So I'm presenting a case of a 29-year-old accountant with chronic hepatitis B infection, treated with oral nucleosides for 3.5 years, and now has normal ALT and AST and undetectable HPV DNA, negative E antigen, and he wants to stop treatment. The questions we'll address is what is the expected outcome of his hepatitis B if the drug is discontinued? Is there clinical value in the use of quantitative hepatitis B surface antigen in monitoring therapeutic response and likelihood of recurrence? And what are the emerging therapies for patients with chronic hepatitis B? Certainly, the treatment of hepatitis B is undergoing a paradigm shift. Currently, with our nucleoside analog therapies, our focus has been on achieving an on-treatment, sustained HPV suppression. For many of our patients, this requires long-term or even indefinite therapy with nucleoside analogs. But as we look to the future, there's now an increasing interest in considering functional cure, which is manifested by having a surface antigen loss with or without hepatitis B surface antibody, and undetectable HPV DNA off-treatment. So the key elements here are this focus on surface antigen loss and to do so off-treatment, which means that we'll have finite courses of treatment. So quite a different treatment paradigm from what we currently have. And why are we making this shift? Well, in part, it's driven by data such as this that show that while HPV DNA suppression is good, loss of surface antigen is better. This is a cohort of patients from Hong Kong. More than 20,000 patients were followed on nucleoside analog therapy. And what we're looking at, if over a mean follow-up of 4.8 years, of which the majority had complete viral suppression, 86.4%, a proportion of those patients achieved hepatitis B surface antigen seroclearance. And when we look at the incidence of HCC among those that achieved seroclearance while on nukes versus those that had sustained suppression, you can see that there's a lower rate in those that lost surface antigen, 0.5% at 4.8 years versus 3.5%. So the incidence of HCC, which is one of the most important clinical endpoints when we think about therapeutics, is improved by loss of surface antigen. So if that's our goal, how are we doing with our current therapy? Well, it's no surprise to anybody in the room that we very infrequently achieve surface antigen loss with our current therapies. Shown here in this table are the rates of S antigen loss with peginephrine and with the preferred nucleoside analogs. And you can see that certainly with the immune modulatory therapy, peginephrine, we have slightly higher rates, and that's an off-treatment response. But our rates overall are quite low with nucleoside analogs. And in particular, for the patients that are E antigen negative, they very infrequently lose surface antigen, which is why we frequently, when these patients start treatment, they're on treatment indefinitely. So with, of course, this low rate of surface antigen and this great desire for HBV cure, it's exciting to look forward and see that there are now many new targets that are being looked at as potential directions for us to go in terms of achieving HBV cure. This loss of surface antigen. And thus far, we've only had nucleoside analogs, which really acted at a very specific point in the replication cycle. But now with several new drug classes that are emerging, and many of these drugs now in phase one and phase two, we are looking at targeting viral entry, transcription, encapsidation, release of virus, and important, also looking at immune modulatory therapies. So many of these coming together, and you're gonna see some of these presented at the meeting here. Most of them are in phase one or phase two, so early. But what I wanna point out is the populations that are being studied. While we're looking at active patients, our typical patients that we consider for treatment, the other group that's really considered a high priority and an interesting and important group to study is those that are on nucleoside analog suppressive therapy, just as this patient is. And as we have these new therapeutics, and acting by different mechanisms to achieve surface antigen loss, we are gonna need new biomarkers to help us understand if the drugs are working, getting an appropriate readout. And also, we're moving not only towards functional cure, but really the holy grail is to achieve sterilizing cure, which is where we not only lose surface antigen, but also eliminate CCC DNA from the liver. Now at the present time, if you wanna measure CCC DNA and determine whether a drug is impacting that form of the virus, you'd have to do a liver biopsy. We already know from studies that have been done that nucleoside analog therapy doesn't affect the CCC DNA, but many of the new drugs that are being developed for hepatitis B, indeed, are expected to reduce CCC DNA as well. And so there are many new targets that we are looking at, and I'm gonna mention a few today. The one that's available to all of us is the hepatitis B surface antigen quantitation. This is a reflection of surface antigen both from hepatic as well as integrated sources. Of course, our viral load, our HPV DNA, is very standard. But we also have some new markers, hepatitis B core-related antigen and HPV DNA, which capture, to some extent, the transcriptional activity and give us some sense about silencing or exhaustion of CCC DNA. And also, we're looking increasingly for immunological markers as well, and I'm gonna show you some data today related to the quantitation of hepatitis B core antibody as one such marker. Now, many of these that are on the cartoon are not available for commercial use for us in the clinic, but I suspect that as we continue to see these used in the context of clinical trials, that they may be something we'll have in our armamentarium in the future. Now, I'm gonna just focus on, really, this E antigen negative patient that I was presented. And I'm gonna go back to thinking about when we start treatment in such a patient and when we stop, and in that context, look at some of the biomarkers that might help us in decision-making. So the indications for treatment are very common across all of the guidelines, whether it's the AASLD, EASL, or APASL. In general, we're targeting patients who are at risk for disease progression, those with immune-active chronic hepatitis B. And that's indicated by presence of an elevated ALT and HPV DNA, and in some cases, we also use histology. Certainly, cirrhotics are a group that every guidance feels should be treated indefinitely, as is individuals with HIV co-infection. Now, if we go to the far right of the slide, though, is the groups of patients that we currently do not recommend for treatment, those that have inactive chronic hepatitis B or those that are immune-tolerant, or have the new term from EASL, chronic hepatitis B infection. And certainly, if we look to the future for HPV therapies, we're hopeful we'll have a therapy for all of these groups. But today, in your clinic, the recommendation is still that these phases of infection be used to make decisions about who should be started on treatment. But I think what we're recognizing is that while we describe in guidelines the phases of infection, and everybody fits very neatly into one phase or another, that in real life, a significant proportion of patients have ALT and HPV DNA values that are in the so-called gray zone. And shown here is data from the HBRN, in which individuals who are entering into a prospective cohort, their HPV DNA and ALT levels were used to say, well, what phase of chronic hepatitis B are they in at cohort entry? E-antigen negative patients are shown on the left, E-antigen positive on the right. And for this analysis, the threshold used to determine a high level of HPV DNA is 10,000, and the ALT level for males and females was 20 and 30, respectively. But what this diagram shows you is that, particularly in the E-antigen negative patients, a significant proportion of patients do not fall into one of the treat or no treat buckets, but rather in that indeterminate group, or so-called gray area, and those are the ones that I think we all struggle with in terms of should we start or should we pause? And indeed, in this study, 38% of patients didn't fit into a specific phase that could allow you to say yes, treat, or no, don't treat. Now there's been a few studies this year that I think have helped us to understand these gray zone patients. And the first is, again, from the HBRN, in which they took patients that are E-antigen negative that have gray zone ALTs and HPV DNA levels under 10,000. So it's a mixture of some inactive carriers and also perhaps those that are in that gray zone. And you can see here that what they're looking at is the rate with which these patients, over time, transition into immune-active disease, meaning they have an elevated HPV DNA and ALT, and would be our typical patient to recommend for treatment. And what you can see here is that, of course, HPV DNA actually is a decent predictor in the sense that those that have an HPV DNA at cohort entry under 100 have a much lower rate of transitioning to active hepatitis B than those that have a higher HPV DNA level. But this study also showed that there are other determinants and it does tell us that it's not just one thing that we should look at, that there's really a composite of information we have to look at in making a decision whether to start or not start a patient on treatment. And as you can see here, genotype is an important determinant with much higher rates of transition to immune-active occurring in those with genotype B compared to, say, genotype D. And here we see that quantitation for hepatitis B surface antigen was also an independent predictor, although it was a modest differentiator at a level of 1,000. But if we're looking at a patient and saying, should I start this patient on treatment? You wanna find the patient who has a low likelihood of transitioning to immune-active hepatitis B. You could use HPV DNA, surface antigen, and genotype to guide you. Looking at it from the other side of the coin, as it were, this is also looking at hepatitis B, E antigen negative patients, again, in that gray zone. This is reveal data that was recently published. And what they're looking at here is the rate of losing surface antigen. So you could say, well, if a patient's going to lose naturally surface antigen, that may also be a patient that I can hold on treatment. And what they showed here in this very large cohort of 2,500 patients, again, with HPV DNA levels predominantly under 10,000 and ALT levels that are 1 to 1.5 times upper limit of normal, that over a two-year follow-up, that the quantitation of hepatitis B core antibody and surface antigen were excellent predictors of who was going to lose surface antigen. And that the two tests together were better than either test alone. And just to highlight that, you can see here that in the individual who had a hepatitis B surface antigen quantitation level under 100 and their anti-HB core level was less than three logs, that their likelihood of achieving surface antigen loss was over 70%. But in that patient with low hepatitis B surface antigen, but had a higher level of anti-HB core, that individual had only a 41% chance of achieving surface antigen loss. So I think this is just pointing us towards the kinds of biomarkers that might be helpful to us in fine-tuning who are the patients we should treat versus just observe. Now moving on to the decision about stopping treatment. So again, I'm showing you the guideline recommendations and there is a lot of consensus, again, across APOSL, EASL, and ASLD. All patients with cirrhosis are recommended to have indefinite therapy. In the e-antigen positive patients, we do acknowledge that patients who achieve e-antigen serial conversion, that they can have treatment stopped after a year of consolidation, although treating until surface antigen loss is also possible. But I'm gonna focus, again, on that e-antigen negative chronic hepatitis B group because this is where there's been the most movement, I would say, over the last two years. The ASLD guideline indicates that we should give these individuals indefinite therapy. And as I showed you before, their likelihood of achieving surface antigen loss with indefinite therapy, or at least with long-term therapy, is very low. And there's been a movement towards thinking about discontinuation as a means to enhance the likelihood of surface antigen loss. And indeed, the EASL guideline, and I highlight it here because I think it points to some of the nuances related to how to do this, is that it indicates that you can consider NA discontinuation in select non-cirrhotic patients who've had HPV DNA suppression for at least three years and can be under close monitoring, something that I think is very important. And so the principle is, is withdrawal of therapy actually a benefit to the patient in terms of them achieving surface antigen loss? And the answer is yes. And this is a very small but very beautifully done study in which they took patients that had been treated for three years with tenofovir and then were randomized to stopping or continuing. And it's very clear from this graphic that you can see that only the patients in which tenofovir was discontinued achieved a decline in surface antigen, and in some cases, hepatitis B surface antigen was lost. Whereas those that continued with TDF did not have that same pattern of response. So it is this idea that if you withdraw therapy that you can trigger an enhanced immune response leading to surface antigen clearance seems to be supported by these data. And indeed, this is a very beautiful diagram, I think, that details the sort of typical natural history when you take somebody off treatment. So after this prolonged period of suppression and treatment is withdrawn, there is a lag period, typically of several weeks to months, where HPV DNA and ALT levels are generally low. And then you go through the reactivation phase. And of course, during this time, first HPV DNA goes up and then ALT, so-called flare. These flares can be severe. And the reason that it's not recommended to be done in serotics is, of course, a flare in somebody with cirrhosis could lead to decompensation. But if you're patient and you don't re-treat that patient during that phase of reactivation, they will, over time, resolve. And in the end, there are three potential outcomes when you look at these patients one to three years later. A proportion will indeed have active hepatitis E antigen, chronic immune-active disease, and they would, in fact, need treatment. But the most interesting aspect is that we've identified individuals who don't need re-treatment, who have inactive chronic hepatitis B. And of course, we also have a proportion that have lost surface antigen. And it's both the achievement of inactive chronic hepatitis B and S antigen loss that are the real clinical benefits of considering a withdrawal strategy. Now, I showed you the results from the small study from Europe. There have now been numerous studies. I show you here studies that have had follow-up of patients for at least a year and a half. And really, just to point out that the results are mixed in terms of the variability in surface antigen loss and the variability in being able to remain off-treatment, meaning that they have inactive chronic hepatitis B. So you can see that surface antigen loss varies from two to 26%, remaining off-treatment 42 to 74%. And that reflects differences in the patient characteristics at baseline, the duration of the nucleoside analog therapy, the criteria for restarting treatment, and in part, how long they followed the patients. So of course, what one would want to have is a marker that would say, this is the patient I should withdraw because they're gonna get the benefits versus this is a patient I should just continue with the nucleoside analog therapy. And this is where quantitation of hepatitis surface antigen, again, has come forward as being a potential biomarker for this process. So shown on the left is one of the larger studies that looked at the level of hepatitis B surface antigen at the end of treatment and then followed those individuals to see which of those patients needed to resume treatment. So re-treatment being really a marker if somebody who has sort of failed the withdrawal in the sense didn't derive inactive disease or surface antigen loss. And what you can see in the graphic is those that have a viral HB surface antigen level under 150 have a much lower likelihood of having to be restarted on treatment than those that had higher viral levels. And there's been a systematic review that's been just completed, 11 studies, 1,700 patients most, in fact, all from Asia. And in this analysis where they looked at clinical relapse, so that's an ALT and HPV DNA elevation beyond 12 months, so they're kind of waiting for the flare to settle down and see who still needs to go on treatment. And you can see that, again, a viral hepatitis B surface antigen level is predictive with those having a level under 100 having a lower likelihood of needing, of experience in clinical relapse than those that had a higher viral level. And indeed, if you look across the numerous studies that have been done now in withdrawing nucleoside analog therapy, several biomarkers or factors have been associated with the success of treatment, with success really deemed by somebody not needing to resume treatment. And surface antigen quantitation is a deem, the one that's most consistently identified, but just to point out that there are others. Genotype, again, is influential. Whether the patient was E antigen positive or negative at the start of their new therapy, the duration of NA therapy and consolidation, even the two type of nucleoside analog has been purported to be important. And then most importantly, absence of retreating. And by that I mean that if you're during that reactivation phase, if you reinitiate treatment too early, studies have suggested that that makes it less likely that the patient will derive the ultimate benefits. But of course we all know that's quite challenging, sitting on a patient who's having a flare is a very difficult scenario for most of us, and so that sort of speaks to really the issues surrounding this strategy. So coming back to this case, a 29-year-old, 3.5 years on a nucleoside analog, and now wants to stop treatment. So what are the expected outcomes? He has a two to 25% chance he's gonna lose surface antigen if you take him off treatment, and a 40 to 75% chance that he'll remain off therapy. Now you may want to get a hepatitis B surface antigen quantitation to help you with your decision, and maybe if you had a genotype prior to starting treatment, that might also influence your decision. Is there clinical value in the use of the quantitative hepatitis B surface antigen? Well I've just answered that, of course I think it's quite helpful, but I would say that it's not the best predictor, and we really need to refine it, and add to it other biomarkers that will help us identify the patients that will achieve the best outcomes with withdrawal. And then in terms of what are the emerging therapies, I mean I could have spent an hour and a half on all the new therapies, there are many. They're all in early stage development, but we should be excited by the many viral and immune-mediated therapies that are in phase one and phase two. This is a very, very bright future for our patients, and I would also highlight that the nucleoside suppressed, nucleoside analog suppressed patients are going to be one of the groups in which many of the studies will be performed. So to summarize, current HPV antivirals achieve suppression with high efficacy, and they're incredibly safe. We're shifting in terms of our thinking away from long-term suppressive therapy towards a finite duration that achieves surface antigen loss. Target groups for the moment remain those that have active disease and significant for fibrosis, because we know that they derive benefit from treatment. But clearly we'd like to expand treatment to all individuals who have hepatitis B. There's a substantial proportion of e-antigen negative patients who fall into this gray zone, I've highlighted that. And this is where new biomarkers may be helpful in risk stratification. Those I highlighted were hepatitis B surface antigen quantitation, genotype, and NEHB core quantitation. The nucleoside analog withdrawal strategy I think is interesting. It offers an opportunity for finite therapy, but I would emphasize that it should be done very selectively, and this too is an area in which I think more biomarkers to help us would actually make this a much more streamlined process. And then really looking to the future of precision medicine, I think that there's gonna be a real need for us to have these new tests, as I've discussed today, really come to market and be available to clinicians concurrent with the new therapies that we're anticipating. Thank you very much.

chronic hepatitis B

nucleoside treatment

hepatitis B surface antigen

therapeutic response monitoring

emerging therapies

CCC DNA elimination