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Where Are We? The State of HBV

Well, great. We're going to come back to those exact same questions. You'll hear the data to support the correct answer in the presentations to come. So please pay attention and we'll come back to that a bit later.

But let's get started. And I'm going to turn the microphone over to Jen Wild, who's going to talk to us about where we are with the state of hepatitis B.

Chronic HBV Burden in the US

Jennifer Wild (University of California, San Francisco): Thanks for having me. And thanks everyone for joining today.

Right now we're just going to go into a little bit of epidemiology and go over some prevalence and incidence rates, mainly to highlight the key populations that are at risk and perhaps underserved.

So overall prevalence for chronic hep B in the United States have – has been steadily going down over the last 40 years or so, and overall, the prevalence is only about 0.35%. However, it's almost four times higher among foreign born persons. And I want to examine mostly the Asian American populations as well as non-Hispanic Black populations in the United States. And for those two groups, prevalence is much higher than in the general population overall.

For Asian Americans, this group represents 60% of all chronic hep B infections in the United States. And among Asian born immigrants who come to the United States, the prevalence is over 7%. In non-Hispanic Black populations, the prevalence is higher, too, but especially among those from East African countries, Ethiopia, Eritrea, that region of the world.

Awareness of Chronic HBV Infection Status

Unfortunately, awareness of the chronic infection status is also rather poor. Worldwide, only nine in 10 people who have chronic hep B – or sorry, only one in 10 who have it are aware. In the United States it's about 50-50. And among Asian Americans, who again, have some of the highest prevalence rates in the United States, only one in three are aware that they have chronic hep B infection.

Screening Recommendations

So there are some universal screening recommendations in the United States. And these also vary to some extent on the state level. We encourage that all adults 18 years and older get universal screening at least once in their lifetime. There is more specific screening for people in certain situations. So all pregnant persons in the first trimester, regardless of their vaccination history. And these people should get the triple panel test, which we’ll – we’ll just briefly touch on here. You can see listed there. It's a surface antigen, the surface antibody and the core antibody.

There's also a risk factor-based testing. So patients that are more involved with high-risk activities or are placed in high-risk situations. That's people who maybe are incarcerated, sex workers, IV drug use or have history of hep C virus.

Now, if the surface antigen for hep B is positive, that should also trigger hep D antibody testing with reflex testing for hep D RNA PCR if it's positive.

Faculty Discussion

Dr. Sulkowski: Well, great. Well, thank you for that overview. Some pretty startling data about low awareness rates. And there are universal recommendations for screening. But at least in – in our academic hospital system that's not really happening. So how do we change that? How do we make people aware, both people that may be – may have hep B and clinicians caring for them. What do we do to change these abysmal numbers for awareness?

Jennifer Wild: Yeah. I think, unfortunately, coming from academic centers, like we all do, we – it's – it’s kind of too late to bring it up. By the time they get referred to us, you know, there have already been multiple failures, failures to – to engage with the patient or the community.

And so I think there are some kind of community outreach programs, there are different mobile testing, going to churches, as silly as it sounds, and I'll touch on that later, but meeting people in the community and not necessarily waiting until they're in clinic in front of us to – to bring it up.

Dr. Sulkowski: So really taking – taking the message to where people are really needs to be done and lots of ways to do that. I know we'll talk about that.

I wanted to dig into the second question here. So let's say you've gotten the message out about screening for the triple panel and people are doing that. I have certainly found in people that I talk to, whether it be medical students or seasoned clinicians, that they may be confused by the results of that.

There's three tests: surface antigen, surface antibody and core antibody. And you're supposed to get all three and you can classify patients. So I'm going to start with a simple one, which is their s antigen is positive, meaning they have active infection. And we won't get into that because Norah is going to tell us how to handle people who have active hepatitis B as she walks through the guidelines.

But let's talk about someone who has core antibody positivity but no surface antigen. What do we do with that person? What do you tell them? Jen, why don't you start with that? And I'm going to ask Jordan next.

Jennifer Wild: Sure. So I think you're referring to people who have a past infection. And for me, coming from the oncology space, HCC and hepatobiliary, we follow guidelines from ASCO when it comes to treating those patients with NUCs with, you know, antivirals if they're going to start certain types of systemic oncology therapy.

Dr. Sulkowski: So they've got prior infection that's not active. Jordan maybe walk through. It's a confusing situation for people. I know patients I've counselled have really kind of said, “Well, wait, how is this possible?” Setting that aside, how do you – what do you tell them about the virus? And Jen has appropriately highlighted the risk of reactivation. But Jordan, let's maybe dig a bit deeper. Why is that coming back? What's going on there?

Dr. Jordan Feld (University of Toronto): So I think one of the important things to highlight to people, I've never loved the term resolved infection, because there is still a trace of hepatitis B remaining in the liver, and that's the real message that the people need to hear. But it's also important not to scare them that they don't have – that they don't have a current infection. And the degree of immune control is quite good when surface antigen is cleared. So it really takes very potent immunosuppression to see reactivation in that setting.

And so I think it's – it's a message of A, reassurance, but B, recognition that there is still a trace of virus there. And probably the most important thing that I find is making sure that they get their family members and partners screened, because that may not have happened prior to this.

Dr. Sulkowski: Great. Well, that's an important point. And there is a very nice, updated guidance for clinicians on how to handle that person and maybe at risk reactivation from the AGA.

Now, I'm going to touch on the – the next group. I'm going to leave alone people who are vaccinated. They are s antibody only. But what about the person with no markers positive? They're not protected against infection, therefore at risk. So, Jen, take us through vaccination recommendations. That used to be a fairly standard topic, but it feels a bit more controversial today.

Vaccination Schedule: Infants

Jennifer Wild: Yeah. So for those patients who are just negative across the board, and to go back to something you said earlier like, yes, a lot of stress with newer clinicians googling for that hepatitis B serologies chart. And just shout out to the Hep B United group. They have a really good serologies chart.

But anyway, yes, if they are negative across the board, that's the perfect person to vaccinate. Now for infants, typically this is the first dose given within 24 hours of birth. And then there are two more vaccines for a total of three. That's, I think, what I see most commonly in – in where I practice. There's also the four dose combination, which is a vaccine that's not just for hep B, but for other childhood illnesses. And that's a four vaccine dosing schedule.

Vaccination Schedule: Children ≥1 Yr of Age and Adults

Then there's a different schedule for children who are over a year old, up through adults up to, I believe, age 59. And that's still a three vaccine schedule. And there's a two-dose monovalent that I think is – is less popular where – where I practice. But – or sorry, I don't see that as much, unfortunately. I wish we did.

Dr. Sulkowski: Yeah, I'll comment. Our system, we aren’t using the two-dose vaccine because of higher responses – and but it depends on what's on formulary at your hospital.

Jennifer Wild: Yeah, what's on formulary. But the two-dose is nice because then there's less opportunity to lose the patient to follow up, and then they don't complete the third one.

Faculty Discussion

Dr. Sulkowski: Well, great. So I feel like maybe a year ago, we would not need to have discussion on this. But how was your approach to vaccination changed in the current era? A lot more people are perhaps questioning the need for vaccine. Maybe I'll ask each of you to comment. And Norah, I've not picked on you yet, so let me start with you. How are you talking to people about hep B vaccination today?

Dr. Norah Terrault (University of Southern California): Well, I think, you know, in – in my clinic, I'm usually getting patients who are being tested for other liver diseases. Then we find they don't have protection and – and recommend that they should be protected because all adults now, at least between 18 and 59, are recommended to be vaccinated. So it's always a recommendation.

But I think what you're referring to is that more often you get a question about, do I really need it? And then probably a little bit more around are there risks? Although I don't think that's really been a big issue. It's more like, do I really need it? Because it seems new to them to be hearing that as adults, they need to be doing catch up vaccine, as it were. So I think explain to them the value of – of the vaccine and that you can get exposed to hepatitis B sort of in ways that you may not even recognize through close contact with individuals who they themselves might not know they're infected.

Really we talked about people not being aware. So, you know, it's all around how do we protect.

Dr. Sulkowski: And that may be an important point, particularly if a newborn doesn't get the vaccine at birth, they may be exposed in other ways. Jordan, you – we chatted about this a bit earlier today. What are your thoughts there?

Dr. Feld: So I think that the discussion around universal birth dose vaccination, which is – I think, where this is now becoming more of a question, particularly in the US with the – the change in the – the CDC recommendations to discuss it with a healthcare provider. It certainly is putting some uncertainty for people. And – and I think where we'll probably not have a problem is people who are born to surface antigen positive mothers that usually the – the – the pathway for getting hepatitis B immune globulin and vaccinating the child at birth is – is really pretty standard.

But where I think we might start to have a higher risk is losing people where another household member, so a father, another – or other parent, a grandparent, another caregiver in the family that they may not routinely be doing universal vaccination in that setting. And I think that's where we really need to remind primary care providers why this is so important to make sure those babies are vaccinated at birth.

Dr. Sulkowski: And perhaps the other comment I'll make is that at the time of birth of a child, no one anticipates the risk they may get into as teenagers or young adults. But having raised four children, I can assure you they – they will change from the time they're born.

So I think we can move on from vaccine and maybe talk about – but it does highlight this, that the way people engage with healthcare information is different today. There's AI. There's a lot more, let's say, perhaps skepticism about the scientific community and that has the potential to actually increase stigma and decrease access to care.

Barriers to HBV Care in Immigrant Communities

So, Jen, maybe take us through some of the barriers to when you've identified somebody with hep B and we know they're at risk for complications, including liver cancer. How do you engage them in care? Maybe you could take us through some of the things that you encounter.

Jennifer Wild: Yeah. I mean, the connection to liver cancer is – is really quite heartbreaking. I myself am a chronic hep B patient. I was adopted from South Korea when I was only three months old. And I got my first vaccine like three weeks later after arrival to the United States. And I didn't know that I was already infected until I was doing all my occupational health screening for my first nursing job, if you can believe that. And it was – it was kind of traumatic because I thought, “Oh my God, can I even still work in the profession I just chose?”

And I think, you know, immigrant communities, especially there – there's unfortunately just a lack of knowledge. And this is a really personal thing for me because so many of my patients, they don't know they have chronic hep B. I believe it's somewhere between 25 and 50% of chronic hep B are – are connected to HCC later in life. And I see patients my age who get, you know, fulminant HCC. And it's quite sad.

So access to care I think is – is a tremendous barrier. Having insurance, knowing how to navigate the health system, knowing how to advocate for yourself.

Stigma, there is still some perception that if you've got this disease, it's because of something you did, some untoward social behavior you participated in. There is unfortunately, too, a misunderstanding between hep B versus hep C in some of these groups. “Oh, there's a cure for that one. If I have it, it doesn't matter. They'll just cure it.” Unfortunately, maybe not. But maybe. We'll – we'll talk about that.

And knowledge about it too. So Dr. Patricia Jones did a nice study interviewing African immigrant populations and comparing them against African American populations that were born in the US. And knowledge and perception towards prevention were quite different in those populations.

They – there is also some – in the middle there, you see religious values and cultural norms. Interestingly, some groups cited that religion was a barrier to seeking care because of a belief that if – if God has given me this illness, then that's what's just going to happen and there's nothing to do about it, unfortunately.

Strategies to Increase HBV Awareness and Debunk HBV Myths

So there are a few strategies and – and ways we can engage communities that have been shared in – in the literature. There are some really good public health campaigns in the United States right now. There's Hep B Free New York, Hep B Free San Francisco. And these are initiatives that have actually combined resources that have been put towards hep C and HIV screening and awareness. And they'll just do all three at once in a mobile van. Go to – go to community fairs, go to street fairs, go to things that are maybe health related, maybe aren't, but just to be present in events in these communities, you know, different neighborhoods that have these immigrant populations.

Second, there is the implementation of processes with healthcare providers, primary care providers. And I feel this one can't really be underscored enough because there was a pretty good study that came out of Mayo some years ago that showed that if the primary care provider gets notification, the charts flagged in advance of an appointment with a high-risk patient.

The likelihood of completing hep B screening increases over fourfold. And so it can really make a difference if we do things like implementing best practice alerts and things like that in our EHRs.

And of course, culturally and linguistically appropriate education is important. When it comes to correcting misconceptions, there are some misconceptions in the Asian American community that some of these liver things may not be attributed to hep B and can be addressed with lifestyle and different dietary changes. And we know that's just not adequate.

And community health outreach too. I think that here – there was something I wanted to say about hep B free and I forgot about it, but I'm just trying to fly through and I'm looking at the clock here. But there are a lot of high risk underserved groups and trying to get them to come to us, I think is – is not realistic. We need to go to them.

Dr. Sulkowski: Well, I think one point you've made nicely is that there's not one solution. It's multiple different things we need to do, tailored to each individual group. Because although we've talked about people from Asia, it's actually an incredibly diverse community of folks. And so I think it's really a nice slide to highlight all those different approaches.

Faculty Discussion

And the other thing that I've seen in patients that we've talked to, I kind of want to get into this discussion is, how do you empower them to now take part in their care? I've seen a lot of people who, maybe 10 years ago, were told they were a carrier, a term that I think has done a lot of harm in how we manage people with hep B. And how do you get them? And they just kind of said, “Okay, I'm a carrier, not a big deal.” And they probably were told that, but how do you get them back engaged in care? Or how do you take someone who's newly diagnosed? And Norah's going to talk to us about shared decision-making. How do we lay that framework at the time of diagnosis? Any thoughts from the – I'll start with the – open up the whole panel.

Dr. Feld: I mean, I think I think you have to really look it's very individual. So I – I think some people want to know a lot about their condition. And some people – unfortunately, there's remarkable availability of information, you know. Obviously, the sources are of varying quality. So I think directing people to useful resources and trying to have those available in your clinic, making sure they're linguistically appropriate. So translated and things can be helpful.

And then you still will find people that are very comfortable just saying, “Tell me what to do? I don't – I don't want to be too engaged in care.” And I – I think we have to be respectful of different people's perspectives on this. But fortunately, more and more people are interested in becoming active participants in their care.

Dr. Sulkowski: I think maybe one point I want to emphasize is that hepatitis B is largely asymptomatic, and there is this kind of phenomenon we all kind of go through. You wake up in the morning, you feel pretty good, so you must be okay. And I tell patients, the liver is very forgiving. It's not going to tell you that it's sick until there's a real problem. And Jen, you talked about people presenting late.

So unfortunately, you can't be guided by symptoms. One of these things you have to be proactive. So perhaps no easy solutions. And maybe it's also been complicated by the fact that the guidelines for who should be treated is somewhat complicated.

And I'm going to turn it over to Norah, who's going to walk us through some new updated guidelines. We'll touch briefly on WHO, but really focus on the AASLD, the liver society just published new guidelines that really kind of perhaps change how we think about decision-making.

So, Norah, I'm going to turn to you and let us walk through kind of what the thinking was. You had a big part in crafting the guidance from the society. So walk us through that.

Dr. Terrault: Well, first of all, I'd say I'm joined on the stage by others who participated in that. But – but I think this is really a – leads very nicely from prior discussion. Because I – the new updated guidance really asks us to think more about having that – each time we see the patient to have a discussion about where they're at with their infection, their disease, and what that means in terms of the decision being made that day. So it is this very active ability to kind of know that the disease changes. And so too they do, their circumstances. And therefore, we need to be adjusting our treatment decisions related to that.

New WHO Guidelines: HBV Treatment

So let me start first with the WHO, which came out with its new guidance actually more than a year ago. The reason this is important is that it really pushed, I think, everyone who was thinking about doing guidelines to thinking about how do we be more expansive. As Mark nicely highlighted, in general, I think it's viewed as complex making decisions about treatment. And I think we want to dispel that. We want to make it easier and more straightforward to take – take decisions regarding treatment.

So – and the WHO, of course, is writing guidelines for the globe. So they're often writing guidelines for places where there's less resources, less ability to do frequent testing. Sometimes they don't even have an HBV DNA level that they can use. So they went really for this very simple approach to – to treatment.

So just to lay out what that is, the WHO guidelines says that if you have somebody who's over the age of 12, that if they have any signs of advanced fibrosis, and this was defined by having an APRI score, for example, greater than 0.5 or elastography of seven or more. So that's not advanced. That's actually just some fibrosis, basically F2 or higher or cirrhosis. That in itself, regardless of ALT or HBV DNA level is a reason to be on treatment.

And then the next level is if they have a viral load over 2,000 and an elevated ALT and ALT normals, you'll see there is 30 for men and 19 for women. Again, that individual should be on treatment.

And then finally, they added a list of other circumstances in which you should think about treatment, which are quite broad actually, co-infections, family history, immunosuppression, which we touched on before. But importantly, they also started to point towards comorbidities that are particularly related to the – the very frequent coexistence of metabolic dysfunction-associated steatotic liver disease, or MASLD.

So that's really a very broad landscape of offering treatment. I will say that it influenced AASLD, although we are somewhat different.

New AASLD 2025 Guidelines

So let me just take you through AASLD. Now, this may look like a busy slide, but I'm going to start at the top, and I – I hope you're going to sort of see this as simpler and – and more expansive. Okay?

So the first on the left is if you have someone with cirrhosis, that hasn't changed. We previously recommended that person should be on treatment indefinitely. That's still the same. So you need to stage the patient, so you know if they have cirrhosis or not.

If they don't have cirrhosis, we still recommend use of e-antigen as a – a risk stratification tool. You'll note the WHO does not do that, but we still feel this is important. So we go down the side of the e-antigen positive patient. Again, we – anybody who's got an elevated ALT level greater than two times the upper limit of normal and a viral load over 20,000, we recommend treatment. That is not new. That was always the case. That’s so-called immune active disease in the e-antigen positive patient.

But what you'll see in that purple box in the middle on the e-antigen positive sign is there's a new one. And it says if you have somebody who's immune-tolerant, okay. So immune-tolerant is somebody who's got an elevated HBV DNA level, but their ALT level is normal, that that individual should be considered for treatment – and I see that this got flipped - if they're over the age of 40 or if they have fibrosis. Okay?

So now for the first time, we're also recommending that immune-tolerant individuals who have an age of 40 or high – that are over the age of 40 should be treated. So that's new in the guidance.

What you'll see also in this slide is, under the e-antigen positive, we have a – a group that we say you should consider treatment in. So this is where that shared decision-making is going to come to – into play, and I'll go through this in a bit more detail. But now we're going to talk about doing treatment as a means of preventing transmission. We're going to talk about the indeterminate group. And again, immune-tolerant here, but now under the age of 40 is also a group in which you can consider treatment. Okay?

Faculty Discussion

Okay. So we have a considered group and we have a definite group. So let me take you through a little bit of the data to kind of, if you don't mind, to just at least talk about the immune tolerant group, just – oh, okay, we can talk about this first.

Dr. Sulkowski: Yeah. Yeah, I think we want to –

Dr. Terrault: Yeah.

Dr. Sulkowski: So this whole – let's pause for a minute.

Dr. Terrault: Yeah.

Dr. Sulkowski: You'll get to the immune-tolerant in a bit.

Dr. Terrault: I will. I will.

Dr. Sulkowski: And I think the key message from immune-intolerant is that everything gets worse when you get older. So being old is bad. Being young is good.

Dr. Terrault: Well, I don't consider over 40 old, but there you go, I guess.

Dr. Sulkowski: Well, Norah, I hate to break it to you, but that's a different conversation. But let's talk about the shared decision-making. We talked earlier about empowering patients. And in my mind, shared decision-making really is empowering patients to be part of that. And we're going to get into that a little bit. And then we'll get into some of those – those unique groups where we're going to apply these tools.

But maybe, Jordan, how do you apply this? What does it mean to you? Shared decision-making?

Dr. Feld: I mean, I will say this has been the biggest change for me because when some of the people look at the guideline, they're like shared decision-making, that's a bit of a waffly term. It's not really definitive one way or the other, but it really has changed the way – it's changed my practice.

I am now regularly having conversations with people every time I see them, and it's really interesting for me to see how people really view this as you walk them through the – the – the recommendations and why we would consider treatment, why we wouldn't consider treatment and really understanding where they're coming from, what are the values that they will place on treatment and the – the risks or benefits that they'll perceive from not being on treatment.

And it’s – it's definitely led me, particularly in people in some of those phases, like the indeterminate group where we really weren't – we're still uncertain. The data are not so clear. And I think actually, people really appreciate when we're honest about that, that the data are not, that there's some ambiguity about the benefits and risks of treatment that they – and they – and then they take part in that decision-making.

Dr. Sulkowski: You can also take into account their own worldview, their life, you know, are they – can they fit in a daily pill into what they're doing? I've certainly talked to a lot of people, have a family member who had liver cancer, which, you know what the guidelines that may be something that sways them as well. So it's really getting to treat that person.

And I'm from Hopkins. We like to quote Osler, but there is a famous Osler quote that says, “You treat the person with the disease, not the disease.” And that's kind of what we're really talking about is taking care of that person.

Improving Engagement in Care: Shared Decision-making

So, Norah, I'm going to throw it back to you and – and just talk through some of the framework that the committee considered.

Dr. Terrault: Yes. I – I think we really were trying to encourage more dialogue. We wanted to give more permission, really, to clinicians to have flexibility in this decision-making. We really didn't want the guidelines to come across as you do it this way and this way only.

Shared decision-making means that you can take the information, take your individual patient, put it together, and then ultimately make a decision around treatment. And – and the data that's available about using that shared decision-making approach is a way that you're educating the patients as you're doing it. So they're gaining from that. They feel – we talked about how do you empower patients. You can empower them by having this improved engagement about why you're – you know, you may be struggling with whether to treat or not.

And you're definitely going to be taking into account what that person's individual circumstances may be. So, for example, you know, we're going to talk about the fact that we now treat as a means to prevent transmission. Well, that means you have to have a discussion with the patient about what are the kinds of behaviors that they may be engaged in, which may put them at risk for transmission to others? It helps you to sort of understand their circumstances, and I think sort of builds the relationship you have with them in order to make the right decisions.

And, you know, we think about the drugs we have. The nucleoside analogues are really very safe, highly effective. And that's why the WHO was also very enthusiastic about really, this is a very safe treatment, which we know works. So that's why they were very kind of expansive in their treatment.

But I think Jordan highlighted that, you know, sometimes a pill a day can be something that's a big deal for a patient. And we know that if we're going to put them on treatment, they're going to be on treatment a long time. So we got to be kind of engaging them about what that means to go on treatment and – and may be a treatment that's going to be for a long period of time.

So ultimately, those conversations build a relationship that really gets to a better decision about whether the patient should be on treatment or not. That was the intent.

2025 AASLD Guidelines: Expanded Treatment Criteria, With Use of Shared Clinical Decision-making

Dr. Sulkowski: And then the – the panel really pulled together some key areas where clinicians should be applying shared decision-making. There were those categories where it was a definitive, yes, treat. But walk us through some of these, how the panel was thinking about that and why they came up with shared decision-making for these?

Dr. Terrault: So this – this, I think is a very nice summary of the changes that came to the guideline. And so you'll see at the top that's not a change. Actually, we just modified when you start treatment. But pregnant women with high viral loads regardless of the antigen status is still a recommended therapy starting at gestational week 28. That's to prevent mother to child transmission. So that modification was only in the timing of the treatment.

But you'll see immune-tolerant now, right? Remember immune-tolerant is defined by somebody whose e-antigen positive, has a viral load that's very high, greater than 10 million. We defined it by, so seven log, and a normal ALT. So less than 19 for a women, less than 30 for a man. That's immune-tolerant.

And what we say now is if you're over the age of 40, right, you treat those patients, right? There's not shared decision-making. This is treat. But if they're under 40, you could consider treating them, again in this shared decision-making approach. And so that gives – that's a very different recommendation from where we were with the prior guidance, where we actually recommended against treating immune-tolerant.

So we've come a long way. We now say you definitely treat if they're over the age of 40 and if they're under 40, it's a shared decision-making situation.

And then the others are indeterminates, which have always caused us grief where they don't quite have a viral load that's high enough or don't quite have an ALT level that's high enough to meet the threshold for being immune active.

Well, now we say that that's also a scenario where you could consider treatment, again, a shared decision-making about the potential benefits of treatment and potential risks.

And then finally, this new category of treat to prevent. So here what we're saying is we're going to consider the individual who has a high level of virus and we're not treating them for their disease or that's not the purpose. It's really to prevent transmission to other individuals. So we're really talking about that as a – as an indication. And again, that's a shared decision-making situation. Okay? So those are big changes.

Defining the Immune-Tolerant Phase

And I'll walk you through just a little bit of data to kind of help inform around the immune-tolerant. One of the key things I wanted to emphasize is how we defined immune-tolerant. We were very specific about the viral load. That has to be over, you know, 10 million. And we also want it to be clear that it's somebody who doesn't have any evidence of fibrosis.

So this is just two studies. Both happen to be from Korea that highlight that. On the left is looking at the risk of cancer by viral load. And you'll see that the risk of cancer is actually very low for those that have viral loads that are the highest, greater than eight logs. And that's that immune-tolerant group actually, right? And then on the right is the importance of really looking at fibrosis here. They're looking at FIB-4. And you can see that in individuals who are untreated, but sort of met their strict definition of immune-tolerant, that if you go one step further and do a FIB-4 and they're under 1.45, that individual really has no risk for liver cancer in this cohort.

So using, you know, the viral load very high and making sure that you're eliminating any presence of fibrosis, you will identify the group that has true immune-tolerant disease. And then again, take into account whether they're over the 40 or not as to whether you're going to treat or do that shared decision-making.

Immune-Tolerant CHB

One of the things you want to think about when you're sort of the pros and cons of treating and I'm going to highlight the reasons to treat, of course. This is one of the groups in which they have high viral loads. They're often young. And this may be a time where transmission to others could be particularly important. So you may treat just to do the prevention of transmission to others.

There is some argument that by treating earlier, perhaps you're going to prevent the integration of HBV DNA into the host, and that may alter the risk for HCC. This is theoretical but – but carries great weight, I would say, to some patients they care a lot about this potential.

And then I think the more important reason that we've kind of shifted towards recommending treatment in those over 40 and being shared decision-making, is that we really don't want to miss the transition. Right? So be very thoughtful. If you're not going to treat at this visit, you still would want to reassess that patient at the next visit to see if things have changed and that maybe you want to think about treatment at that time. But most importantly, we don't want to miss somebody who's gone from being immune-tolerant to now being more immune active, meaning their viral load starting to fall, their ALTs are starting to go up.

All right. So – and then the main reason that people have really moved towards treatment is that it's safe, cheap and very, very simple to do. It's a pill a day.

But there are some downsides and I'll just emphasize those. So when you're talking to patients about starting treatment, this is what you need to share with them is that they're probably going to be on long-term therapy, at least until we get curative therapies, because there's very low rates of e-antigen and s antigen loss when these individuals are put on any therapy.

This idea that we're reducing the risk of liver cancer is not actually established by epidemiological data for true immune-tolerant patients. And then you have to think about the pill burden adherence. And this is maybe particularly relevant in young individuals where the idea of taking a pill for the rest of your life may not be as attractive as somebody who's, you know, at the age of 35, perhaps, even though that's still young.

But just anyway, my point being, think about the pill burden. So again, just to emphasize, immune-tolerant is very much changed in the new guidelines. Over 40 you treat, under 40 shared decision-making considering these elements.

Indeterminant Phase Is Common in CHB

Now I'll move – shift gear a little bit to the immune tolerant – indeterminate group. So just so everybody's on the same page here. Indeterminate means that their ALT levels doesn't meet the threshold of two times upper limit of normal, and their HBV DNA levels are – don't meet the threshold of 20,000 if they are e-antigen positive, or 2,000 if they are e-antigen negative, that's indeterminate. So they fall into this zone where they don't quite meet the criteria for being immune active.

This slide on the left shows you that it's common. So look at this. When you see individuals for the first time who have chronic hepatitis B, about 40% are indeterminate. And there's data that shows that if you follow these people for the next five years, they remain indeterminate most of the time. So that has led us to thinking, well, you know, we used to say on the prior guidance, if you had somebody who was indeterminate, just follow them, that they'll eventually declare themselves one way or the other. Turns out that's not great, actually advice because they don't declare themselves.

So we've shifted here in terms of the AASLD recommendations. This group of indeterminate is another group in which we now recommend consideration of treatment using a shared decision-making approach.

Risk of HCC in HBeAg-Negative, Noncirrhotic Patients in Indeterminate Phase

And a little bit of data just to kind of highlight the – the nuance a little bit here. Probably the most important group in which there appears to be risk is in the group that has an elevated HBV DNA level in particular, maybe less so than the person who's got an elevated ALT but a low level of virus.

But nonetheless, what this study shows you is when you look at these indeterminate patients, there is a risk for liver cancer. You'll see that there is a small risk here, and it's a small risk for the both types of indeterminates, those whose ALT levels don't meet criteria, and for those whose HBV DNA levels don't meet criteria.

But what's interesting in this study is that it shows that whether they're on treatment or not didn't change their risk for HCC. Right? So this is why it's a – this is why the recommendation is a shared decision-making rather than treat them, right? Because we actually still lack data that treatment will necessarily be a benefit. But you know, it's a risk of HCC. People worry about that. So you need to have a discussion with your patient to say, “Is this something that, you know, you want to consider?” So shared decision-making in this setting.

Treatment for Prevention of Transmission: New Indication for HBV Therapy

And then lastly was this whole new emphasis on doing treatments solely for the reason to prevent transmission. So you need to talk to your patients around these scenarios. Are they engaged in unprotected sex or have multiple sex partners? Do they inject drugs or have any other sort of injection practices which are – where they're not consistently doing harm reduction? Are they living in households with susceptible members?

And then we all are healthcare providers. So, of course, we're pretty familiar with the need to treat healthcare providers if they're engaged in error-prone procedures. But the idea is this is a new area where you should be having discussions and where it's very appropriate to consider treatment again, using the shared decision approach.

Faculty Discussion

Dr. Sulkowski: Well, let's – let's pause there for one minute. Are there other –

Dr. Terrault: That's a lot, right?

Dr. Sulkowski: It’s a lot to digest.

Dr. Terrault: There's a lot of information but…

Dr. Sulkowski: So maybe we'll start. Jordan, you suggested that you're changing that. So let me give you a very specific scenario. Viral load of 5,000, ALT of 20. How are you guiding that shared decision-making process today in your clinic?

Dr. Feld: Yeah. I – I mean, I think Norah really showed that that slide, like because I think sometimes people think about this and they think, “Why didn't we just recommend treatment in that setting? Because maybe that would have been easier.” But I think it's important to sort of have some equipoise around it and recognize that the data really are not very compelling, that treatment makes a difference.

And that's why that really has to be a conversation with the person, because some people are going to say, “Well, I want to do everything possible. I would much rather – I'm worried about cancer. I'm worried about cirrhosis. I would rather take treatment even if it's not helpful.” And there's someone else that says, “Really, I don't like taking pills. I'm not going to take treatment unless you can really show me that it's useful.”

And I think this is this group where it's not so certain and it's – I'm quite comfortable being honest about that, that we don't have strong data. And so for that exact patient, I would have a conversation and say, “Look, let's see where your – what your feelings are about treatment? And we're going to discuss this every time we speak. If you decide not to go on treatment today, we're going to continue to monitor you. And next time when the viral load maybe has gone up, or maybe it's come down, or maybe it's, as Norah showed, stayed in the same level, we're going to have this conversation again. And my experience is already people's decisions sort of change over time, I think leaning a little more towards treatment, but that's – that's a bit anecdotal.

Dr. Sulkowski: So, Norah, I've generally told patients that the pendulum is shifting towards treating more that if you look at Europe, Asia, US, WHO guidelines, the pendulum is shifting. So I may be guiding my patients towards antivirals a bit more than Jordan. Am I interpreting the global trend incorrectly there?

Dr. Terrault: No, you're – you're absolutely interpreting the trend correctly. I also think, and – and maybe I'll just say this. I think that if you yourself don't feel – like Jordan's having a very nuanced kind of discussion with this patient, right? But if – if – you know, you're not comfortable having that nuanced discussion, I think the guideline also says the information you share with your patient, ultimately you have something to say about that too.

And, you know, you may have patients where your own personal experience around this is such that you feel, you know, “I've had a patient who got cancer.” How – how many times has that happened? And now you're more inclined to thinking about doing treatment.

That's okay in the guidelines, right? You – you bring something to that discussion. You interpret it because, you know other guidances are shifting towards being more expansive, more inclusive to treating the indeterminates. That's okay. Right? But sharing it – but I think the idea is to make sure you understand what the patient's perspective is in that, right? That's the idea.

But you're right. I think – what I always say to people, “If you're unsure, treat, just treat.” Right? The drugs are safe. They’re – they're easy to give. The patients will do well with them. So if you're – if you ourself are uncertain, treat.

Dr. Feld: Well – and I think one of the most important changes in the guidelines is that there's no longer a statement that says don't treat.

Dr. Terrault: Yeah.

Dr. Feld: So there used to be a recommendation for certain populations of don't treat unless or unless they meet these criteria. And that's been taken out. And I would fully agree with you. And I think it was the wise Mark Sulkowski who – who said this, but we have traditionally had the feeling that when the sort of conservative thing is when in doubt, don't treat. And I think we should be saying now we're shifting it to say, when in doubt, consider or – or treat.

Speaker: All categories. There is not a single category.

Dr. Feld: There's no single category anymore. The word do not treat is now taken out of the guidelines. Well, that's – it's been replaced by shared decision-making.

Dr. Sulkowski: Yes.

Dr. Feld: Very frequently, but not – there's no – there's no statement of do not treat. And that's true in the WHO and actually in the EASL guidelines as well. So that's a big change from the global perspective around hep B treatment.

Dr. Sulkowski: And I think that's important because I think you felt – when I did treat people in one of these categories, you kind of felt you were doing something wrong even though it felt right, you know? So I think it's really making that. I think it's a really important point. When in doubt, treat. But for every person in front of you, treatment should be part of that discussion.

Well, I'm going to move to talk about another area which is hepatitis B quantitative surface antigen. And maybe I'll just ask a quick question to each of our panelists. Are you routinely recommending this for your patients today? Jen?

Jennifer Wild: Yeah, I – this has all been very fascinating for me because I – when I was diagnosed almost 20 years ago now, I was what's now defined as immune-tolerant. And yeah, the do-not-treat was there. And I was getting – you know, I was seeing hepatology at an academic center, not the one I work at, but I remember my hepatologist saying, I really would like to treat you, but I'm not supposed to. And I was – you know, also, my mom is watching for the continuing Ed units, but I'll just say it anyway.

I was in my 20s, I was dating. I didn't want to be a risk to other people. And I wanted to be treated. And so eventually what ended up happening was that I enrolled in the clinical trial for a TAF. That was my sneak into treatment. But I'm now at the point where I have undetectable surface antigen after starting with over 10 million. And so we're – my hepatologist and I are having this conversation now. I think after we have a few sustained surveillance labs with continued loss we might consider it. But me as the patient, like taking off the hat of like looking at someone else's chart, I'm like, “I don't want to let go of my meds. I want to keep taking them.”

Dr. Sulkowski: I think that shared decision-making, I wanted to stop.

Jennifer Wild: Yes.

Dr. Sulkowski: Well, let me pause there. So I mean, the way – thank you for sharing that, because if you had a conversation, that same conversation today, 2025 guidelines, back when you were having those conversations, it would have been very different.

Jennifer Wild: Yeah.

Dr. Sulkowski: And you would have given where your mindset was, these guidelines would have led you and your clinician to start treatment. So that's – that's really a fascinating example. And obviously you made the right choice because losing s antigen, as Jordan's going to tell us, is the whole – whole goal.

Jennifer Wild: Yeah.

Dr. Sulkowski: So that's a really interesting story. And you are debating that stopping NUC question, which is not a clear cut. And we'll talk more about that. Norah, are you measuring surface antigen routinely quantifying s antigen in your patients?

Dr. Terrault: I – I use quantitative surface antigen. I – I typically get it with every patient I see for the first time, just part of my kind of profiling them. And then I – I actually obtain it annually in patients who are on NAs, or those that are not, but have very low levels of viral – or undetectable virus to see – to give me an idea of when I think they're going to be losing surface antigen.

So I typically get it annually in my patients on NUCs who are e-antigen negative, or those that are not on NUCs but have undetectable HBV DNA level. Those are the ones where I'm anticipating the next step in their natural history is to lose surface antigen. And so I use the quantitative value to help me understand sort of that trajectory and to give them information also about that.

Dr. Sulkowski: It's also an insight into what's going on in the – in the liver cell, because DNA is suppressed. And Jordan, what's your practice been?

Dr. Feld: So we've – we’ve been fortunate to have surface antigen – quantitative surface antigen for a while. So I've really incorporated into our practice and do exactly what Norah does, so measure it on first visit and then annually with people. And – and we really do actually – I find it extremely helpful in talking to patients about particularly when people are – have been on NUCs for a long time and they're coming back and every year their DNA is undetectable and their ALT is normal and they're kind of like, “When can I stop?”

And this is really helpful for showing them, “Look, there's still a lot of virus in your liver or there's not a lot of virus in your liver and we're getting close to being able to – to even consider stopping or getting to the point of clearing s.” So I find it very helpful.

Dr. Sulkowski: Yeah, it's sort of an insight into another phase of the virus and gives you a rough idea how close they are to functional cure. And we'll talk about that. But Norah, first, take us through scenarios in which you would stop NUCs and the guideline also touch on this kind of question about stopping NUCs and how s antigen might play into that. So walk us through s antigen more and what the guidelines say?

What Can qHBsAg Be Used for in Clinical Practice?

Dr. Terrault: Well, this slide really captures, I think, the scope of practice. This is not what was in the guidelines, I'll tell you. But I do think that there are increasingly more data that are supporting its use in clinical practice. At the bottom is really what I think Jordan and I were speaking about. We're trying to give an idea of the probability of s antigen clearance in our patients that are on therapy. And you'll see there's one value less than 100 means, you know, we're expecting it's going to be hopefully soon, maybe in the next few years.

But, you know, there's other ways. There is some data that are relating it to HCC development. There are data that show you can help your – help you to kind of decide those individuals in the indeterminate – indeterminate phase, kind of whether they're more like somebody who has relatively inactive chronic hepatitis B, so it's used there.

But I think you're going to see that we're increasingly use it really within the context of treatment. And I won't steal Jordan's thunder. But you'll see that in all the new therapeutics in which we're kind of moving towards using that surface antigen quantitation is going to be really integral to how we are going to select patients for therapy and how we think about their response. So I think it's evolving.

Withdrawal of Antiviral Therapy in Persons With HBeAg-Negative CHB

But what I can get to in the guidelines now is, in the prior guidance in 2018, we actually stated that you could consider withdrawing antiviral therapy in individuals who are e-antigen negative, not those that had lost surface antigen, but just those that had been on long-term suppressive therapy. And the idea was by removing the NUC, taking them off the NUC, that you could actually enhance their likelihood of getting s antigen loss. So that was kind of the idea.

And that's shown in the cartoon here where you have somebody who's been on treatment for three years, you stop their nucleoside analogue and then you'll see they get a little bit of a flare, but ultimately somewhere between 2 to 20% of people over the next several years will lose surface antigen.

qHBsAg Is Best Predictor of HBsAg Loss

So these data actually help to inform the prior guideline where we said you should probably - you know, you can consider it in certain people. And who would be the certain people? Well, this is where the surface antigen quantitation came into play. And this is a – a large, multicenter study that really helped to refine, I think, how we thought about doing withdrawal of nucleoside analogue therapy. So again, taking these virally suppressed people who are e-antigen negative.

And then if they were Caucasian and had a surface antigen level under 1,000, you can see that if you stop their NUC, their chance of getting surface antigen loss was 41%, which is really tremendous actually. But if their viral – but if their surface antigen level was over 1,000, it was quite low.

And then similarly, if they were Asian, you could see the thresholds are different. If they're under 100 and you stop, their likelihood of losing surface antigen was 33%. So out of these data came the idea that you could use the surface antigen quantitation as a way to, you know, refine your decision-making about who are you going to stop the NUCs in versus who should you continue? All right. You can see that along the bottom.

2025 AASLD Guideline Recommendations for Stopping Treatment

But what I want to tell you is that at the guidelines, we actually came out against doing this practice. All right. So this is one where in 2018 we were like, “Yeah, you could consider it.” And now we're saying, “Don't do it.” The new guidelines say don't stop the – the NUCs until they lose surface antigen, like Jennifer has. Then you can consider stopping. So you're going to have that discussion.

But that's the scenario. That's the only scenario now in which we're recommending that you stop NUCs. We, of course, in the guidelines did also say that if you have a patient who's like insistent upon coming off NUCs, again, it's shared decision-making. But we made it very clear that certain criteria should be met. And what you'll see here is again, surface antigen level is one of those criteria. So we don't recommend that you would even consider it unless there's surface antigen levels less than 100. And then there's other aspects that were – were emphasized here.

But key is the surface antigen level.

Future Directions for HBV Management and Getting to Functional Cure

So it's definitely coming into the – to how we consider treatment. You heard Jordan and I talk about how we use it sort of in our everyday kind of practice. It's clearly important if you're going to consider withdrawal, even though the guideline says, please don't do that. But again, you're an independent provider, shared decision-making, you can do it. And then I think you're going to hear a lot more about surface antigen from Jordan.

Dr. Sulkowski: Well, I think what the panel also did was really emphasized that the goal is s antigen loss.

Dr. Terrault: Yeah.

Dr. Sulkowski: And so if you've got someone on NUC, you're going to continue to hit your goal not some partial goal.

Dr. Terrault: Correct.

Dr. Sulkowski: And now I'm going to turn it over to Jordan to walk us through because no one's happy with how often people lose s antigen. It – it just doesn't happen as often as we'd like it to in practice. So Jordan, walk us through the future directions and how we're going to get more of our patients functionally cured? But maybe first tell us what the heck a functional cure is.

Goals of New HBV Therapy

Dr. Feld: Yeah. So I think that the goal of therapy has really focused on learning from the natural history. So for a long time, long-term follow-up data have shown us that obviously there's a lot of variable outcomes in people with chronic hepatitis B infection. But you can see that if people on the left – the right I guess - on the left, you see that the – the very inactive disease at the – at the top, you can see that people tend to do pretty well.

But the – the real benefit of losing surface antigen is that that's what when you really see the reduction in liver cancer, which is shown in the graph on the right. So you can see that even in people who stay within active disease, unfortunately, they still continue to have a risk of liver cancer. And it's only with surface antigen loss that that risk of liver cancer really diminishes. And it can even be altered by things like age and the presence of fibrosis as well. But it's because of this that it's really been the focus of – first, get the disease is inactive, but the real goal is to get surface antigen loss.

Shifting Therapeutic Goals

And so that's been really the goal of what we would like to see with new therapy, because our current therapy has been really focused on sustained HBV DNA suppression and trying to prevent progression of fibrosis. And the move with the hope of new therapy, because our current therapy is good at doing that, it's unfortunately not good at leading to surface antigen loss. And that's what really led to this idea of functional cure. And the reason we haven't used the term complete cure is because unlike with hepatitis C, we're not getting rid of all of the virus in the liver.

So this notion of complete cure, where you could eradicate all traces of hepatitis B from the liver, including cccDNA, and even integration of HPV into the host genome, that's at least with what we currently have available, not very achievable.

So the idea of functional cure, and that's where this term has come from, is that this is pretty good. When we look at the natural history, this is associated with a very good long-term natural history. And so the focus has been s antigen loss with undetectable HBV DNA, ideally, but not requiring the development of anti-HBs.

A Consensus on Therapy Goals

And that was really the consensus of the field. So EASL and AASLD have put together a couple of these HBV endpoints conferences. And it was felt that aiming for therapy to require really complete cure, get rid of every trace of hepatitis B from the liver. That would be great, but probably too hard to achieve with our current technology and just getting that as a sort of sustained suppression of HBV DNA, even off therapy, but without surface antigen loss wasn't enough because that would still leave people at risk of liver cancer.

And so this notion of functional cure was felt to be challenging, but at least a potentially achievable goal, and the majority of experts in the field felt that this is where we should land.

Poll 3

Dr. Sulkowski: Well, great. Another opportunity for a poll question. And what do you see as the greatest benefit of functional cure for your patients? Go ahead and type that in. So this is not a vote kind of question. You can type it in. We're very interested in your responses.

Faculty Discussion

And you know, so Jordan, you talked us through how a bunch of experts who got into a room, I think it was in DC and kicked this around for a while and then wrote a paper or thought about this. But let's talk about what the perspective is for people with hepatitis B, and – and Jen, maybe we'll start with you. You just told us that you had achieved s antigen loss, which now Jordan tells us that that's a functional cure, except the definition is off antiviral therapy. So talk us through a little bit about the perspective of that? You already did a little bit, but I'm curious to learn more.

Jennifer Wild: Yeah. I mean, in the – in the setting of currently still taking NUCs and having to approach the shared decision-making conversation, that's one thing. But, you know, let's pretend it was last year and I still had surface antigen. And – and I get this news that, “Oh, there might be functional cure.” It is really exciting. At the same time, knowing now what I know for myself, if I could tell my 22-year-old self, you could take NUCs for 20 years, or you could do this therapy that has a lot of adverse events, which would you pick? I don't know which one I would pick, and that's where I – I have so many other questions to – to ask from the data and – and look for answers.

I mean, I'm wondering like how different genotypes maybe respond to treatment differently if there's information about predicting which populations may be more or less responsive to one treatment or the other. But either way, it's really exciting because I think that when you have things like hep B that are really making the – the most detrimental impact on less wealthy, less insured, less educated people and populations in the US, it's not something that I expected in my lifetime to see a lot of money or time or research go into for a cure. And so it's – it – it feels really good.

Dr. Sulkowski: That's – that's great. And thank you for sharing that. I'm curious though, what – what is your practice, Jordan, on when you – let's say someone is fortunate to lose s antigen on NUC or spontaneous – let's say on NUC. What is your practice on stopping? Obviously recognizing it's a shared decision-making, but what do you do? Is it a year or more of NUC. What?

Dr. Feld: Yeah. So I – typically I do like to see whether people develop anti-HBs. So – so one important thing is it means you have to check surface antigen. So we talked about quantitative surface antigen. But I've actually had people referred to me that have been on NUCs for years and no one's checked their surface antigen. They've been checking DNA annually and ALT, but never actually rechecked the surface antigen. And I checked the surface antigen is negative.

So make sure even if you're not doing quant, that you're at least checking the surface antigen so that you may be able to stop people. And we typically have had this recommendation of continuing treatment for at least six months and maybe up to 12 months after surface antigen loss. I don't know if that's actually required, but that is generally what most people do. And then look for the development of anti-HBs, which gives you, I think, more confidence about stopping. It's not required to see it.

And then there are a few populations where I still would not stop treatment. And – and particularly people with cirrhosis, that's really the group where I would be a bit uncomfortable stopping even with surface antigen loss. But in other people, I'm going to have a conversation with them. And – and I would certainly be encouraging them to come off therapy. So I think it is really a real benefit for them.

I also find that people feel that it's a big milestone, like Jen, like you talked about, and can also be destigmatizing that some people feel like now I'm – I’m not a risk to other people of infecting them and – and other considerations.

Dr. Sulkowski: And maybe one question that came in, I'll just post it here now. When you say, s antigen loss, is that not detected in the blood?

Dr. Feld: Yeah. So - so surface – so there are two – there are two tests. There's the qualitative surface antigen test and the quantitative surface antigen test. We've been talking mostly about the quant today. But the qualitative test has a cut-off of 0.05. And I will say as I started using quant surface antigen, it did take me a while to get used to the numbers.

So as you start seeing them come in, you're probably familiar with DNA and certainly ALT levels. What do these surface antigen levels mean? It does take a little bit of practice to get used to them. But 0.05. So we are really looking for a very low level of – of surface antigen that is detectable.

Dr. Sulkowski: Oh, great. So we – I think there's an agreement between the experts and people with hep B that a functional cure is a good thing. And so how do we get there?

Jordan, walk us through the pipeline.

HBV Treatment Pipeline

Dr. Feld: So this is an intentionally complicated slide. This is looking at the hepatitis B viral life cycle. And the good thing about it is that there are a lot of potential places to interfere with the viral life cycle. And you can start up at the top right, where you look at blocking entry of the virus. So preventing the virus from getting into liver cells. And then the virus goes in and it goes into the nucleus of the cell, and it forms that long-lasting version of covalently closed circular cccDNA. And that's kind of the holy grail. That's what we'd really like to target.

So you can – there are therapies that are now in development to look at, either trying to directly destroy that or silence it. So epigenetically silence the cccDNA, because if you could do that, that would really get us to sort of that complete cure. But short of that, we can still target a number of different steps in the viral life cycle. So the cccDNA gets transcribed into RNA. And so we can target those HBV RNA transcripts. They then get made – get packaged. So you can see down at the bottom targeting packaging where – and there are drugs that block this packaging step.

And then it's only our current drugs that target DNA synthesis. So they're blocking the formation of new HBV DNA. And you can even try to prevent the virus from getting out as it gets packaged and assembled into a new virus.

And then the last thing that you can aim to do is to try to use the immune system to our advantage. So stimulate either the innate or the adaptive immune response to try to get immune control to – to clear the virus, as that is – is what happens in – in natural infection.

So we'll first start by just focusing on targeting HBV RNA, the transcript. And the reason for that is these are the drugs that are furthest along in development.

Small Interfering RNA and Antisense Oligonucleotide

And so there have been really two approaches to doing this. And this has been either the small interfering RNAs or siRNAs or the so-called antisense oligonucleotides or ASOs. And both of these take advantage of the fact that if you look at the – the genome of HBV, there's – these – all of the HBV RNA transcripts all share a common sequence. So you can target – just by targeting one sequence, you can get all of the different viral proteins. You can prevent these RNA from getting made into the viral proteins.

And because of the life cycle of hep B, if you target the RNA, you also block viral replication. So you sort of have two for one. You bring down this antigen level by preventing the proteins from being made. And that is thought to be driving the immune exhaustion that prevents the immune system from clearing the virus. And you can also block replication directly. And both of these work in similar but slightly different approaches, one through the argonaute system using the microRNA processing in the cell and the other through this RNase H pathway. They're similar, but the end goal is that they both get rid of the hepatitis B RNA.

B-Clear: Bepirovirsen Added to NA

And so bepirovirsen is an antisense oligonucleotide that's furthest along in development. And these are the data from the B-Clear phase II trial, which looked at using bepirovirsen in people who were already suppressed on NUCs or in people who were not on NUCs.

And I'll highlight the orange bars. So you see that people were given 300 milligrams with a loading dose of bepirovirsen. So this is a sub-cu injection given frequently over a six-month period. And what you can see is that a high proportion of people, about 30% lost surface antigen on treatment. But then the real kicker is what happens after you stop treatment.

So that looking at functional cure, remember functional cure is off of therapy. And so you can see 24 weeks off of bepirovirsen. You see that in both groups about 10% of people maintain surface antigen loss in this highest dose group, whereas in the lower doses, the responses were – were lower.

B-Clear: Primary Outcome by Baseline HBsAg and HBeAg Status

So importantly, if you look at this group carefully, you can start to tease apart some of these predictors of response like Jen was asking for. Can we identify people who are more likely to do well with this therapy? And by – by far and away, the most important marker of this is quantitative surface antigen level. So the lower the level you start with, the higher the chance of clearing surface antigen on therapy and of it persisting off therapy.

And you can see that the threshold of a surface antigen level below 3,000 was really the – the determinant of dividing people into a high and a low chance of clearing surface antigen.

B-Clear: ALT Flares

Now, interestingly, when you give this drug, what happens is you see the surface antigen go down, but at the time that you see it go down, you typically see an ALT flare. So this happens at the time of surface antigen loss. This is important because you're going to see these in clinical practice.

You're going to take the people with low s levels. And you're expecting that if they see an ALT flare, that's not a bad thing. That's a good thing in most people. You still have to follow them carefully. We don't have a huge amount of data to know that these are always safe flares, but we think that most of the time that is what we want to see, that the ALT goes up and surface antigen goes down at the same time. And these are people who are likely to go on to s loss.

B-Well 1 and B-Well 2: Bepirovirsen Added to NA

So fortunately, we're finally at the stage of having phase III data almost available with the – looking at bepirovirsen. And there have been trials going on in North America and Europe and Asia looking at bepirovirsen added on to people who are suppressed on NUCs. And we're excited that these data will be presented in a few weeks at the European liver meetings in Barcelona.

And this trial, based on those phase II data, is enrolling people with a surface antigen level below 3,000, and then giving them the six months of therapy. And the real question is what happens, not at the end of therapy, but six months after stopping therapy? How many people will maintain surface antigen loss? And we're excited to see those data very shortly.

Future HBV Treatment: Mix and Match Combination Therapies

Now what's going to happen next? So this is the first drug to get to phase III data since – since TAF. So it's been – it's been a while since we've had anything new to treat people with hepatitis B with. So it's exciting, but there's a lot more to follow. In that life cycle that I showed you, there are drugs in development at every step of that pathway, and in general, they fall into these three categories.

One is to try to suppress viral replication, as our current NUCs do. But you can potentially do this more potently. The capsid assembly modulators, or CAMs are very potent replication inhibitors, as are the siRNAs.

The second group is to try to bring down the viral protein production, the antigen production, with the hope that this may reinvigorate the immune system to some degree to get you to – to lead to some degree of immune control, and then bring in this sort of knockout punch with an immune target, either the innate immune targets with things like toll-like receptor agonists, or potentially even our old friend, interferon, which is making a bit of a comeback, or things that have been tried in the past, like therapeutic vaccines, which didn't work so well. But maybe when you combine these and you can imagine that there's a whole bunch of different approaches and thinking about how to combine these, how to sequence them, which patients are most likely to benefit from them becomes very complex.

So this becomes a bit of a complicated matrix of how to choose the right combination regimens. And these are all now in different stages of development from phase I to – early to late phase II trials.

Faculty Discussion: Are You Ready for Potential New Therapies if They Are Approved?

Dr. Sulkowski: Well, Jordan, you shared with us a really exciting story that is a new therapy for hep B that delivers functional cure more than placebo. And we're going to see that data in less than one month at the EASL meeting in Barcelona. So really looking forward to that. I think that's going to be exciting.

And then one would anticipate assuming the FDA review goes as planned, that will be available to us in clinics, which leads me to a simple question. Are you – we've been giving people NUCs. We prescribe them, they get them filled. They get lab tests every six months. Pretty simple. Are we ready for this shared decision-making that will occur, and do we have the infrastructure in place?

I think the first question is, do you have access to quantitative s antigen level? Because you – as you nicely outlined, to be a candidate, you have to have an s antigen level below 3,000. We'll get more data, obviously, later in the month. We talked about having access to it, but what's it like around the world and particularly in United States?

And Norah, maybe I'll start with you. When you talk to clinicians around the United States, are they routinely ordering this quant s?

Dr. Terrault: No, I – I think – I think we're still building knowledge around what it's useful for. And I would say that maybe up until now, you could argue it was maybe less useful. But I think clearly, as we move into this new therapeutic era of going for functional cure, we're going to need to understand where people are in their journey on their nucleoside analogue. So I think we will absolutely now, I think, have a lot of motivation, right, to get the quant done.

And there was a time actually where it was not accessible in the United States. So I'll just say it's really only the last few years that we could get the quantitative surface antigen through commercial labs. So that was a barrier before, but fortunately that's now accessible to us. But I'm not going to say it's not without a few little hiccups, right? Because I would say that even the labs sometimes misinterpret when you ask for the quantitative surface antigen. They give you the qualitative or they give you an antibody sometimes to s.

So, you know, I think getting familiar with what's the code for the quantitative surface antigen and making sure that you're ordering the right test is going to be part of our learning as we move forward to putting this kind of into play for future therapies.

Dr. Sulkowski: So a really important point. It is available at commercial laboratories in North America and the United States, but it may not be able to be ordered in your EMR.

Dr. Terrault: Yeah.

Dr. Sulkowski: And I – I still have some grey hairs kind of here from a long fight to get this order in our EMR. So one take home would be to check whether or not you can order EMR. And if not, might be the time to file that. We call them tickets to get it added.

Dr. Terrault: Right.

Dr. Feld: But it's going to be important because people – when these phase III trial data come out and this drug gets approved, people are going to come and want to know whether they're a good candidate for this drug. And it's – even to determine whether they're eligible for it, you're really going to need the quant s. And it's going to be preferable if you have that up front.

Dr. Sulkowski: Yeah, and so one of the reasons I've been – I've been following Norah. I've been measuring that every year – when I – every year typically. And I'm measuring them now to prepare for potential therapy.

I guess another question that this raises, and I touched on this earlier, Jen, you're in oncology. There's a lot of infrastructure in place to get people through a wide range of therapeutics. In your typical hep B practice, we've been sending prescriptions to local pharmacy. Are there some lessons we can learn about the infrastructure we need? Maybe walk us through what you think it will take?

Jennifer Wild: Well, you know, something that came to mind already is that unfortunately, I find that sometimes patients, when we want to check their quant, they – their insurance may not cover it. Or if it gets ordered with the wrong order code, it doesn't get covered. And so that can be a barrier because you have one flub with ordering it and the patient doesn't want to do it again. They don't want to get that $5,000 statement.

You know what I mean? Yeah. It's very expensive.

Dr. Feld: At least in our labs, about 300.

Dr. Sulkowski: Maybe. I know things are more expensive in San Francisco, but in Baltimore it's about 300.

Jennifer Wild: And so then I think when it comes to – are you talking about like trying to screen patients who are eligible?

Dr. Sulkowski: No. So you've got a candidate, someone who comes in and says, “Yeah, I am ready to go. Sign me up. I want to achieve functional cure.” And now we've got to figure – Jordan walked us through. This is an injection. There'll be the – there'll be some steps of education, how we think through support. And I know back in the days of hep C, when we had some pretty challenging injectable therapies, we used to have nurses and pharmacists on the team. They kind of all went away. I lost them all. They work in oncology now.

Jennifer Wild: Yeah. You know, in – in my oncology space, as a clinic nurse, one of the main parts of my role is patient education. So every time we start a patient on an antineoplastic therapy of any kind, they have to meet with the clinic nurse for a one-hour session, usually by video to go over, you know, the expected side effects, what to do about them, confirming that they had a risk benefit, alternative discussion with the provider.

And so that kind of thing could be very useful here. And that's a process that in the nursing sphere we call nursing navigation. And so there may be an increased need for nurse navigators in hepatology clinics.

Dr. Sulkowski: Yeah, it's a really great point. In fact, we're planning among our group in June after the data is presented, to really talk through it with our clinicians, our pharmacy team and our nursing team, and – and really get a game plan for how we're going to roll this out because it is – I wouldn't say it's uncharted territory. We've done it before in hepatitis, but it's been a while since we did it. And the resources that you have in the cancer center aren't in my clinic.

Jennifer Wild: No. I know. Why is that cancer centers are always very well resourced comparatively.

Dr. Sulkowski: They are.

Jennifer Wild: I'm sorry.

Dr. Sulkowski: And yeah, maybe we'll – you know, we're running short on time. But maybe I'll just, you know, one – one other conversation we're having to just touch on that bullet point. I've got a few patients who have, through shared decision-making, have not started a NUC. And actually just this week, I started the patient on a NUC in anticipation that they might be an excellent candidate for functional cures. So I weighed the coming functional cure into our shared decision-making, and it tipped the tide towards starting a NUC. So that may be another conversation to have as we – as the data is released and published and we start to talk with our patients about another element of shared decision-making will be functional cure with bepi.

Dr. Terrault: Particularly with use of surface antigen quant to help you inform that decision. Right? So if you have that data and then you're having the discussion with your patient, I think it's particularly, you know, make decisions around any therapy related to that as well. So it's one more factor.

Pretest 1

Dr. Sulkowski: So in the interest of time, I'm going to take us to the pre-test questions. So I'll remind you you've seen these before. And for pre-test question one, Dr. Terrault talked about the 2025 AASLD guidelines. And the question is, what would you recommend for an older 45-year-old who is antigen positive, has a high DNA of greater than seven log and a normal ALT? And the options are:

1. Defer treatment and monitor;
2. Obtain non-invasive testing for fibrosis to determine the need;
3. Consider treatment using shared clinical decision-making; or
4. Begin treatment.

So go ahead and vote.

Well, I can't quite see the entire chart, but the correct answer here was begin treatment in this 45-year-old. And 38.5% post had that correct. And that went up from baseline.

Posttest 1: Rationale

Dr. Terrault: So just to, you know, again, I'm going to bring it home. It's that age of over 40, right? So if they're over 40, you treat. Under 40, you're going to use that shared decision-making, right? So it's just a really key element is that landmark of age here influencing your decision.

Dr. Sulkowski: Although I will say it's a major change right. We spend a lot. We spend 30 years educating people not to treat. And now you just flipped it. So – and 40% of people are – are with the guidelines.

Dr. Terrault: Yeah.

Dr. Sulkowski: We got to get the other 60.

Posttest 2

So post-test question two. I recognize the potential role for quantitative surface antigen testing in my practice.

1. Strongly disagree;
2. Disagree;
3. Neither agree nor disagree;
4. Agree; or
5. Strongly agree.

Go ahead and vote.

Dr. Feld: I think it means there's a lot of strongly agree at the bottom.

Dr. Sulkowski: Yeah, there we go. There we go. We – we couldn't see. For those of you who wonder why we look so confused, we couldn't see on the monitor in front of us the strongly agree. So we talked about this quite a bit. And I think the consensus among the panel is there is a real role for quantitative s antigen in practice.

Pretest 3

So pre-test question three, and Dr. Feld walked us through this. A functional cure is defined as:

1. Sustained undetectable DNA and normal ALT on antiviral therapy;
2. Sustained s antigen less than 100 and undetectable DNA off antiviral therapy;
3. Sustained s antigen loss, undetectable DNA with or without anti-HBs off antiviral therapy; and
4. Eradication of all traces of hep B from the liver, including cccDNA, integrated DNA off antiviral therapy. So go ahead and vote.

Oh, awesome. Well, great. And the correct answer is highlighted here. We went from 42.9 to 78.6.

Posttest 3: Rationale

Functional cure is indeed the loss of s antigen, undetectable DNA with or without anti-HBs off antiviral therapy.

Posttest 4

Okay, post-test four. I feel prepared to integrate new therapies to achieve functional cure into my practice once they're available.

1. Strongly disagree;
2. Disagree;
3. On the fence;
4. Agree; and
5. Strongly agree.

Go ahead and vote.

Good. Well, we certainly have a shift towards strongly agree. And I love the optimism, because I still have some work to do in my clinic to get ready for it, but I'm excited.

Pretest 5

The last question, I believe. In the B-Clear trial of bepi, response rates were high – were as follows:

1. They were higher in those with lower baseline s antigen, no ALT flare;
2. They did not differ based on s antigen level where ALT flare was not observed;
3. They were higher in those with low s antigen in whom ALT flare was observed;
4. They did not differ by baseline s antigen where ALT was observed.

So go ahead and vote.

Posttest 5: Rationale

Great. And the correct answer was you had to have a low s antigen, and it was good to have a flare. We call them good flares. And that's what was observed in the phase II B-Clear study. And we'll see the results in the – of the phase III trials at EASL at end of the month.

Dr. Feld: Just to highlight that that should be…

Dr. Terrault: C.

Dr. Feld: C, not D that the circle is in the wrong place.

Q&A

Dr. Sulkowski: Yeah. So we have – we have a few questions that have come in online, although we are at time. So what I will recommend is that maybe we can answer some of these questions as we talk amongst the group. But maybe I'll just try to do a couple of really kind of simple questions that came in from the group and ask if anyone in the audience has any questions they want to bring forward.

Norah, someone asked about genotype and Jen mentioned it too. What are the guidelines say about genotype in practice, HBV genotype?

Dr. Terrault: We are silent on that because we don't think it has a role to play at this time. For example, with our current nucleoside analogue therapy, there's no differential response based on genotype. So it's currently not recommended.

Dr. Sulkowski: And Jordan, one for you. Someone asked for a point of care. They said wouldn't screen be easier if we could do a point of care s antigen test? Where is it and are we going to get one in?

Dr. Feld: I wish we had one. It would be helpful both for screening for hep B, but also for making hep C treatment easier at a lower barrier by being able to do point of care hep B testing at the time of initiating hep C treatments. It - it is my understanding that there are hep B – point of care hep B tests globally not approved in the US. My understanding is that that may be in the process of changing, but I'm not sure of a timeline. I don't know if you know.

Dr. Sulkowski: It's under investigation, but like you, I don't have a sense of the timeline.