASLD Special Interest Group for Hepatitis B and the Global Chair of the International Symposium on Viral Hepatitis and Liver Disease. And it's really my pleasure to have Dr. Janssen now take the opposing viewpoint on not stopping antiviral therapy in patients with chronic hepatitis B. Harry, please. Yeah, thank you very much, Mark, for the introduction. Thanks, first of all, for the invitation. I'm most happy to give kind of the opposite view on why I recommend not to stop nucleoside analogues until seroclearance of HBs antigen after Dr. Yang gave, I think, a very nice talk on why we would stop. So yeah, this is the disclosures. Here are my disclosures. And stopping therapy is really a matter of is the glass half full or is the glass half empty, I would say. And I wouldn't want to call myself too much of a pessimist, like drinking fluids only postpone death rather than that it's nice to do. But I definitely think we should be a bit careful with stopping therapy. And for me, the glass is not half full but still half empty. So first of all, the benefit of antiviral therapy of chronic hepatitis B is phenomenal. On the left side of this slide, you see how people move on in having hepatitis B with terrible consequences like cirrhosis and liver cancer. And on the right side of this slide, you see what we can do with nucleoside analog therapy. There is a great improvement of liver fibrosis in 85% by three years and 100% by five years. We're able to reverse cirrhosis into non-cirrhotic patients, really unprecedented, I would say, in a vast majority of patients. And like 20 years ago, we would never even thought that this would be possible. And more importantly, we're also decreased, we can decrease the adverse outcome like liver cancer, and we can also decrease liver related mortality. And that's what it's all about in this. So what people should not forget that this is really unprecedented success in medicine. Again, 20, 30 years ago, hepatitis B and C were untreatable diseases. Now we're able to cure 95% of our hepatitis C patients, and we're able to get more than 95% of our hepatitis B patients in continued remission. So there are pros and cons to everything in life, and also to stopping therapy for hepatitis B. The pros obviously that has been delineated in Rachel's talk is the concern about lifelong therapy, the side effects and adherence to financial concerns, and the increased rates of HBS loss, question mark. The cons is that therapies that we have in our hands are very effective, very cheap, very well tolerated over a long-term, even beyond 10 years, I would say, and have shown to improve long-term outcomes. Monitoring is quite simple. One pill a day keeps the hepatitis away. We see the patients once every six to 12 months. And as HPV causes cancer, patients must remain HPV DNA negative to reduce the risk really to the largest extent. And there are no good predictors to identify patients who can stop therapy. So I'll give you three different outcomes, viral response, flares, as well as retreatment, to make my point. First of all, the rates of virological remission after nucleoside analog discontinuation. This is a study that's already been quoted by George Papateodoydous from Greece in a co-production with a group in Taiwan. And as you can see here, the viral response is quoted to be 38% overall in the patient, and then there's a difference between those who are E positive at the start of therapy and those who are E negative at the start of therapy. But I would like to remind you that the post-treatment viral response was defined by an HPV DNA level of less than 20,000, which I really consider as still quite high. And I wouldn't dare to say that all of these patients are really in virological response. A virological remission, a virological response would be an undetectable HPV DNA for me. I'll come back to that in a minute. Then these are the first cohort studies that have been published. And if you look on the right side, the incidence of HBS antigen loss is not bad. It's over the years, it varies really from 13 to 46% or 55% even here. However, the biggest study by the previous speaker, Rachel Yang, quoted the lowest rate with an estimated annual S loss of not more than 1.7%. And I would also remind you that most of these studies are not very large. A lot of them are very small, just initial experiences. So the problem with many of these nucleoside analog stop cohorts that most studies were small retrospective studies that did not correct for any selection or measurement bias. So it's typically a selected number of patients that have been stopped and have been reported on. Most of these studies were from Asia and stop therapy according to the apostle guidelines for which reasons to stop treatment were also economical and not just scientific. So there are several countries where they're not just able to give therapy for a long period of time. And the regulators told the doctors, well, you should stop after three years. And kind of some of the guidelines were adapted to that which is the reverse order. Guidelines should also always be founded on scientific basis and never on an economical basis. Patients were followed and retreated at the physician's discretion, rather than with standardized criteria, really confounding the between study comparisons. So there's a great difference in retreat and strategies and HBS and E antigen serial reversions were not often accounted for. So if you move to the randomized control trials, there's two larger trials published. I'll leave out the study from Thomas, the first study from Thomas Berkowitz at only 21 patients. This is the first randomized control trial that I'll show to you. And basically with the RCTs, you'll see that the response rate drops significantly. In other words, the better the study, the lower the S antigen response rate. So here on the left side, you can see what happens when you stop nucleoside analog therapy. On the left panel, you see really that the DNA goes up, which you would expect the LT goes up. And there's a lot of, I would say, there's some action in the S antigen levels, where if you go to the right side of that panel, you see all flat lines if the treatment is continued. So I don't debate that there are some patients with S antigen decline after stopping therapy, but the question is to what extent is that happening? In our hands, 38% of the treatment of the patients were retreated. And if you look at the response of this randomized control perspective study, you see that there was one patient in the stop arm and one patient in the continuation arm that lost S antigen. So very, very disappointing, in fact. And because the continuation arm was a bit smaller, we had a two to one randomization rate. You see that's 4.5% versus 2.2%. So in fact, a little bit better even in the continuation arm. Then obviously the HPV DNA lower than 20 is hardly present in the stop arm, whereas it is still present, obviously, in 91% of if you continue nukes, ALT normalization better in the continuation arm and the clinical response also better in the continuation arm. And this is after one and a half year after stopping therapy. So then a larger randomized control trial just presented by Florian von Bommel recently at the EASL in 2020 with 158 patients, nicely randomized, mostly Caucasian population, had an S antigen loss rate of around 10% in the stop arm, whereas it was not present in the continuation arm. And I would say in our trial, we had one patient lost S on nukes, which is not common, but it happens now. And then if that would have happened here, it would by no means in any way be significant anymore. So 10% S loss rate after two years, which is also depicted here in the left side of the screen, you see S loss of 10.3%. And then it also shows really that retreatment was initiated at a very low rate. And the authors kind of advertised as that being a good thing for stopping therapy. But I would like to remind you, if you look on the right side of the slide, like the criteria of retreatment are not very strict, in fact. So you can have an ALT up to two times the upper limit of normal and a fairly high viral load level before you're ever retreated. So the question really is those patients who are not retreated in these studies and are deemed to be in clinical response, but still are S antigen positive. The question is really, are those patients who are in true remission, or do they have some activity of hepatitis B, or do they develop more activity of hepatitis B? And because they're S antigen positive, I think they might well be able to develop a more active hepatitis over time. So what about ALT flares? There's the risk factor for dangerous flares is the fibrosis state, the retreatment policy. The more loose that is, the more risk you're running. The serological status at the end of stopping, at the time of stopping, I should say. So E positive patients run the biggest risk, then E negative patients, and obviously when you're S antigen negative, then you're most safe. Absence of anti-HPE has been advocated as a factor. The rise of HPV DNA, I'll give you an example of that, and definitely the amplitude, and even more so, I would say, the area under the curve of the flare. So particularly flares that are very high and last for a while, for a longer period of time, are risky. And last but not least, obviously comorbidity. So if you look at the ALT values according to different viral relapses, you'll see that after two years, two years after this continuation, still 55% of the patients have an increased ALT, which you typically definitely won't have if you would continue NUCC. And there are even here in this case with an HPV DNA above 20,000, 12% of the patients who have, after two years, an ALT above 10 times the upper limits of normal. So significant number with raised transaminases remain after two years. And the risk of severe flares is also something that we have to take into account. And this happens, in our experience, also particularly in patients who have a very quick increase of their HPV DNA. And here you see two examples from a German study. The HPV DNA goes up very quickly. And then in the bracket line, you see the flares occurring afterwards to levels of ALT to around or above 1,000. So really not insignificant. And in our Toronto STOP studies, through 70 weeks of therapy, 84% of our patients had an ALT above the upper limit of normal. Of those who stopped in 49, so in 50%, it was more than five times the upper limit of normal. And in one third of the patients, the ALT went up 10 times the upper limit of normal, up to 40 times the upper limit of normal. So again, not insignificant. And if these patients would not be well-controlled, you might be in big trouble, really. So they really have to be, to come back quite frequently to your clinic. So what about, is a flare really good for you? Even that in the setting of stopping therapy is very questionable. Here you see five patients that developed S antigen loss over time. As you can see in the left upper panel of this slide, and in the right lower panel, you can see the ALT profile. And the ALT doesn't go up very much, actually, in these patients. It's only to two times the upper limit of normal. Some of them, it doesn't even rise. And the highest is around three and a half times the upper limit of normal. So not very high. So HBS antigen loss is not necessarily associated with flares in this case. So what about the reported fatal outcomes due to hepatic flares and decompensations after stopping therapy? And this is something we typically, as doctors don't want to publish about. The patients which are quickest forgotten are those who don't do very well sometimes, and they're often not published on. But if you look carefully at the literature, there are actually nine patients reported with a fatal outcome after stopping therapy. And they're here in this table. And they come from different studies around the globe. And in the right side of this table, you can see that these patients were not just cirrhotic patients. And the guidelines exclude cirrhotic patients, which I can understand. But I would definitely like to tell you that also in non-cirrhotic patients, big troubles have occurred. And obviously there are many patients who have stopped, but these nine cases are frightening, in fact. And we have to be very, very careful here. And then there's also patients, obviously more patients who developed hepatic decompensation and some of them recovered. So I would say that decompensation and ACC rates among those who remain on nucleoside analogs and those who stop is very difficult to compare. Definitely not across studies as the baseline criteria are different. And there's a huge selection bias. So the argument made that if you stop therapy or if you continue therapy, you would have the same outcome towards death, decompensation. And ACC is very difficult to make because we haven't done just, you kind of need a long-term, very big randomized controlled trial to really assess that. Because definitely patients have been selected to be stopped and that can be partly, I would say, tackled by matching the patients, but most of these studies are pretty small. So what about follow-up and compliance? So follow-up needs need to be very strict and frequent among patients who have, and the patients may have severe complications. So you need to see the patients every couple of weeks, as Rachel Yang just mentioned. And this may be actually more expensive than a yearly visit on a nucleoside analog, which is very cheap. So you have to keep that in mind, really. And non-adherence is never a good thing, but it's even worse if a patient has stopped and doesn't come back to your clinic. So non-adherence for those after nucleoside analog treatment discontinuation may well be more dangerous than non-adherence for those on nucleoside analog therapy. And if the patient is on therapy and he misses an appointment and he continues therapy and he comes back, it's no problem. We've also had patients where we stopped treatment and they went back to their general practitioners and we never heard from them back again until they came in with an ALT of 1500. So it is, we have to be very careful. So what about retreatment? The retreatment criteria for after stopping therapy, really the guidelines do not give those. There's no specific criteria there. As Rachel mentioned already, there's indications for retreatment, particularly if there's a flare and definitely if there's synthetic dysfunction of the liver with INR or bilirubin rises, persistent mild to moderate liver disease activity of two times the upper limit of normal or an HPV than more than 2000 is used. And timing of retreatment is very difficult, particularly for a doctor who's not well-trained in this because you'll have a viral rebound in almost everyone and that should be permitted to a certain extent, but not at the cost of dangerous flare. So this balance is a challenge for many doctors. So how many patients are actually retreated? It's roughly 40% over most of the studies after around two years. So on the left upper panel, you see the Greece-Taiwan collaboration with 40% retreatment, a German study 40% on the right side, our own study is 38% on the left lower corner and then in the Taiwan study, it was also 40.6%. So that seems to be kind of similar. I would, however, say that those patients who remain HBS positive, as I've said before, and deemed to be in remission, often have mild active disease, which is really not comparable to a state on the nucleoside analog therapy and it may worsen over time. So in circled in red, you see on the right upper corner, the German study where they were still deemed to be in remission if the ALT was less than two times the upper limit of normal. In our own study in Toronto, we took 1.5 if you look at the bottom and this is really not what I would call a true remission. So we really have to be careful with those patients and only the patients who develop S loss, I would call them true responders of stopping therapy and not anyone else. The other interesting point that you see in this slide that actually the curve doesn't stop to go down. If you look at the, there's more and more patients retreated even over time after two years or three years of follow-up. In other words, the glass may become more empty with prolonged follow-up. So the glass might be half empty and might become more empty with prolonged follow-up. So we really need longer follow-up to see what will be going on here. So to get more data, we found it from the Toronto group, actually this worldwide consortium network called the RETRACT-B study, where we collaborate with groups in North America, in Europe and in East Asia, groups who have published on this on stopping nucleoside analog therapy who have good databases. And we collected the individual data from all of their patients into one database to really give data with some more confidence. And this is what we recently presented. In 1,541 chronic hepatitis B patients who discontinued nucleoside analog therapy, the cumulative S loss rate was 3%. In the multivariable model, the S loss was only associated with race and was about six times higher in Caucasian patients compared to Asians. And there's few studies who have like a mixture of both races, I would say. The studies either come out of Europe with mainly Caucasian patients or come out of Asia with Asian patients. And also our Toronto stop study was actually 95% Asians because we have such a large Asian community in Toronto. The cumulative rate of retreatment was 30% at one year and reached 56% at four years. Univariate and multivariate analysis, the rate of retreatment was about two times higher among patients who were older. We had 15%, so 1% of our patients experienced hepatic decompensation and 12% which is almost, 12 patients, sorry, which is almost 1% died of which 75%, so nine to 12 were reported as liver related deaths, both decompensation and HCC. So the critical issues to be addressed in future studies is that retreatment criteria monitoring frequency should be standardized. Essentially all patients will experience a biological relapse so that cannot be used as an endpoint for retreatment. Biomarkers are needed to distinguish beneficial for detrimental flares as early as possible, which may be extremely challenging. And well-defined criteria are needed to assess which patients will decompensate and a threshold that only excludes serotic patients from stopping nukes might be too liberal. So in conclusion, Mr. Chairman, why am I reluctant to stop nucleoside analog before HBS loss? A significant heterogeneity among patients is present and the heterogeneity among studies and few of them are really prospective, I would say most of the studies are just cohort studies and we have very little good data. There's a variable HBS loss rates, but in general, the better the study, the lower the S antigen loss rate and they are the lowest in the randomized control trials. Many patients who remain HBS antigen positive and who are not retreated might have active disease or mildly active disease. ALT flares and cirrhosis and even in non-cirrhotics might be life threatening, so be careful. It is unclear what the risk is of HCC in those who stop nucleoside analog and the retreatment rates are around 40% of two to three years, but increasing with time. Follow-up after nucleoside analog discontinuation is often far from ideal and non-adherence loss to follow-up and costs for frequent follow-up and complications may outweigh those from nucleoside analog continuation. So I'm not saying that we should never stop treatment in nucleoside analogs, but I'm saying that we actually need more and better data from prospective randomized control trials before advocating this in general clinical practice. And I think if you're very experienced and you're on top of your patients and an expert in the field, you can still do that. But I've also seen many kind of accidents happening of doctors who are stopping treatment and who are less, I would say, well familiar with this field. Thank you very much for your attention and with that, I'd like to give the word back to the chairman. Thank you, Professor Jensen for your great presentations. So now we move on to the Q&A. So we have a brilliant presentation from both sides and we have some questions from the audience as well. So the first question is about how to differentiate host or viral flare or good of flare. After stopping the nuke, I think that Dr. Chen is the right person to answer the questions, how you determine whether it is viral or host-related flare. This is a very interesting question. From our recent practice and study, we assess the S-endogen at the time point of end of treatment, three month, six month, nine month and one year during the therapy follow-up. And when the patient have the ALT flare, we assess the S-endogen additionally at a time point when the ALT excess greater than five times upper limit of normal. And to compare that level to the previous level, if the level is increasing greater than 10% increase, then we define it as a bad flare. And if the S-endogen level decrease greater than 10% of the previous level, we define it as a good flare. And we hope that it will help the physician to differentiate the effective and ineffective immunocurrents since the S-endogen also stands for the intrahepatic ccDNA transcription activity. Okay, but it's just a proposal, right? Yeah, we have the data. What I typically do is I look at the S levels and if they tend to go down, I consider it as a good flare and otherwise as not so good of a flare. Yes, yeah. And it's better than if the reduction is greater than 10%. So I wonder if I could ask another question to both panelists. In particular, Dr. Jiang, you presented some data on criteria for restarting treatment, but I think it's not settled yet. What is the optimal time point for restarting antiviral therapy after clinical relapse? And there is this trying to weigh up safety of the patient versus trying to allow the patient to achieve surface antigen loss. So the question is, what is this Goldilocks time? What is the sweet spot at which we should consider restarting antiviral therapy after clinical relapse? And as a second part to the question is, can there be a one-size-fit-all recommendation? It's a very critical question. Actually, for the last one, there is one answer for all. I think that we haven't been able to come to that conclusion. But if you are asking what to do with the clinical relapse, it depends on the ALT level. If the ALT level is less than five times alkaline abnormal, I think that these patients can observe for a period of time, maybe weekly or biweekly for three months. But if the inflammation prolongs longer than three months, then retreatment should be considered. But if the patient has the hepatitis flare, it is able to use our suggestion as a combination of the S antigen sequential assessment along with the ALT. If the bad flare or the infected immunocurrence is found, then the retreatment can be given in such population. And these will lead to the rapid decline and no need to wait for even further higher ALT level. And Harry, perhaps you'd like to provide your perspective. Yeah, I agree with what Rachel mentioned. I think for me, retreating is really a safety issue. You want to, obviously the HPV DNA will go up in everyone. Definitely if the HPV DNA goes up a lot, I'm very cautious to look for the flare which might come. Because I've shown you that those patients have a pretty high flare sometimes. But then I really let it depend on the ALT and obviously on the bilirubin and the INR. That's a small minority, luckily, where this goes up. If the ALT is above five times the upper limit of normal, I become very cautious. And if it doesn't go down afterwards, I really retreat out of safety for the patient really. In the beginning, we've been a bit more liberal and we've burned our hands as well in some of these patients. So it is a very difficult, I would say, balance. And in general, I would recommend people to start treatment if the ALT is more than five times the upper limit of normal. So I think a key point here is safety of the patient and you need to monitor HPV DNA, ALT and surface antigen level to help in your decision to restart treatment. Yes, definitely. We do have some questions from the audience regarding how to use a biomarker to determine when to stop. So some raised the question about the level of quantitative surface antigen and a question asked about the role of HPV RNA. So may I have the opinions from both experts? I go first. Go ahead. Go ahead. Yeah. Across these biomarkers, especially the novel one is HPV RNA, which is not commercial yet and not available in many clinical practice hospital. That most discussed one or the most with the consensus is the S antigen quantification test. No matter that you use the Roche or Abdi manufacturers, it do good. In our previous study and in the others previous study that the lower S antigen level at the end of treat leads to the lower clinical relapse rate and higher S antigen loss rate. However, the cutoff value is varied across the study. The most talk about the value is about 100 international unit per milliliter, but this is the level which will lead to the highest probability for subsequent S antigen loss during the follow up, maybe as high as 39% or more. However, in our practice that patients whose level above the 100, we still stop the therapy because after stop, the S antigen level will decline and due to the immune restore and the clearance of the virus. So the S antigen is not the absolute criteria to decide who to stop or who not to stop. But as for the other biomarkers, such as correlative antigen, Holden have a very good study which called a SCOBY calculator. It can help the physician by combination use of the correlative antigen, the type of new tenofovir or anticovir and the patient's age to stratify the risk of clinical relapse. And if you have limited resources for the patient to come back to visit, and this SCOBY score may be helpful to differentiate who may be less, will encounter less problems such as clinical relapse during the therapy follow up. But if the feasibility for our therapy follow up is affordable, then I think that there is no restricted criteria for such biomarkers level. Yeah, so I think the S level is the biggest factor, really. So, I mean, there's also a Dutch study with HPV RNA and correlated antigen that might help you to predict who those who will relapse and will not. The problem of these biomarkers is that they're not available in most of the countries. Also, the other problem is that many negative patients who are on treatment are or the sensitivity of the test is rather low. So a lot of people already have like an undetectable of both. So you cannot use it as a quantitative factor anymore. I think S level is probably the best. And I would, I mean, if people really think they should treat and don't believe me or what I said, but they, I would advertise them to be very careful to do it in non-steroidic, mainly Caucasian patients with an S level below 1000 or preferably below 100, really. Those would be your best bet. So as a follow up, Harry and Rachel, if you take patients, let's say with a surface antigen level under a hundred, do we know what's the best strategy for those patients? Should you continue antiviral therapy or should you stop? Will they, will they yield the same outcome? I would stop, but yeah, but need to mention to the audience, since not all the audience are hypothetologists, that the therapy course vary according to the new you choose. The anticoagulant, the stopping anticoagulant has a later clinical relapse around the median time to relapse about seven months, while the other nukes, such as tenofovir, and recently we have the data about TEF, it occurs much earlier and a majority, 90, 80% of the clinical relapse occur within the fourth month after stopping nuke. So it shall be mentioned that the rebound of the virus seem to be surge abruptly and the patient who used the nuke other than the anticoagulant. And the surface antigen level is also vary according to the different nukes. As 100 is okay for anticoagulant, but if you use the tenofovir or TEF, maybe lower, such as 80 or 70, international unit may be better prediction of the therapy course. Yeah, I think all of the above that Rachel mentioned would be solved by a good randomized controlled trial that we can control for those factors. So it will be very, the answer from my perspective, Mark, is we really don't know. We don't know if these people with lower S antigen level would do better on treatment or off treatment. And so we need more and better studies, prospective studies to sort that out. So that will be, so I wouldn't know. A lot of patients, I must say, who will continue on treatment with an S level below 100 remain for a long time at S levels, which remain positive, I would say. So it's definitely worthwhile doing these type of studies. Yeah, thanks. I mean, I think I agree that we need more data to answer this question and you really need to have a careful discussion with the patient to decide what their views are as well. And I have a question from the audience. I think maybe the two experts will have different opinions on this. The question asks whether the presence of cirrhosis would change the recommendation about stopping the nuclear therapy. Would the presence of liver cirrhosis influence your decision to, you know, about a recommendation? Yeah, I think it definitely does for me and I would never stop in a patient who has cirrhosis or has had cirrhosis at starting therapy, because some of these patients, it disappears over time. I would be quite reluctant to do that with the current data. And I've showed you that even in non-cirrhotic patients, there have been problems. Yes. As for cirrhosis, I think that it depends on the cirrhotic status, because the cirrhotic is a very wide range and stoppage can be only considered in the common city cirrhosis, especially when after a long period of suppression, since the current period biopsy data are showing that cirrhosis may turn to non-cirrhosis about 75 to 100% after three to eight years of antiviral treatment. But yes, it should be very cautious when you stop the antiviral therapy in the previous cirrhotic patients, since these patients may have the less liver reserve and the monitoring strategy should be stringent and to keep very close contact to the patients. So from these real-world data that we have the data for the stoppage in the cirrhotic patients. But yeah, the safety is of the most concern and retreatment decision should also be loosened in this population. So Rachel mentioned the duration, there's a question regarding what duration is safe. And so you talk about in patients with cirrhosis, maybe the duration should be longer than the question is how long would the duration be considered safe? Yeah, just as a follow-up to that, just to be provocative, Harry presented data showing that antiviral therapy could lead to reversal of cirrhosis. So as Dr. Shi is intimating, if you've treated a cirrhotic for some period of time, can you ever consider stopping therapy in such a patient? Yes, and we do have faced the issue of the patient's willingness to continue for longer therapy and they ask if they can stop. So we still have the issue of such population. And I think that, yeah, after at least after three years, or maybe five years, I have no the optimal treatment duration for such population, but selected patients with compensated cirrhosis are most important and not to consider in those with portal hypertension or the any presence of the decompensation sign. Okay, maybe a couple of other questions. So I think a sort of a key point here is, do we really know the long-term outcome of patients after discontinuation of therapy? Dr. Yang, you presented some data suggesting that rates of decompensation and cancer are low, but then Dr. Janssen presented some data saying that you can't really compare the trials head to head. And there hasn't really been long-term follow-up of the randomized studies and recall that all these patients originally had an indication for therapy and for patients who sort of languish in the gray zone or even inactive carrier status with HPV DNA levels around 20,000. Do we know what the long-term rates of cancer development will be in such patients after discontinuation of treatment? It's a very important and interesting question. And I think that the merit of the stoppage is the increase in the S antigen loss, which is the optimal endpoint. And as I calculated the S antigen loss in our serotype patient who stopped the nuke, there is none of these patients had HCCC occurrence during the six years of follow-up, while in patients without S antigen loss, the six-year cumulative incidence is about 9%, and which is similar to that reported in the long-term treated cohort. So I think that the long-term, it depends on how long you desire to know the answer, maybe 10 years or longer. But until now, we only have the data until the sixth year. And not in only our study, but the other cohort study also showing that even though the patient have the transient relapse, maybe more than half may return to normal and maybe leads to the reduction in the S antigen and subsequent S antigen loss. So the retreatment rate among these studies are not so high and less than half, actually. Yeah, I think it's a very difficult question. So I think if the patient has not developed an S loss, stopping treatment is almost a failure, I would say. And people say, well, you can go back into a state of immune, of being a carrier, so immune control, which might have had, I mean, if you've been treated someone for 20 years and you stop therapy, you might indeed end up in that state, which would have happened in the natural history as well. Because if you wait over time for 20 years in a patient, you get a different set point, basically, you're going into immune control state. But definitely, if I look carefully at those patients, a lot of them have raised transaminases, their ALTs are, yeah, in the 20,000 range are a little bit higher. And I would consider those patients as still being active. And so I have a very low threshold. If people do not develop S antigen loss, which is really my major endpoint in stopping therapy, to put them back on treatment over time, because it's, but we need long term follow up to see what will happen there. But even though in the Toronto STOP study, the recruitment rate is less than 40, right? But yeah, it goes up over time, right? So that is the, so if you continue to look at those patients carefully, some of them are developing more active disease. So, and I really, if I would have to choose between an HPV DNA of 20,000 and an HPV DNA of zero or undetectable, with a drug, which is quite safe, and has been shown to be so effective, I would rather choose the latter, to be honest. It's maybe a matter of taste, Rachel, I don't know. I mean, there's no right or wrong here. Yes, I know. Yeah. And it depends on the fish condition we have and how the facility or the feasibility to reach a doctor. Yeah, yeah. That's the other thing I, for me, it's easy to practice where drugs are reimbursed in a well-funded healthcare system. If you're in a country that doesn't have that, it's, it is a real different game. I understand that quite well. So, may I have one last question? It's about discontinuation of a nucleotherapy in patients who lost, who lost surface antigen during the therapy. So the question, the audience asks, in that situation, should we stop treatment right away, or should we prolong the treatment for maybe another year in patients who lost surface antigen? And he also, he or she also asked whether the presence of cirrhosis would change the recommendation. Please, both of you who would like to answer the question first. Okay. Stoppage may consider once the S antigen loss, since only 40% of the patient will presence with the anti-HPS antibody at the same time. I know that the APASO-Gonnelly proposed that additional one year after the S antigen loss is recommended, but actually in real-world practice, there's no any evidence to support that idea. And if the patient is not an ACUBI infection, the S antigen loss itself is safe enough to represent the inactive transcription of the CCCDNA and also the integration form. So in serotype patient, yes, if the patient has the S antigen loss, it can be stopped. And yes, of course, need to monitor. And how about the S antigen reversion rate and recent evidence from the recent meta-analysis just published weeks ago, that the reversion rate is about 6%. So I think the S antigen monitoring during the therapy follow-up is still required. And it should be mentioned that to a word that the patient need to avoid a so-called immunosuppressant. If the immunosuppressant is going to be given, then the virus data should be reassessed. This is my opinion. I largely agree. So I typically move on for another half year or a year of kind of consolidation therapy after the patient is S negative, then I want to repeat that and confirm that. And then I stop therapy and I follow up. And I haven't seen, I mean, definitely S loss is a much more solid endpoint for stopping antivirals than E loss or HPV DNA undetectability, I would say. And I have seen very, very few people relapse after that. So the presence of cirrhosis is not a consideration in this scenario, right? No, for me, it's not. So if the patient has cirrhosis, it's likely disappeared. And this is such a much more solid endpoint that I'm daring to do it there. So I'm sure everyone, including myself has enjoyed informative one hour, more than one hour with the presentations from both presenters and also from the very interactive discussions with questions from the audience. So I would like to share my takeaways from these webinars with the audience. First, I learned from the presentations, there are some data, including three random control trial regarding the rates of substantive loss after stopping nuke. Well, I would say some patients has the chance, but the practice is, of course, challenging and there are risks. So if a final therapy, it is the practice, it must be closely monitored. So according to the presentations, I think weekly or biweekly monitoring is necessary if there is signs of clinical relapse, if the practice is practiced. And there is, according to my point of view, there is certainly so far no solid rule for retreatment. So we definitely need more answers, more study on this to discuss whether a patient should resume antiviral treatments in the clinical relapse or we should wait for a while. Although Dr. Chen presents some data about dynamic surface antigen monitoring. And from the torrential stop trial and the stop nuke trial, and also from the RETREX study, I think the issues kind of differ across the regions, according to the ethnics, according to the patient populations. So I agree with Dr. Ghani that probably a science cannot fix old. I would definitely look forward to seeing more evidence, more data from different parts of the world and among different patient populations. That's my takeaway from this webinar. Dr. Ghani, would you like to add something? No, I just also would like to thank everyone, both presenters for their wonderful and informative talks and for the audience for their great questions and my co-moderator for running this webinar. And thank you so much for your participation and attention. And enjoy the rest of your day. Thank you. Thank you. Thank you very much, everyone.

ASLD webinar

finite nucleoside nucleotide analog therapy

chronic hepatitis B

nucleoside analogs

covalently closed circular DNA

integrated HPV DNA

surface antigen loss

antiviral therapy

liver fibrosis

cirrhosis

liver cancer risk