Well, thank you very much. It's truly a pleasure to be here, and I really want to thank the organizers for inviting me. To cover all of current therapies in 15-20 minutes would be a bit of a challenge, and so I was very grateful that they sort of highlighted the issue of pitfalls and gray zone, and that is going to be where I'm going to spend most of my time focusing. And I think it's very timely still to remind ourselves about sort of where the guidelines are, or guidance documents are, and yet the very real shift that is occurring in terms of how we think about treatment. Currently, our goals with undertaking treatment is we do it in a selective fashion. Our goals are to treat those that are at greatest risk for complications, and our on-treatment goal is to get HPV DNA to be undetectable. In most cases, that translates into long-term and even indefinite nucleoside analog therapy, but this is well-recognized to be associated with excellent outcomes in terms of reducing rates of cancer, decompensation, and liver-related death. But on the horizon, and increasingly we hear more and more about functional cure as really our thinking related to treatment. Here we're, and we'll hear much more from the next speaker about the targeted therapies that we hope will be more broadly applicable to all patient groups, where the goal becomes surface antigen loss and to have a more finite treatment in which you can achieve that. So I'm not going to be talking about the future, but just to sort of say that idea about losing surface antigen is influencing a lot of what we're now seeing come out in publication. This is one, this year, two multi, multiple analyses or meta-analyses were performed to look at, well, how often do we see surface antigen loss, both spontaneously and in the context of treatment, and those two analyses really yielded very similar results, and the number to sort of hold in your head is that it's about 1% per year. And so as shown in the figure on the bottom, if you have an individual who's infected at birth and you're following them over their lifetime, indeed they will lose surface antigen, but that rate is obviously slower than what we'd like, and it occurs often at a point in which they've already incurred significant liver injury that places them at risk for complications. And although treatment can enhance that, it does not enhance it in the way that we would like. And you could argue that perhaps, you know, we are really needing to push the therapies we have, and I want to give you a sense of, well, what do we achieve with current treatment? Shown here is just data for three years, and in the case of peginiferone, this is off-treatment data. In the case of the preferred therapies, entecovir, xenofovir, EDF, and TAF, those are on-treatment results. But the bottom line is that while we see higher rates of S antigen loss in people who start out being E antigen positive when we initiate treatment, those rates are still in the range of only sort of up to 8, maybe 10% after three to five years of treatment. But remarkably, in the E antigen negative group, it's almost never seen in the case of individuals on therapy with nukes. And so while we may, I think, want to see this as our endpoint for therapy, and indeed the guidelines embrace this as something that's desirable, it's very infrequently achieved with current treatment. So in the absence of having curative therapy, meaning that we have those individuals that get to functional cure, all of the guidance documents continue to be focused on targeting patients who are at greatest risk for complications. Not to say that that's highly desirable. I think we all would like to have a broader range of drugs that can achieve a greater rate of S antigen loss, but this is where we are currently. So in the Treat Now group are individuals who we term to have active chronic hepatitis B, and as I'll show you, that's defined really by three parameters, ALT levels, HPV DNA levels, and to some extent stage. We recommend treatment of all serotics, and then there's certain subgroups in which treatment is also recommended, which is those immune-compromised groups, those with co-infections, and family history of HCC is also regarded as an important consideration for treatment. But there's groups in which we defer treatment, and I'm going to speak a little bit more about those groups, because I think that's in fact where the gray areas lie, and that is in those that have inactive chronic hepatitis B, and those that have immune-tolerant, or the new term chronic hepatitis B infection. So when we are considering treatment currently, these are the guidelines that I put up, the guidelines from ASLD, ESL, and APOSL. They're very similar in terms of recommendations in the sense that they're focused on using HPV DNA levels, ALT, and do consider stage as being important. While there are some subtle differences I would say, you could argue maybe they're more than subtle, some use upper limit of normal, some use two times upper limit of normal. What the cutoff is for upper limit of normal also varies from guideline to guideline. But the basic tenet here with who are we trying to identify for treatment is you want to have somebody whose ALT you believe is related to their HPV disease, and that there's enough virus to make that sort of believable. So what we want to avoid is treating somebody who's got fatty liver and ALT elevation and a low HPV DNA, for example, or someone in whom we think the risk for their complications is low. So while we use cutoffs of 2,000 and 20,000 for E antigen negative and E antigen positive respectively, I think that really the message I always sort of convey is that these are guidance sort of statements. So don't get too hung up on the numbers, it's more of the concept. We're looking for individuals whose liver disease is being driven by ongoing HPV related injury. Now the gray zone was one of the aspects that I was asked to speak about and I thought I would just present to you some data about what does gray zone look like. And I use the term and maybe I'll define it for you so that we're all sort of speaking the same language. It's really these individuals who don't fit into a nice bucket of having an ALT and HPV DNA level that's high enough to say, oh yes, this is somebody I definitely need to treat, or low enough that you can say, I definitely don't have to treat. And so shown in this diagram, which is data from the Hepatitis B Research Network, where these are untreated individuals who presented for cohort follow-up, what it shows you here is on the bottom is the DNA levels and on the y-axis is ALT. And I'm showing this for males and females here just to give you, and these are E antigen negative patients that I focused on. But you can see that in terms of where are the gray zone patients, if we focus here, majority of them are individuals who have an HPV DNA level that's low, but an ALT level that tends to be higher than upper limits of normal. So this gray zone here. There's also sort of another gray zone, which is the individual who's got a higher level of HPV DNA, but maybe has normal ALT, but you can see that's much less frequent. So it's this gray zone group that I think causes the most grief for all of us in the sense that you have somebody who's ALT levels higher than you would sort of feel comfortable with, but their HPV DNA level remains low. Should you treat or should you not? And there's been a few papers that have come out in the last year that I think help inform that. This is, again, a paper from the HBRN in which they took patients with this gray zone phenotype. Meaning an ALT level, in this case, they didn't look at ALT levels, they looked under two times upper limit of normal, but they used an HPV DNA level that's under 10,000. These were all e-antigen negative patients and then looked to see, well, what happens to them over time? How many of them declare themselves as being e-antigen negative chronic active hepatitis B? Meaning that their ALT levels rose to a level and HPV DNA levels rose to that which we would consider should be treated. And what you can see here is that it certainly does seem to be influenced by the baseline HPV DNA level and that you can see in the bar at the bottom is the individuals that had an HPV DNA level that was less than 100. This is between 100 and 2,000 and this is over 2,000, up to 10,000. And you can see that, yes, clearly the higher level of virus, the more likely is that you transition into having active hepatitis B. But I'll draw your attention to the fact that this is over five years of follow-up, that overall the rates are still very low, ranging from 5% over that period of time, 5% per year up to 12% per year. What this says is that the vast majority of individuals in this gray zone tend to remain either in the gray zone or as inactive carriers. So it does support the current guidance which generally says you should follow these individuals to allow them to declare themselves. There's also a nice study that came out of Europe. This is predominantly with the Caucasian patients and what they did here, again, they're focused on those gray zone patients that are e-antigen negative. Here they use an HPV DNA level under 20,000 and an ALT under 80. And you could argue some of those may be in that realm where you might think about treatment. Here what they're looking at is how likely are they to lose surface antigen and do they lose surface antigen more quickly if they truly are inactive carriers, meaning HPV DNA levels under 2,000 in a normal ALT versus being in this gray zone. And that's what's shown here. So you can see here that this is the gray zone patients and those are the inactive carriers. It shows that the inactive carriers lose surface antigen sort of more quickly, but after you follow these individuals for a period, in this case, a median follow-up of around 300 months, you can see that they get to the same place. So with this median follow-up, they found no difference in terms of achieving surface antigen loss. And since that is becoming our new endpoint or desired endpoint for treatment, you could argue again, do we need to treat the gray zone patients or will they just as easily get to where we want them to be? So I'm gonna just sort of close by saying that I think the current data, the emerging data is focusing on this gray zone group, but that watchful waiting rather than treating seems to be supported by the current data. I'm sure there'll be some discussion about this. There are new biomarkers that I didn't go into, but I think are still emerging that might help us to put patients into one bucket versus the other. Hepatitis B-correlated antigen and maybe the quantitative anti-HPC are sort of emerging as markers that might help us in terms of identifying those individuals we should treat. Of course, we'll let other causes of elevated ALT and I was... I think most of us are looking for other reasons why we have to treat. So not to forget the patient that gets older, the patient that's got the family history, and I was looking to see if anybody's got significant disease. These would be other reasons to initiate treatment in a patient in the gray zone. Now the other gray zone, I would say it's not so much a gray zone, it's just a controversial group, is in the e-antigen positive patients. So you'll notice here that, again, this is the same diagram, HPV DNA levels here, ALT levels here. The first thing you'll see is that there's not very many true gray zone patients here. Most of them fall into being either e-antigen positive chronic hepatitis B, which would be individuals with HPV DNA levels over 20,000 and an elevated ALT, and then there's this immune tolerant or chronic hepatitis B infection group. This group currently is not recommended to be treated. These are individuals that have a normal ALT and a high HPV DNA level, but I think there's been a lot of concern that viremia, we know, is associated with HTC and should we be treating the immune tolerant patients? I show you here again the guidance documents. Where are we in terms of thinking about this? Well for that immune tolerant group, which I'll remind you is very high levels of viremia, normal ALTs, they're typically young age and they have normal histology and or liver stiffness. Really that's the definitive group of immune tolerant or chronic hepatitis B infection. All the guidance documents are really consistent. They say no, do not treat. But what's interesting is that they really bring the age into play and I think this is something that we perhaps have not focused on and we should because you'll see there's some variability across the guidance documents on when you might want to think about pulling the trigger. The reason is that generally as people get older we do worry that they actually may have underlying disease or that we worry about the duration of their viremia and how that might be influencing future cancer risk. But just to highlight there's some variability. With the PASL and ESL recommending consideration of treatment above the age of 30, ASLD using 40. So I think that this still remains very controversial. The cons, the reasons why we continue to recommend in the guidance documents not to treat is that we haven't shown in a prospective study that if you treat somebody who's in the immune tolerant phase for decades that you reduce their HCC risk. So we don't have that data. We would like to have it, but it's not there. It's actually challenging to achieve HPV DNA suppression. I'll show you some data on that. They have very low rates of E antigen loss and essentially no S antigen loss which is our new goal for therapy. And then I would argue that there may even be some downsides that those individuals might naturally transition in a way that we would change by treating them. Now what are the pros though of treatment? Well I would say the first one is that it makes us feel better because most of us are pretty uncomfortable with all that virus and not sort of doing something. You know, you've got a hammer, you sort of want to hit that nail. But, and I would say there are some instances in which you would treat. You want to decrease risk to others. So that's why we treat healthcare professionals. We might treat, you know, we treat mothers that are going to give birth. So there are subgroups in which we want to use it as a transmission risk reduction. But I guess what we're all wondering is really if we treat, will we reduce that risk of cancer for the future? So I am only going to just remind you of how hard it is to treat. And this is very nice data from Hong Kong. It was a randomized trial in which they treated patients with either TDF or a combination of TDF and tricitabine. These were typical immune tolerant patients. Median age was 33. Very high levels of virus. And you can see their liver ALTs were normal. So the first thing I'll point out to you is the proportion that are not suppressed. And this is after four years of treatment. You can see that in the TDF group, which is here, that only about 60% of the patients have an undetectable HPV DNA level. So that tells us that it is actually quite challenging to get them to be HPV undetectable. And if we don't achieve that end point, do we in fact derive the benefits we're looking for? And you can see here also E antigen loss, S antigen loss are very low. Now a paper came out this year that sort of I think made us all pause and think well maybe we need to rethink it. This is a study out of Asia. And what they did here is they compared HCC risk in patients that were untreated versus those that had immune tolerant versus those that had treated immune active chronic hepatitis B. So taking that as the control group as it were. What they showed here in red is that the IT group indeed had a higher rate of HCC and it was the hazard ratio of around two. And it was a very well done analysis with lots of attempts to try to control for confounding. And so that was a pretty strong message that maybe treatment indeed should be undertaken. But I want to highlight for you that this is not sort of your typical IT population that was studied. Their median age was a little bit older, 38. You can see that their viral loads, while a proportion of them are in the high viral loads that we associate with immune tolerant, there was about 25% of the patients that had viral loads that I'd say were lower may represent actually immune active disease and also reflected by having lower platelets. So there's a mixture here is my point. Some of these patients were immune tolerant, but when you're looking at these studies you have to kind of ask yourself how many of the immune active patients might be in there. So this misclassification of individuals who have low level immune activation is really I think the question we have to ask ourselves. How do we find those patients? And again I think age is probably going to be an important determinant for us going forward in terms of thinking about when we should stratify the immune tolerant patient into treatment. Now I see that I have only a few minutes left. I want to finish by just focusing on sort of the preferred therapy. And this is I think a good segue into the second proportion of the talk for this afternoon. I think Mindy gave a very nice review of kind of how the populations of patients with chronic hepatitis B are changing. So we have three preferred therapies that are oral. Of course peginephrine is also recommended, but I didn't include it here since it's infrequently used. And sort of how do you decide? Well the guidance documents all say that we have these three drugs and we recommend them all in individuals with no comorbidities. For individuals that are at risk for either bone or renal disease in general it's recommended that TAF or Entecovir be prioritized over TDF. And then if you have that subgroup of patients that either have HIV infection or prior lamivudine exposure then you would prioritize TAF or TDF over Entecovir. And I think very nicely shown is that our population of hepatitis B patients is indeed aging. And if we use the criteria based on age alone a large number of our patients now are going to be prioritized to this group which would be TAF or Entecovir. Now the one other factor that sort of came in, and this is to set the stage for the remainder of the talk, is the question sort of came up is, is there one more factor that we need to consider when we're choosing our initial nucleoside, nucleotide analog? And that is, is there a differential effect of the nucleoside analogs on cancer risk? And as you know last year a very provocative study was published in JAMA Oncology in which they showed that individuals who had been on Entecovir treatment compared to Tenofovir had higher rates of HCC. It was a very well done study, very rigorously conducted and then reconducted. And then there's been really additional studies since then. This is the most recent one published in Gastroenterology from the Hong Kong group. Again, very rigorous statistical approaches to try to control for confounding. And a similar differential scene in terms of Entecovir versus Tenofovir. Begging the question of do we have to think about that as well when we're selecting our nucleoside, nucleotide analog. I've always been concerned, and I think anybody who looks at retrospective data has to ask ourselves, well is there still some residual confounding present? Are there more smokers in one group than the other? Is there more NAFLD in one group than the other that's pushing them towards having more HCC? And I would say this is probably an area where there's going to continue to be more studies, but I'm just pointing out a few that have been showing the opposite. So I'm sure you'll hear more about them, but this is just one study. Showed no difference between Entecovir and Tenofovir. And I've listed three others that have come out and there's several more at this meeting. So this I think remains a very controversial area and one in which I think we're going to hear more about today. But really I think one more issue that has come into play in terms of us thinking about our treatment for hepatitis B. And with that I'll close. Thank you.

hepatitis B treatment

challenges in therapy

high-risk individuals

personalized treatment approaches

antiviral medications